Variants in the interleukin 8 gene and the response to inhaled bronchodilators in cystic fibrosis

array:25 ["pii" => "S2255553617300794" "issn" => "22555536" "doi" => "10.1016/j.jpedp.2017.07.002" "estado" => "S300" "fechaPublicacion" => "2017-11-01" "aid" => "512" "copyright" => "Sociedade Brasileira de Pediatria" "copyrightAnyo" => "2017" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "J Pediatr (Rio J). 2017;93:639-48" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 914 "formatos" => array:3 [ "EPUB" => 91 "HTML" => 594 "PDF" => 229 ] ] "Traduccion" => array:1 [ "en" => array:20 [ "pii" => "S0021755717306344" "issn" => "00217557" "doi" => "10.1016/j.jped.2017.03.005" "estado" => "S300" "fechaPublicacion" => "2017-11-01" "aid" => "512" "copyright" => "Sociedade Brasileira de Pediatria" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "J Pediatr (Rio J). 2017;93:639-48" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 708 "formatos" => array:3 [ "EPUB" => 84 "HTML" => 347 "PDF" => 277 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Variants in the interleukin 8 gene and the response to inhaled bronchodilators in cystic fibrosis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "639" "paginaFinal" => "648" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Variantes no gene da interleucina 8 e a resposta a broncodilatadores inalatórios na fibrose cística" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4239 "Ancho" => 3284 "Tamanyo" => 641459 ] ] "descripcion" => array:1 [ "en" => "Association of rs4073 and rs2227306 variants of IL-8 (interleukin-8) with the response to inhaled bronchodilators in cystic fibrosis patients. (A) Association between forced expiratory volume in 1s (FEV1) of forced vital capacity (FVC) and rs4073, dominant model and two identified mutations in the CFTR gene (cystic fibrosis transmembrane regulator) belonging to classes I, II, and/or III (CFTR-B group) (p=0.028; pc=0.112). (AA+AT) n=39; mean of 4.77±8.95; median of 4 (ranging from −9 to 48). (TT) n=21; mean of −0.86±5.42; median of −1 (ranging from −6 to 15). (B) Association of FEV1/FVC ratio with rs4073, over-dominant model and CFTR-B group (p=0.029; pc=0.116). (AA+TT) n=30; mean of 1.17±7.36; median of 0 (ranging from −12 to 23). (AT) n=29; mean of 4.76±7.58; median of 4 (ranging from −9 to 32). (C) Association of forced expiratory flow of 50% (FEF50%) of FVC with rs4073, dominant model, and CFTR-B group (p=0.046; pc=0.184). (AA+AT) n=37; mean of 17.38±24.18; median of 16 (ranging from −20 to 89). (TT) n=21; mean of 4.95±20.8; median of −2 (ranging from −19 to 55). (D) Association of FEF50% with rs2227306, dominant model, and CFTR-B group (p=0.05; pc=0.083). (CC) n=15; mean of 1.47±17.22; median of 0 (ranging from −20 to 29). (CT+TT) n=44; mean of 15.84±25.04; median of 10.5 (ranging from −28 to 89). (E) Association of FEF50% with rs2227306, over-dominant model, and CFTR-B group (p=0.033; pc=0.083). (CC+TT) n=33; mean of 6.06±20.27; median of 4 (ranging from −20 to 55). (CT) n=23; mean of 19.96±26.43; median of 19 (ranging from −28 to 89). (F) Association of forced expiratory flow of 75% (FEF75%) of FVC with rs4073, co-dominant model regardless of identified mutations in the CFTR gene (CFTR-A group) (p=0.044; pc=0.058). 1≠3. (AA) n=28; mean of 29.93±39.98; median of 30 (ranging from −47 to 142). (AT) n=42; mean of 24.81±53.57; median of 14 (ranging from −58 to 235). (TT) n=28; mean of 9.14±36.95; median of 2.5 (ranging from −35 to 119). (G) Association of FEF75% with rs4073, dominant model, and CFTR-B group (p=0.024; pc=0.096). (AA+AT) n=38; mean of 33±55.23; median of 16 (ranging from −27 to 235). (TT) n=21; mean of 5.43±35.93; median of 2 (ranging from −35 to 119). (H) Association of FEF75% with rs4073, dominant model, and CFTR-A group (p=0.034; pc=0.058). (AA+AT) n=70; mean of 26.86±48.34; median of 18 (ranging from −58 to 235). (TT) n=28; mean of 9.14±36.95; median of 2.5 (ranging from −35 to 119). (I) Association of FEF75% with rs4073, recessive model, and CFTR-A group (p=0.04; pc=0.058). (AA) n=28; mean of 29.93±39.98; median of 30 (ranging from −47 to 142). (AT+TT) n=70; mean of 18.54±47.95; median of 10 (ranging from −58 to 235). (J) Association of FEF between 25% and 75% (FEF25–75%) of FVC with rs4073, co-dominant model and CFTR-B group (p=0.012; pc=0.024). TT≠AA and AT. (AA) n=9; mean of 25.78±23.14; median of 30 (ranging from −21 to 57). (AT) n=29; mean of 18.38±29.04; median of 14 (ranging from −33 to 117). (TT) n=21; mean of 2.14±23.74; median of 0 (ranging from −51 to 65). (K) Association of FEF25–75% with rs4073, dominant model, and CFTR-B group (p=0.007; pc=0.024). (AA+ATT) n=38; mean of 20.13±27.64; median of 18.5 (ranging from −33 to 117). (TT) n=23; mean of 2.14±23.74; median of 0 (ranging from −51 to 65). (L) Association of FEF25–75% with rs4073, dominant model, and CFTR-A group (p=0.029; pc=0.1). (AA+AT) n=82; mean of 15.48±27.2; median of 15 (ranging from −40 to 117). (TT) n=33; mean of 5.94±27.33; median of 0 (ranging from −51 to 76). (M) Association of FEF25–75% with rs4073, recessive model, and CFTR-B group (p=0.047; pc=0.063). (AA) n=9; mean of 25.78±23.14; median of 30 (ranging from −21 to 57). (AT+TT) n=50; mean of 11.56±27.89; median of 8 (ranging from −51 to 117). The dot corresponds to median values and the bar corresponds to the 95% confidence interval." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Larissa Lazzarini Furlan, José Dirceu Ribeiro, Carmen Sílvia Bertuzzo, João Batista Salomão Junior, Dorotéia Rossi Silva Souza, Fernando Augusto Lima Marson" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Larissa Lazzarini" "apellidos" => "Furlan" ] 1 => array:2 [ "nombre" => "José Dirceu" "apellidos" => "Ribeiro" ] 2 => array:2 [ "nombre" => "Carmen Sílvia" "apellidos" => "Bertuzzo" ] 3 => array:2 [ "nombre" => "João Batista" "apellidos" => "Salomão Junior" ] 4 => array:2 [ "nombre" => "Dorotéia Rossi Silva" "apellidos" => "Souza" ] 5 => array:2 [ "nombre" => "Fernando Augusto Lima" "apellidos" => "Marson" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "pt" => array:9 [ "pii" => "S2255553617300794" "doi" => "10.1016/j.jpedp.2017.07.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2255553617300794?idApp=UINPBA000049" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755717306344?idApp=UINPBA000049" "url" => "/00217557/0000009300000006/v1_201711050042/S0021755717306344/v1_201711050042/en/main.assets" ] ] "itemSiguiente" => array:20 [ "pii" => "S2255553617300824" "issn" => "22555536" "doi" => "10.1016/j.jpedp.2017.08.001" "estado" => "S300" "fechaPublicacion" => "2017-11-01" "aid" => "515" "copyright" => "Sociedade Brasileira de Pediatria" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "J Pediatr (Rio J). 2017;93:649-54" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1102 "formatos" => array:3 [ "EPUB" => 105 "HTML" => 716 "PDF" => 281 ] ] "pt" => array:13 [ "idiomaDefecto" => true "cabecera" => "Artigo Original" "titulo" => "Neonatal screening: 9% of children with filter paper thyroid‐stimulating hormone levels between 5 and 10 μIU/mL have congenital hypothyroidism" "tienePdf" => "pt" "tieneTextoCompleto" => "pt" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "649" "paginaFinal" => "654" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Triagem neonatal: 9% das crianças com TSH em papel filtro entre 5 e 10μUI/mL têm hipotireoidismo congênito" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "pt" => true ] "contienePdf" => array:1 [ "pt" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1189 "Ancho" => 1667 "Tamanyo" => 92256 ] ] "descripcion" => array:1 [ "pt" => "Fluxograma da triagem para hipotireoidismo congênito de abril de 2003 a setembro de 2009." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Flávia C. 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A. Associação entre o volume expiratório forçado no 1° segundo (VEF1) da capacidade vital forçada (CVF) e rs4073, modelo dominante e duas mutações identificadas no gene do RTFC (regulador da condutância transmembrana da fibrose cística) pertencente às classes I, II e/ou III (grupo RTFC‐B) (p=0,028; pc–0,112). (AA +AT) n=39; média de 4,77±8,95; mediana de 4 (variação de −9 a 48). (TT) n=21; média de 0,86±5,42; mediana de −1 (variação de −6 a 15). B. Associação da proporção VEF1/CVF à variante rs4073, modelo superdominante e grupo RTFC‐B (p=0,029; pc=0,116). (TT) n=30; média de 0,86±7,36; mediana de 0 (variação de −12 a 23). (AT) n=29; média de 4,76±7,58; mediana de 4 (variação de −9 a 32). C. Associação do fluxo expiratório forçado de 50% (FEF50%) da CVF à variante rs4073, modelo dominante e grupo RTFC‐B (p=0,046; pc=0,184). (AA+AT) n=37; média de 17,38±24,18; mediana de 16 (variação de −20 a 89). (TT) n=21; média de 4,95±20,80; mediana de −2 (variação de −19 a 55). D. Associação do FEF50% à variante rs2227306, modelo dominante e grupo RTFC‐B (p=0,050; pc=0,083). (CC) n=15; média de 1,47±17,22; mediana de 0 (variação de −20 a 29). (CT+TT) n=44; média de 15,84±25,04; mediana de 10,50 (variação de −28 a 89). E. Associação do FEF50% à variante rs2227306, modelo superdominante e grupo RTFC‐B (p=0,033; pc=0,083). (CC+TT) n=33; média de 6,06±20,27; mediana de 4 (variação de −20 a 55). (CT) n=23; média de 19,96±26,43; mediana de 19 (variação de −28 a 89). F. Associação do fluxo expiratório forçado de 75% (FEF75%) da CVF à variante rs4073, modelo codominante independentemente das mutações identificadas no gene do RTFC (grupo RTFC‐A) (p=0,044; pc=0,058). 1 ≠ 3. (AA) n=28; média de 29,93±39,98; mediana de 30 (variação de −47 a 142). (AT) n=42; média de 24,81±53,57; mediana de 14 (variação de −58 a 235). (TT) n=28; média de 9,14±36,95; mediana de 2,5 (variação de −35 a 119). G. Associação do FEF75% à variante rs4073, modelo dominante e grupo RTFC‐B (p=0,024; pc=0,096). (AA+AT) n=38; média de 33±55,23; mediana de (variação de −27 a 235). (TT) n=21; média de 5,43±35,93; mediana de 2 (variação de −35 a 119). H. Associação do FEF75% à variante rs4073, modelo dominante e grupo RTFC‐A (p=0,034; pc=0,058). (AA+AT) (n=70; média de 26,86±48,34; mediana de 18 (variação de −58 a 235). (TT) n=28; média de 9,14±36,95; mediana de 2,5 (variação de −35 a 119). I. Associação do FEF75% à variante rs4073, modelo recessivo e grupo RTFC‐A (p=0,040; pc=0,058). (AA) n=28; média de 29,93±39,98; mediana de 30 (variação de −47 a 142). (AT+TT) n=70; média de 18,54±47,95; mediana de 10 (variação de −58 a 235). J. Associação do FEF entre 25 e 75% (FEF25‐75%) da CVF à variante rs4073, modelo codominante e grupo RTFC‐B (p=0,012; pc=0,024). TT ≠ AA e AT. (AA) n=9; média de 25,78±23,14; mediana de 30 (variação de −21 a 57). (AT) n=29; média de 18,38±29,04; mediana de 14 (variação de −33 a 117). (TT) n=21; média de 2,14±23,74; mediana de 0 (variação de −51 a 65). K. Associação do FEF25‐75% à variante rs4073, modelo dominante e grupo RTFC‐B (p=0,007; pc=0,024). (AA+ATT) n=38; média de 20,13±27,64; mediana de 18,50 (variação de −33 a 117). (TT) n=23; média de 2,14±23,74; mediana de 0 (variação de −51 a 65). L. Associação do FEF25‐75% à variante rs4073, modelo dominante e grupo RTFC‐A (p=0,029; pc=0,100). (AA+AT) n=82; média de 15,48±27,20; mediana de 15 (variação de −40 a 117). (TT) n=33; média de 5,94±27,33; mediana de 0 (variação de −51 a 76). M. Associação do FEF25‐75% à variante rs4073, modelo recessivo e grupo RTFC‐B (p=0,047; pc=0,063). (AA) n=9; média de 25,78±23,14; mediana de 30 (variação de −21 a 57). (AT+TT) n=50; média de 11,56±27,89; mediana de 8 (variação de −51 a 117). O ponto corresponde aos valores medianos e a barra corresponde a intervalo de confiança de 95%." ] ] ] "textoCompleto" => "IntroduçãoA resposta a broncodilatadores inalatórios (BD) na fibrose cística (FC) (OMIM: n° 219700) é muito variável e depende do genótipo do RTFC (Regulador da Condutância Transmembrana da Fibrose Cística), dos sintomas pulmonares e, principalmente, de variantes nos genes modificadores, como o Receptor Adrenérgico Beta 2 (ADRB2).<a class="elsevierStyleCrossRef" href="#bib0155">1</a> Até agora, apenas alguns estudos investigaram essa resposta.As mutações no gene do RTFC causam FC, devido a deficiência, disfunção ou ausência da proteína do RTFC.<a class="elsevierStyleCrossRef" href="#bib0160">2</a> A FC é caracterizada por um ciclo contínuo de inflamação crônica das vias aéreas, que pode ser exacerbada pela interleucina 8 (IL‐8), um importante mediador pró‐inflamatório. A IL‐8 é responsável por iniciar e aumentar a resposta provocadora na presença de patógenos específicos, causa ativação e migração de neutrófilos do sangue periférico para os tecidos.<a class="elsevierStyleCrossRef" href="#bib0165">3</a> A inflamação crônica das vias aéreas é o caminho comum final de lesão pulmonar. Ela é responsável pelo aumento na permeabilidade vascular, contribui para edema intersticial, alveolar e das vias aéreas.O tratamento da doença pulmonar na FC inclui anti‐inflamatórios, corticosteroides inalatórios, antibióticos, mucolítico, solução salina hipertônica e fisioterapia. Dentre as possíveis terapias, há pouca comprovação que corrobore um papel dos BD na FC.<a class="elsevierStyleCrossRefs" href="#bib0170">4,5</a> Contudo, os BD normalmente são prescritos por um tempo maior devido a episódios de pieira e dispneia na FC.<a class="elsevierStyleCrossRef" href="#bib0180">6</a> Os BD reduzem a liberação de mediadores, responsáveis pelo recrutamento e pela ativação de células inflamatórias, ativam a neurotransmissão colinérgica, e por melhorar a permeabilidade vascular. Eles também aumentam o transporte mucociliar, levam à redução da inflamação pulmonar.<a class="elsevierStyleCrossRef" href="#bib0185">7</a> A resposta a BD depende, em parte, da proteína do RTFC, que interage com a proteína do ADRB2 para promover broncodilatação.<a class="elsevierStyleCrossRef" href="#bib0190">8</a> A espirometria é o principal método de avaliar a função pulmonar, a gravidade e a progressão da doença, bem como a resposta a BD.Inflamação neutrofílica intensa e baixa hiperreactividade brônquica são características comumente observadas na FC.<a class="elsevierStyleCrossRef" href="#bib0195">9</a> Ademais, a resposta das variantes genéticas aos BD é pouco conhecida.<a class="elsevierStyleCrossRef" href="#bib0155">1</a> Pode‐se destacar o papel da IL‐8 no componente neutrofílico da doença pulmonar na FC. Os genes que podem estar associados à gravidade da FC e possivelmente à resposta a BD foram relatados aqui e na literatura científica de todo o mundo.<a class="elsevierStyleCrossRefs" href="#bib0155">1,10–12</a> O gene da IL‐8 deve ser destacado, pois ele tem influência direta sobre a inflamação pulmonar e pode ser eficaz na resposta a BD. Portanto, este estudo comparou as variantes genéticas da IL‐8 rs4073, rs2227306 e rs2227307 com a resposta a BD em pacientes com FC, com o uso da espirometria.Material e métodosPacientesFoi conduzido um estudo transversal com 186 pacientes com FC, selecionados em dois centros universitários de referência (Faculdade de Medicina de São José do Rio Preto e Universidade de Campinas) para tratamento de FC, de 2013 a 2015. O estudo foi aprovado pelo Comitê de Ética em Pesquisa da Universidade Estadual de Campinas, São Paulo, Brasil (n° 528/2008). Todos os participantes foram informados sobre o estudo e assinaram o Documento de Consentimento Informado. Para os pacientes com menos de 18 anos, o Consentimento Informado foi assinado pelo pai/mãe ou guardião. O estudo seguiu as recomendações da Declaração de Helsinque.O diagnóstico de FC foi confirmado pela presença de duas concentrações alteradas de sódio e cloreto no suor (nível de cloreto acima de 60 mEq/L). Além disso, nenhum paciente foi submetido a teste inicial de tripsinogênio imunorreativo (IRT). Em um grupo de 91 pacientes, houve duas mutações no gene do RTFC pertencentes às classes I, II e/ou III (associadas à maior gravidade da doença, devido à ausência ou não funcionalidade da proteína do RTFC);<a class="elsevierStyleCrossRef" href="#bib0215">13</a> 60 pacientes não apresentaram mutação identificada do gene do RTFC ou apresentaram duas mutações que pertencem às classes IV, V ou VI; e 35 pacientes apresentaram uma mutação no gene do RTFC que pertence às classes I, II ou III e uma mutação não identificada ou pertencente às classes IV, V ou VI (<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Variáveis clínicasAs seguintes variáveis foram analisadas: escores clínicos (Shwachman‐Kulczycki, Kanga e Bhalla); índice de massa corporal (IMC) de pacientes com mais de 18 anos, com a fórmula IMC=peso/altura;<a class="elsevierStyleCrossRef" href="#bib0160">2</a> a versão 3.0.1 do programa Anthro (Organização Mundial de Saúde [OMS], 2006) foi usada para crianças com menos de cinco anos e a versão 1.0.2 do programa Anthro Plus (Organização Mundial de Saúde [OMS], 2007) foi usada para crianças de cinco anos a adolescentes de 18 anos; idade do paciente e idade na época do diagnóstico; primeiro sintoma clínico (um sintoma geral, sintomas pulmonares e digestivos); período até a primeira colonização por Pseudomonas aeruginosa mucoide (PAM); microrganismos identificados na cultura de escarro de rotina (P. aeruginosa, Achromobacter xylosoxidans, Burkolderia cepacia e Staphylococcus aureus mucoides e não mucoides); saturação de oxigênio no sangue arterial transcutânea (SaO2); espirometria e comorbidades (pólipos nasais, osteoporose, íleo meconial, diabetes mellitus e insuficiência pancreática).A espirometria foi feita em pacientes com mais de sete anos, com o espirômetro CPFS/D (MedGraphics, Saint Paul, Minnesota, EUA). Os dados foram registrados pela versão 3.8B do software PF BREEZE para Windows 95/98/NT (American Thoracic Society) e avaliados em percentagem de valores preditivos para: capacidade vital forçada (% de CVF), volume expiratório forçado no 1° segundo da CVF (VEF1), proporção VEF1/CVF, fluxo expiratório forçado a 25% da CVF (FEF25%), fluxo expiratório forçado a 50% da CVF (FEF50%), fluxo expiratório forçado a 75% da CVF (FEF75%), fluxo expiratório forçado entre 25% e 75% da CVF (FEF25‐75%), fluxo expiratório forçado máximo (FEFmax) e volume de reserva expiratória (VRE). Os dados da espirometria são mostrados em percentual do valor preditivo de acordo com as equações de Polgar e Promadhat (1971); Pereira et al. (2007) e Duarte et al. (2007).<a class="elsevierStyleCrossRefs" href="#bib0220">14–16</a>Todos os pacientes submetidos a espirometria fizeram o teste antes e 15 minutos após administração dos BD [albutrol–C13H21NO3 (400 mg)]. Os pacientes em terapia com BD foram orientados a interromper a medicação oito horas antes da espirometria, caso estivessem em tratamento com BD de curta ação, e 48 horas antes, caso estivessem em tratamento com BD de ação prolongada. A mudança no percentual pós‐BD foi usada na análise estatística. Os critérios de resposta a BD, definidos como aumento de > 12% e 200 mL de VEF1 inicial, foram usados como o segundo modelo para avaliar a associação entre as variantes do gene da IL‐8 e a resposta a BD.Extração do DNA e genotipagemO DNA genômico foi extraído de amostras de sangue periférico com o método padrão fenol‐clorofórmio e quantificado por espectrofotômetro GE NanoVue™ (GE Healthcare Biosciences, Pittsburgh, EUA). Neste estudo, a concentração final da amostra foi estabelecida em 50 ng/μL.As mutações do RTFC foram analisadas por reação em cadeia da polimerase (PCR) (F508del) após digestão enzimática (G542X, R1162X, R553X, G551D e N1303 K). Outras mutações no gene do RTFC podem ser identificadas por sequenciamento ou com o uso do método SALSA MPLA (Amplificação de Múltiplas Sondas Dependentes de Ligação) Kit P091‐C1 CFTR‐MRC‐Holland S4X, 2183A > G, 1717‐G > A, I618 T com MegaBace1000® (GE Healthcare Biosciences, Pittsburgh, EUA) e ABI3500 (Biossistemas Aplicados – Thermo Fisher Scientific, São Paulo, Brasil).<a class="elsevierStyleCrossRef" href="#bib0235">17</a>As variantes do gene da IL‐8 foram analisadas por PCR após digestão com enzimas de restrição. Para a variante rs4073, foram usados os iniciadores 5’‐CCA TCA TGA TAG CAT CTG TA‐3′ e 5′‐CCA CAA TTT GGT GAA TTA TTA A‐3′ e a enzima de restrição AseI; para a variante rs2227306, foram usados os iniciadores 5′‐CTC TAA CTC TTT ATA TAG GAA TT‐3′ e 5′‐GAT TGA TTT TAT CAA CAG GCA‐3′, bem como a enzima de restrição EcoRI; e para a variante rs2227307, foram usados os iniciadores 5′‐TAA AGG TTT GAT CAA TAT AGA‐3′ e 5′‐CTT CCT TCT AAT TCCA ATA TG‐3′, bem como a enzima de restrição ScrFI.<a class="elsevierStyleCrossRefs" href="#bib0240">18,19</a> Os produtos da restrição enzimática foram submetidos a eletroforese em gel de poliacrilamida a 12%, ou gel de agarose a 4%,<a class="elsevierStyleCrossRefs" href="#bib0240">18,19</a> e corados com gel Red®.Análise estatísticaFoi feita com a versão 22.0 do SPSS (SPSS Inc., Chicago, EUA). Foi usada a versão 3.1.9.2<a class="elsevierStyleCrossRef" href="#bib0250">20</a> do software GPower para calcular o poder da amostra, considerou‐se o genótipo das variantes analisadas e adotou‐se o poder para valor acima de 80%. As condições a seguir foram aplicadas para calcular o poder da amostra: (teste de análise da variância no lugar do teste de Kruskal‐Wallis, considerou‐se que a análise de variância é um teste mais forte) tamanho do efeito=0,25, α=0,05, poder=0,80, grau de liberdade do numerador=2, número de grupos=3, n° ideal=158; (teste de Mann‐Whitney–bicaudal) tamanho do efeito=0,5, α=0,05, poder=0,80, proporção de atribuição N2/N1=1, n° ideal–134; (teste χ<a class="elsevierStyleCrossRef" href="#bib0160">2</a>) tamanho do efeito=0,3, α=0,05, poder=0,80, grau de liberdade=2, n° ideal=108.Os testes de Mann‐Whitney e Kruskal‐Wallis foram usados para comparação entre diferentes genótipos e os grupos de variantes do gene da IL‐8 e a resposta a BD. Em caso de diferenças significativas entre os grupos do teste de Kruskal‐Wallis, foram feitas identificação e avaliação adicionais das diferenças entre os genótipos com o software para Windows MedCalc®, versão 16.1 (MedCalc® Software, Ostend, Bélgica).O teste χ2 e o teste exato de Fisher foram usados para comparação entre os diferentes genótipos e grupos de variantes do gene da IL‐8 e a resposta a BD definidos como um aumento de > 12% e 200 mL de VEF1 inicial.Para a identificação de mutações no gene do RTFC, os pacientes foram analisados com base em dois contextos: (RTFC‐A) todos os pacientes com FC, independentemente das mutações do gene (n=186 pacientes); (RTFC‐B) pacientes com duas mutações pertencentes às classes I, II e/ou III (n=91 pacientes). Quanto às variantes, foram adotados quatro modelos de análise: (i) codominante (teste de Kruskal‐Wallis); (ii) recessivo (teste de Mann‐Whitney); (iii) dominante (teste de Mann‐Whitney); (iv) superdominante (teste de Mann‐Whitney), aplicados em associação às variáveis clínicas. Para todas as análises, o valor alfa foi estabelecido em 0,05.Para análise do equilíbrio de Hardy‐Weinberg (HWE) foi usado o software Online Encyclopedia for Genetic Epidemiology Studies (OEGE).O teste da taxa de falsa descoberta (FDR) foi aplicado para corrigir a comparação múltipla de testes. A FDR é uma abordagem ao problema de múltiplas comparações. Em vez de controlar a chance de qualquer falso, os controles da FDR controlam a proporção esperada de falsos positivos entre os resultados significativos. O limite da FDR é determinado a partir da distribuição do valor de p observado e, assim, é adaptativo ao valor de sinal nos dados.<a class="elsevierStyleCrossRef" href="#bib0255">21</a> O valor de p (p) e o valor de p corrigido (pc) foram mostrados no manuscrito. A análise de desequilíbrio de ligação foi feita na versão 4.2 do software Haploview.ResultadosOs dados clínicos e laboratoriais dos pacientes com FC são descritos na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>. A descrição do genótipo e da frequência de alelos das variantes do gene da IL‐8 encontra‐se na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>. A <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> mostra os dados com valores de p e valor de p corrigido para associação das variantes do gene da IL‐8, consideraram‐se os quatros modelos de análise propostos e o genótipo do gene do RTFC.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia>A variante rs2227307 não foi associada à resposta a BD em nenhum dos modelos estudados; ao passo que a variante rs2227306 foi associada a FEF50% para pacientes com genótipo CC (modelo dominante; p=0,05; pc=0,083) e genótipo CT (modelo superdominante; p=0,033; pc=0,083) no grupo RTFC‐B (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>D e E).Deve‐se enfatizar de modo especial a variante rs4073, associada às variáveis de espirometria: FEV1, proporção VEF1/CVF, FEF50%, FEF75% e FEF25‐75%. A menor resposta a BD foi observada para genótipo TT (modelo dominante) e pacientes do grupo RTFC‐B a VEF1 (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>A), FEF50% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a> C), FEF75% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>G) e FEF25‐75% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a> K). O mesmo foi observado para o grupo RTFC‐A para FEF75% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>H) e FEF25‐75% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>L). Na análise codominante, o genótipo TT apresentou menor resposta a BD para VEF75% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>F) e FEF25‐75% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a> J), respectivamente para os grupos RTFC‐A e RTFC‐B. Para o indicador VEF1/CVF, o genótipo AT nos pacientes do grupo RTFC‐B mostrou menor resposta a BD (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>B). Por fim, nos pacientes dos grupos RTFC‐A e RTFC‐B, respectivamente, o genótipo AA (modelo recessivo) para rs4073 mostrou maior resposta a BD para FEF75% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a>I) e FEF25‐75% (<a class="elsevierStyleCrossRef" href="#fig0005">fig. 1</a> M).A distribuição de haplótipos para as variantes do gene da IL‐8 é apresentada na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>.Para comparação entre as variantes do gene da IL‐8 e a resposta a BD definida como aumento de > 12% e 200 mL de VEF1 inicial, não foi encontrada associação positiva (p > 0,05).DiscussãoMostramos anteriormente a influência das diferentes variantes do gene da IL‐8 sobre a gravidade clínica da FC.<a class="elsevierStyleCrossRef" href="#bib0260">22</a> Além disso, este estudo mostra a associação das diferentes variantes do gene da IL‐8 e sua modulação à resposta a BD, avalia o impacto do medicamento sobre a função pulmonar. A variabilidade das respostas aos BD é determinada por vários fatores, como inflamação e obstrução pulmonar,<a class="elsevierStyleCrossRef" href="#bib0265">23</a> bactérias<a class="elsevierStyleCrossRef" href="#bib0270">24</a> e sintomas pulmonares,<a class="elsevierStyleCrossRef" href="#bib0275">25</a> bem como genes modificadores.<a class="elsevierStyleCrossRef" href="#bib0280">26</a> Contudo, até agora, nenhum estudo investigou o papel da IL‐8 como mediador pró‐inflamatório de FC e sua relação aos BD e se as variantes do gene da IL‐8 podem explicar a resposta individual aos BD na FC. Acredita‐se que os beta‐2 agonistas de curta e longa duração podem ser benéficos para pacientes com FC e com hiperresponsividade brônquica positiva.<a class="elsevierStyleCrossRef" href="#bib0180">6</a>Em doenças pulmonares progressivas, foram avaliados diferentes marcadores e o uso dos BD parece fornecer melhor resposta ao FEF25‐75%, em comparação com outros marcadores, o que indica envolvimento de vias aéreas de menor calibre na FC.<a class="elsevierStyleCrossRef" href="#bib0285">27</a> Nosso estudo, em concordância com a literatura de referência, encontrou uma associação da variante rs4073 para o marcador FEF25‐75% nos modelos dominante (para os grupos RTFC‐A e RTFC‐B), codominante (grupo RTFC‐B) e recessivo (grupo RTFC‐B). Houve melhoria em diversos outros marcadores de espirometria para rs4073, como VEF1, VEF1/CVF e FEF50% e FEF75%, o que mostra impacto sobre os padrões de respiração dos pacientes.O estudo de Hillian et al. encontrou uma associação das variantes rs2227307 e rs4073 do gene da IL‐8 e a gravidade da doença pulmonar.<a class="elsevierStyleCrossRef" href="#bib0290">28</a> Nesse estudo, os pacientes foram divididos em duas coortes: (1) pacientes homozigotos F508del; (2) pacientes com outros genótipos do gene do RTFC. Na coorte 1, as variantes rs4073, rs2227306 e rs2227543 não foram associadas a doença pulmonar e a variante rs22227307 mostrou associação, independentemente do sexo. Na coorte 2, as variantes rs4073 e rs2227306 foram associadas a gravidade da doença pulmonar em homens. Assim, o sexo do paciente, o genótipo do gene do RTFC e os genes modificadores podem modular a gravidade da doença pulmonar.<a class="elsevierStyleCrossRef" href="#bib0290">28</a> Nesse estudo, o genótipo rs2227307 não teve impacto sobre a variabilidade da resposta a BD. Isso sugere que, apesar de esse genótipo estar associado a doença pulmonar em pacientes homozigotos F508del, sua resposta a BD não é relevante.O alvo dos BD é a proteína ADRB2, expressa no músculo liso das vias aéreas. As variantes de ADRB2 estão associadas à resposta à medicação. Essa proteína foi amplamente estudada em asma e ainda muito raramente em FC. A eficácia da resposta a BD e aos corticosteroides inalatórios no manejo de inflamação das vias aéreas em asma está confirmada e depende das variantes Arg16Gly (rs1042713; c.46A>G) e Glu27Gln (rs1042714; c.79C>G) do gene ADRB2.[29] A variante Gln27Glu concede resistência à proteína ADRB2 na resposta a BD. Os alelos 46*G e 79*G protegem contra asma, reduzem o risco em 27%.<a class="elsevierStyleCrossRef" href="#bib0295">29</a> As variantes do alelo G induzem alterações na regulação do receptor, devido ao aumento da susceptibilidade à degradação de proteínas. Este estudo constatou que as variantes Arg16Gly e Gln27Glu do gene ADRB2 influenciam a respostas aos BD na FC. Na espirometria e em outros marcadores de gravidade, a variante Arg16Gly mostrou associação positiva, ao contrário da variante Gln27Glu. O genótipo Arg/Arg da variante Arg16Gly foi associado a melhores valores de VEF1 e FEF25‐75%. A resposta a BD nas análises de haplótipo foi positiva na ausência dos genótipos Gly16Gly e Glu27Glu para a proporção VEF1/CVF.As variantes de ADRB2, capacidade de difusão dos pulmões para monóxido de carbono, condutância da membrana capilar alveolar, volume sanguíneo na capilar alveolar e SaO2, foram avaliadas na resposta a BD em 18 pacientes e 20 controles saudáveis, antes e depois da administração de salbutamol (30, 60 e 90 minutos). Os indivíduos saudáveis não apresentaram alterações nos marcadores avaliados para a variante Glu27Glu. Contudo, na FC, essa variante influenciou a resposta a BD: a melhor resposta encontrada na presença de pelo menos um alelo 27Glu. Houve uma diferença de difusão pulmonar e SaO2 periférica de acordo com a variação do gene ADRB2 na posição 27 e a dosagem do medicamento deve ser prescrita de acordo com essa variação.<a class="elsevierStyleCrossRef" href="#bib0300">30</a>A maior parte dos estudos foca nas variantes do gene ADRB2 na resposta a BD. Contudo, este estudo demonstra que, mesmo indiretamente, as variantes do gene da IL‐8 e possivelmente em outros genes, que modulam a resposta pulmonar inflamatória, podem potencializar ou diminuir o efeito dos BD e, ainda, influenciar a resposta ao medicamento.Com relação ao HWE, conforme discutido anteriormente por nosso grupo,<a class="elsevierStyleCrossRef" href="#bib0260">22</a> duas variantes (rs4073 e rs2227306) não estavam em equilíbrio. Devemos lembrar que o HWE pressupõe uma população ideal, sem a interferência de fatores evolucionários. Contudo, em genes envolvidos em controle de imunidade, inflamação e infecção, o desequilíbrio do HWE parecer estar associado de forma secundária aos mecanismos de seleção que favoreceram um alelo específico que pode trazer uma resposta mais efetiva. O desequilíbrio não invalida o estudo de associação, pois os grupos fazem parte da mesma população.Limitações do estudo: (i) banco de dados transversal (a resposta a BD foi avaliada em um único momento); (ii) há vários dados ausentes, se levarmos em consideração os problemas para obter as informações nos registros; (iii) caso a resposta a BD seja diferente com base no VEF1 de base, principalmente em indivíduos saudáveis; (iv) possíveis variáveis de confusão com relação aos resultados, como gravidade da doença, terapias atuais, adesão à medicação e esforço adequado no teste de função pulmonar.As variantes do gene da IL‐8 (rs2227306 e especialmente rs4073) podem estar associadas à resposta a BD durante a espirometria. Esse medicamento pode ser uma opção para o tratamento da doença, na maior parte do tempo em pacientes com vias aéreas de menor calibre. Devem‐se conduzir estudos que envolvam dose e combinações de medicamentos para determinar o melhor tratamento de acordo com o genótipo do paciente com FC, o gene do RTFC, bem como os genes modificadores.FinanciamentoFALM: Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp), em apoio às pesquisas n° 2011/12939‐4, n° 2011/18845‐1, n° 2015/12183‐8 e n° 2015/12858‐5; Fundo de Apoio à Pesquisa, ao Ensino e à Extensão da Universidade Estadual de Campinas, em apoio à pesquisa n° 0648/2015; JDR: Fapesp, em apoio às pesquisas n° 2011/18845‐1 e n° 2015/12183‐8. LLF: Fapesp, em apoio à pesquisa n° 2013/19052‐0.Conflitos de interesseOs autores declaram não haver conflitos de interesse." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres934979" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec908956" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres934978" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0045" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0050" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0055" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0060" "titulo" => "Conclusões" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec908955" "titulo" => "Palavras‐chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introdução" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material e métodos" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Pacientes" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Variáveis clínicas" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Extração do DNA e genotipagem" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Análise estatística" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Resultados" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussão" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Financiamento" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflitos de interesse" ] 10 => array:2 [ "identificador" => "xack315684" "titulo" => "Agradecimentos" ] 11 => array:1 [ "titulo" => "Referências" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-08-02" "fechaAceptado" => "2017-01-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec908956" "palabras" => array:4 [ 0 => "CFTR" 1 => "Disease severity" 2 => "Interleukin 8" 3 => "Lung function" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras‐chave" "identificador" => "xpalclavsec908955" "palabras" => array:4 [ 0 => "CFTR" 1 => "Gravidade da doença" 2 => "Interleucina 8" 3 => "Função pulmonar" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveInterleukin 8 protein promotes inflammatory responses, even in airways. The presence of interleukin 8 gene variants causes altered inflammatory responses and possibly varied responses to inhaled bronchodilators. Thus, this study analyzed the interleukin 8 variants (rs4073, rs2227306, and rs2227307) and their association with the response to inhaled bronchodilators in cystic fibrosis patients. MethodsAnalysis of interleukin 8 gene variants was performed by restriction fragment length polymorphism of polymerase chain reaction. The association between spirometry markers and the response to inhaled bronchodilators was evaluated by Mann‐Whitney and Kruskal‐Wallis tests. The analysis included all cystic fibrosis patients, and subsequently patients with two mutations in the cystic fibrosis transmembrane conductance regulator gene belonging to classes I to III. ResultsThis study included 186 cystic fibrosis patients. There was no association of the rs2227307 variant with the response to inhaled bronchodilators. The rs2227306 variant was associated with FEF50% in the dominant group and in the group with two identified mutations in the cystic fibrosis transmembrane conductance regulator gene. The rs4073 variant was associated with spirometry markers in four genetic models: co‐dominant (FEF25‐75% and FEF75%), dominant (FEV1, FEF50%, FEF75%, and FEF25‐75%), recessive (FEF75% and FEF25‐75%), and over‐dominant (FEV1/FVC). ConclusionsThis study highlighted the importance of the rs4073 variant of the interleukin 8 gene, regarding response to inhaled bronchodilators, and of the assessment of mutations in the cystic fibrosis transmembrane conductance regulator gene." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "ObjetivoA proteína interleucina 8 promove respostas inflamatórias, o que inclui sua atuação nas vias aéreas. A presença de variantes no gene da interleucina 8 causa respostas inflamatórias alteradas e possivelmente respostas variadas ao uso de broncodilatadores inalatórios. Assim, este estudo analisou as variantes da interleucina 8 (rs4073, rs2227306, rs2227307) e sua associação à resposta a broncodilatadores inalatórios em pacientes com fibrose cística. MétodosFoi feita análise das variantes genéticas da interleucina 8 por restriction fragment length polymorphism da reação em cadeia da polimerase. A associação entre os marcadores da espirometria e a resposta a broncodilatadores inalatórios foi feita pelos testes de Mann‐Whitney e Kruskal‐Wallis. A análise incluiu todos os pacientes com fibrose cística e posteriormente pacientes com duas mutações no gene cystic fibrosis transmembrane conductance regulator pertencentes às Classes I a II. ResultadosEste estudo incluiu 186 pacientes com fibrose cística. Não houve associação da variante rs2227307 à resposta a broncodilatadores inalatórios. A variante rs2227306 foi associada a FEF50% no grupo dominante e no grupo com duas mutações identificadas no gene cystic fibrosis transmembrane conductance regulator. A variante rs4073 foi associada a marcadores da espirometria em quatro modelos genéticos: codominante (FEF25‐75% e FEF75%), dominante (VEF1, FEF50%, FEF75% e FEF25‐75%), recessivo (FEF75% e FEF25‐75%) e overdominante (VEF1/CVF). ConclusõesEste estudo destaca, principalmente, a importância da variante rs4073 do gene da interleucina 8, na resposta a broncodilatadores inalatórios, concomitantemente ao genótipo das mutações no gene cystic fibrosis transmembrane conductance regulator." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0045" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0050" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0055" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0060" "titulo" => "Conclusões" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Como citar este artigo: Furlan LL, Ribeiro JD, Bertuzzo CS, Salomão Junior JB, Souza DR, Marson FA. Variants in the interleukin 8 gene and the response to inhaled bronchodilators in cystic fibrosis. J Pediatr (Rio J). 2017;93:639–48." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Estudo feito na Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brasil." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4239 "Ancho" => 3276 "Tamanyo" => 668369 ] ] "descripcion" => array:1 [ "pt" => "Associação das variantes rs4073 e rs2227306 da IL‐8 (interleucina‐8) à resposta a broncodilatadores inalatórios em pacientes com fibrose cística. A. Associação entre o volume expiratório forçado no 1° segundo (VEF1) da capacidade vital forçada (CVF) e rs4073, modelo dominante e duas mutações identificadas no gene do RTFC (regulador da condutância transmembrana da fibrose cística) pertencente às classes I, II e/ou III (grupo RTFC‐B) (p=0,028; pc–0,112). (AA +AT) n=39; média de 4,77±8,95; mediana de 4 (variação de −9 a 48). (TT) n=21; média de 0,86±5,42; mediana de −1 (variação de −6 a 15). B. Associação da proporção VEF1/CVF à variante rs4073, modelo superdominante e grupo RTFC‐B (p=0,029; pc=0,116). (TT) n=30; média de 0,86±7,36; mediana de 0 (variação de −12 a 23). (AT) n=29; média de 4,76±7,58; mediana de 4 (variação de −9 a 32). C. Associação do fluxo expiratório forçado de 50% (FEF50%) da CVF à variante rs4073, modelo dominante e grupo RTFC‐B (p=0,046; pc=0,184). (AA+AT) n=37; média de 17,38±24,18; mediana de 16 (variação de −20 a 89). (TT) n=21; média de 4,95±20,80; mediana de −2 (variação de −19 a 55). D. Associação do FEF50% à variante rs2227306, modelo dominante e grupo RTFC‐B (p=0,050; pc=0,083). (CC) n=15; média de 1,47±17,22; mediana de 0 (variação de −20 a 29). (CT+TT) n=44; média de 15,84±25,04; mediana de 10,50 (variação de −28 a 89). E. Associação do FEF50% à variante rs2227306, modelo superdominante e grupo RTFC‐B (p=0,033; pc=0,083). (CC+TT) n=33; média de 6,06±20,27; mediana de 4 (variação de −20 a 55). (CT) n=23; média de 19,96±26,43; mediana de 19 (variação de −28 a 89). F. Associação do fluxo expiratório forçado de 75% (FEF75%) da CVF à variante rs4073, modelo codominante independentemente das mutações identificadas no gene do RTFC (grupo RTFC‐A) (p=0,044; pc=0,058). 1 ≠ 3. (AA) n=28; média de 29,93±39,98; mediana de 30 (variação de −47 a 142). (AT) n=42; média de 24,81±53,57; mediana de 14 (variação de −58 a 235). (TT) n=28; média de 9,14±36,95; mediana de 2,5 (variação de −35 a 119). G. Associação do FEF75% à variante rs4073, modelo dominante e grupo RTFC‐B (p=0,024; pc=0,096). (AA+AT) n=38; média de 33±55,23; mediana de (variação de −27 a 235). (TT) n=21; média de 5,43±35,93; mediana de 2 (variação de −35 a 119). H. Associação do FEF75% à variante rs4073, modelo dominante e grupo RTFC‐A (p=0,034; pc=0,058). (AA+AT) (n=70; média de 26,86±48,34; mediana de 18 (variação de −58 a 235). (TT) n=28; média de 9,14±36,95; mediana de 2,5 (variação de −35 a 119). I. Associação do FEF75% à variante rs4073, modelo recessivo e grupo RTFC‐A (p=0,040; pc=0,058). (AA) n=28; média de 29,93±39,98; mediana de 30 (variação de −47 a 142). (AT+TT) n=70; média de 18,54±47,95; mediana de 10 (variação de −58 a 235). J. Associação do FEF entre 25 e 75% (FEF25‐75%) da CVF à variante rs4073, modelo codominante e grupo RTFC‐B (p=0,012; pc=0,024). TT ≠ AA e AT. (AA) n=9; média de 25,78±23,14; mediana de 30 (variação de −21 a 57). (AT) n=29; média de 18,38±29,04; mediana de 14 (variação de −33 a 117). (TT) n=21; média de 2,14±23,74; mediana de 0 (variação de −51 a 65). K. Associação do FEF25‐75% à variante rs4073, modelo dominante e grupo RTFC‐B (p=0,007; pc=0,024). (AA+ATT) n=38; média de 20,13±27,64; mediana de 18,50 (variação de −33 a 117). (TT) n=23; média de 2,14±23,74; mediana de 0 (variação de −51 a 65). L. Associação do FEF25‐75% à variante rs4073, modelo dominante e grupo RTFC‐A (p=0,029; pc=0,100). (AA+AT) n=82; média de 15,48±27,20; mediana de 15 (variação de −40 a 117). (TT) n=33; média de 5,94±27,33; mediana de 0 (variação de −51 a 76). M. Associação do FEF25‐75% à variante rs4073, modelo recessivo e grupo RTFC‐B (p=0,047; pc=0,063). (AA) n=9; média de 25,78±23,14; mediana de 30 (variação de −21 a 57). (AT+TT) n=50; média de 11,56±27,89; mediana de 8 (variação de −51 a 117). O ponto corresponde aos valores medianos e a barra corresponde a intervalo de confiança de 95%." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Tabela 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "N, tamanho da amostra; RTFC, regulador da condutância transmembrana da fibrose cística." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genótipo \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">% \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grupo de pacientes \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">−/‐ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29,6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="6" align="left" valign="top">Pacientes sem mutação no gene do RTFC ou com uma ou duas mutações pertences às classes IV, V ou VI</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">V562I/‐ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">I507V/‐ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">D110H/V232H \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G576A/R668 C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">p.Glu528G>A/TG11‐5 T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/‐ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12,4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="10" align="left" valign="top">Pacientes com uma mutação do RTFC pertencentes às classes I, II ou III e uma mutação não identificada ou pertencentes às classes IV, V ou VI</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X/‐ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/3272‐26A>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/P205S \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X/P205S \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X/R334 W \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3120+1G>A/L206 W \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">622‐2A>G/711+1G>T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">R1162X/‐ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X/I618 T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/F508del \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26,3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="22" align="left" valign="top">Pacientes com duas mutações do RTFC pertencentes às classes I, II e/ou III −Mutações G2 (grupo CFTR‐B)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/G542X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/N1303 K \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/R1162X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/R553X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/1584‐18672pbA>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/c.1717‐1G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3120+1G>A/R1066 C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/2183AA>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/2184insA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Duplicação do éxon F508del/6B a 16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/G85E \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/S549R (T>G) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/S4X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X/2183AA>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X/R1162X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">A561E/A561E \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/R1066 C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">R1070Q; S466X/G542X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del/1812‐1G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2183AA>G/2183AA>G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3120+1G>A/3120+1G>A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1580263.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Todos os pacientes avaliados neste estudo foram incluídos (grupo RTFC‐A)." ] ] ] "descripcion" => array:1 [ "pt" => "Distribuição dos pacientes com fibrose cística para genótipo do RTFC e classes de mutações identificadas.<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Tabela 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CVF, capacidade vital forçada; FEF25%, fluxo expiratório forçado a 25% da CVF; FEF25‐75%, médio do fluxo expiratório forçado entre 25% e 75% da CVF; FEF50%, fluxo expiratório forçado a 50% da CVF; FEF75%, fluxo expiratório forçado a 75% da CVF; FEFmax, fluxo expiratório forçado máximo; SaO2, saturação de oxigênio no sangue arterial; VEF1, volume expiratório forçado no 1° segundo da CVF; VRE, volume de reserva expiratória.Os dados da espirometria são mostrados em percentual de valor preditivo. Todos os pacientes avaliados são descritos." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variáveis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Distribuição<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sexo (masculino) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">92/186 (49,5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Etnia (branca) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">169/180 (93,9%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Idade (meses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">169; 201,41±171,98; 143 (7 a 932) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Início dos sintomas (meses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">159; 38,23±114,03; 3 (0 a 720) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diagnóstico (meses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">171; 87,90±158,39; 20 (0 a 833) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Início dos sintomas digestivos (meses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">140; 41,2±112,61; 3 (0 a 720) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Início dos sintomas pulmonares (meses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">156; 46,33±123,64; 6 (0 a 720) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Índice de massa corporal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">178; 17,28±4,08; 16,28 (6,5 a 35,67) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Polipose nasal (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28/162 (17,3%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diabetes mellitus (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32/164 (19,5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Osteoporose (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25/162 (15,4%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Insuficiência pancreática (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">130/162 (80,2%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Íleo meconial (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23/162 (14,2%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1ª Pseudomonas aeruginosa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">121; 103,03±171,74; 31 (0 a 872)<a class="elsevierStyleCrossRef" href="#tblfn0015">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">P. aeruginosa mucoide (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">74/173 (42,8%)<a class="elsevierStyleCrossRef" href="#tblfn0020">c</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">P. aeruginosa não mucoide (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99/173 (57,2%)<a class="elsevierStyleCrossRef" href="#tblfn0020">c</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Achromobacter xylosoxidans (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17/174 (9,8%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Burkolderia cepacia (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25/174 (14,4%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Staphylococcus aureus (presença) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">131/174 (75,3%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SaO2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">159; 94,87±4,28; 96 (66 a 99) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Escore de Bhalla \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">113; 8,9±5,77; 8 (0 a 25) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Escore de Kanga \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">118; 18,78±5,82; 17,5 (10 a 40) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Escore de Shwachman‐Kulczycki \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">143; 65,97±16,78; 65 (20 a 95) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CVF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">142; 72,13±23,86; 77 (19 a 126) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEV1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">141; 60,99±25,75; 63 (17 a 116) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VEF1/CVF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">144; 79,08±14,99; 81 (39 a 113) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF25% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">119; 61,28±31,71; 60 (7 a 138) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">119; 46,2±31,25; 40 (3 a 126) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF75% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">116; 36,32±28,77; 27,5 (4 a 142) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF25‐75% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">140; 47,16±32,51; 39 (5 a 150) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEFMax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">114; 75,54±25,59; 73,5 (25 a 137) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VRE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">112; 80,96±52,39; 69 (3 a 248) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Resposta a broncodilatador inalatório</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CVF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">117; 1,74±8,19; 1 (−17 a 32) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEV1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">117; 3,51±8,0; 3 (−12 a 48) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VEF1/CVF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">111; 2,14±7,43; 2 (−19 a 32) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF25% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99; 9,99±24,41; 5 (−45 a 110) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99; 13,08±26,06; 9 (−41 a 114) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF75% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99; 20,93±46,47; 16 (−64 a 235) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF25‐75% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99; 12,28±27,77; 9,5 (−51 a 117) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEFMax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">116; 2,63±14,48; 3 (−42 a 69) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VRE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100; 23,04±101,08; 0 (−90 a 670) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1580261.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Os dados com distribuição categórica são apresentados da seguinte forma: n° de variáveis/n° total (percentual); os dados com distribuição numérica são apresentados da seguinte forma: tamanho da amostra; média±desvio padrão; mediana (mínimo a máximo)." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "Os valores ausentes para primeira P. aeruginosa correspondem a pacientes com fibrose cística que nunca apresentaram cultura positiva para P. aeruginosa." ] 2 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "c" "nota" => "Um paciente com fibrose cística apresentou cultura positiva para P. aeruginosa, com valores negativos para IgG específico do antígeno P. aeruginosa e o paciente foi excluído para estimativa de frequência." ] ] ] "descripcion" => array:1 [ "pt" => "Análise descritiva dos marcadores clínicos e laboratoriais de pacientes com fibrose cística" ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Tabela 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "fa, frequência absoluta; IL‐8, interleucina 8; %, percentual; χ2, qui‐quadrado." "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variantes \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genótipo \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Número (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Alelo \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Número (fa) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">χ2 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Valor de p<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">rs4073</td><td class="td" title="table-entry " align="left" valign="top">AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54 (29,2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">187 (0,51) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">3,94</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">< 0,05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">79 (42,7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">183 (0,49) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52 (28,1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">370 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">185 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">rs2227306</td><td class="td" title="table-entry " align="left" valign="top">CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">70 (38) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">211 (0,57) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">8,21</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">< 0,05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">71 (38,6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">157 (0,43) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43 (23,4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">368 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">184 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">rs2227307</td><td class="td" title="table-entry " align="left" valign="top">GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31 (17,4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">139 (0,39) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">1,48</td><td class="td" title="table-entry " rowspan="3" align="left" valign="top">>0,05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">77 (43,3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">217 (0,61) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">70 (39,3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">356 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">178 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1580260.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">rs4073/rs2227306/rs2227307 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequência \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentual (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CC GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CC GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CC TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13,6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CT GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CT GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CT TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4,0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA TT GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA TT GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA TT TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT CC GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7,3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT CC TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4,0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT CT GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16,9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT CT TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5,6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT TT GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT TT GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3,4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT TT TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CC GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CC GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CC TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CT GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CT GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3,4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CT TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT TT GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6,8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT TT GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT TT TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2,8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">177 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1580262.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "χ2 e valores de p fazem referência ao cálculo de equilíbrio de Hardy‐Weinberg. 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Knowles" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/gene.2008.42" "Revista" => array:6 [ "tituloSerie" => "Genes Immun" "fecha" => "2008" "volumen" => "9" "paginaInicial" => "501" "paginaFinal" => "508" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18563170" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0295" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systematic review and meta‐analysis of the association between β2‐adrenoceptor polymorphisms and asthma: a HuGE review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Thakkinstian" 1 => "M. McEvoy" 2 => "C. Minelli" 3 => "P. Gibson" 4 => "B. Hancox" 5 => "D. 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Patanwala" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.pupt.2011.06.001" "Revista" => array:6 [ "tituloSerie" => "Pulm Pharmacol Ther" "fecha" => "2011" "volumen" => "24" "paginaInicial" => "610" "paginaFinal" => "616" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21703359" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack315684" "titulo" => "Agradecimentos" "texto" => "Luciana Montes Rezende, Luciana Cardoso Bonadia e Stephanie Villa‐Nova por seu apoio técnico durante a extração do DNA e na identificação de mutações do gene do RTFC. Marcela Augusta de Souza Pinhel, Michele Lima Gregório, Rafael Fernandes Ferreira, Graciele Domitila Tenani e Heloisa Cristina Caldas por seu apoio técnico na padronização da genotipagem da IL‐8. Maria Ângela Gonçalves de Oliveira Ribeiro por fazer os testes de função pulmonar (LAFIP/Ciped/Unicamp). Rafaella Maionchi Pereira Martins por seu apoio técnico na determinação dos escores clínicos. Maria de Fátima Corrêa Pimenta Servidoni por promover um elo entre ambas as universidades." "vista" => "all" ] ] ] "idiomaDefecto" => "pt" "url" => "/22555536/0000009300000006/v1_201711030110/S2255553617300794/v1_201711030110/pt/main.assets" "Apartado" => array:4 [ "identificador" => "16682" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Artigos originais" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/22555536/0000009300000006/v1_201711030110/S2255553617300794/v1_201711030110/pt/main.pdf?idApp=UINPBA000049&text.app=https://jped.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2255553617300794?idApp=UINPBA000049"]

Estatísticas

Artigo Original

Variantes no gene da interleucina 8 e a resposta a broncodilatadores inalatórios na fibrose cística

Larissa Lazzarini Furlana, José Dirceu Ribeirob, Carmen Sílvia Bertuzzoc, João Batista Salomão Juniord,e, Dorotéia Rossi Silva Souzaf, Fernando Augusto Lima Marsonb,c,

Autor para correspondência

fernandolimamarson@hotmail.com

Autor para correspondência.

a Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, SP, Brasil

b Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas, Departamento de Pediatria, Campinas, SP, Brasil

c Universidade Estadual de Campinas (Unicamp), Faculdade de Ciências Médicas, Departamento de Genética Médica, Campinas, SP, Brasil

d Faculdade de Medicina de São José do Rio Preto, Hospital Universitário, Departamento de Pediatria, São José do Rio Preto, SP, Brasil

e Faculdade de Medicina de São José do Rio Preto, Hospital Universitário, Departamento de Pneumologia Pediátrica, São José do Rio Preto, SP, Brasil

f Faculdade de Medicina de São José do Rio Preto, Centro de Pesquisa de Bioquímica e Biologia Molecular, Departamento de Biologia Molecular, São José do Rio Preto, SP, Brasil

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p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;024&#41;&#46; &#40;AA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ATT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#59; m&#233;dia de 20&#44;13<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;64&#59; mediana de 18&#44;50 &#40;varia&#231;&#227;o de &#8722;33 a 117&#41;&#46; &#40;TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>23&#59; m&#233;dia de 2&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#44;74&#59; mediana de 0 &#40;varia&#231;&#227;o de &#8722;51 a 65&#41;&#46; L&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#224; variante rs4073&#44; modelo dominante e grupo <span class="elsevierStyleItalic">RTFC&#8208;A</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;029&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;100&#41;&#46; &#40;AA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>82&#59; m&#233;dia de 15&#44;48<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;20&#59; mediana de 15 &#40;varia&#231;&#227;o de &#8722;40 a 117&#41;&#46; &#40;TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#59; m&#233;dia de 5&#44;94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;33&#59; mediana de 0 &#40;varia&#231;&#227;o de &#8722;51 a 76&#41;&#46; M&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#224; variante rs4073&#44; modelo recessivo e grupo <span class="elsevierStyleItalic">RTFC&#8208;B</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;047&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;063&#41;&#46; &#40;AA&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#59; m&#233;dia de 25&#44;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#44;14&#59; mediana de 30 &#40;varia&#231;&#227;o de &#8722;21 a 57&#41;&#46; &#40;AT<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#59; m&#233;dia de 11&#44;56<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;89&#59; mediana de 8 &#40;varia&#231;&#227;o de &#8722;51 a 117&#41;&#46; O ponto corresponde aos valores medianos e a barra corresponde a intervalo de confian&#231;a de 95&#37;&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">A resposta a broncodilatadores inalat&#243;rios &#40;BD&#41; na fibrose c&#237;stica &#40;FC&#41; &#40;OMIM&#58; n&#176; 219700&#41; &#233; muito vari&#225;vel e depende do gen&#243;tipo do <span class="elsevierStyleItalic">RTFC</span> &#40;Regulador da Condut&#226;ncia Transmembrana da Fibrose C&#237;stica&#41;&#44; dos sintomas pulmonares e&#44; principalmente&#44; de variantes nos genes modificadores&#44; como o Receptor Adren&#233;rgico Beta 2 &#40;<span class="elsevierStyleItalic">ADRB2</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> At&#233; agora&#44; apenas alguns estudos investigaram essa resposta&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">As muta&#231;&#245;es no gene do <span class="elsevierStyleItalic">RTFC</span> causam FC&#44; devido a defici&#234;ncia&#44; disfun&#231;&#227;o ou aus&#234;ncia da prote&#237;na do <span class="elsevierStyleItalic">RTFC</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> A FC &#233; caracterizada por um ciclo cont&#237;nuo de inflama&#231;&#227;o cr&#244;nica das vias a&#233;reas&#44; que pode ser exacerbada pela interleucina 8 &#40;<span class="elsevierStyleItalic">IL&#8208;8</span>&#41;&#44; um importante mediador pr&#243;&#8208;inflamat&#243;rio&#46; A <span class="elsevierStyleItalic">IL&#8208;8</span> &#233; respons&#225;vel por iniciar e aumentar a resposta provocadora na presen&#231;a de pat&#243;genos espec&#237;ficos&#44; causa ativa&#231;&#227;o e migra&#231;&#227;o de neutr&#243;filos do sangue perif&#233;rico para os tecidos&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> A inflama&#231;&#227;o cr&#244;nica das vias a&#233;reas &#233; o caminho comum final de les&#227;o pulmonar&#46; Ela &#233; respons&#225;vel pelo aumento na permeabilidade vascular&#44; contribui para edema intersticial&#44; alveolar e das vias a&#233;reas&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">O tratamento da doen&#231;a pulmonar na FC inclui anti&#8208;inflamat&#243;rios&#44; corticosteroides inalat&#243;rios&#44; antibi&#243;ticos&#44; mucol&#237;tico&#44; solu&#231;&#227;o salina hipert&#244;nica e fisioterapia&#46; Dentre as poss&#237;veis terapias&#44; h&#225; pouca comprova&#231;&#227;o que corrobore um papel dos BD na FC&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4&#44;5</span></a> Contudo&#44; os BD normalmente s&#227;o prescritos por um tempo maior devido a epis&#243;dios de pieira e dispneia na FC&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> Os BD reduzem a libera&#231;&#227;o de mediadores&#44; respons&#225;veis pelo recrutamento e pela ativa&#231;&#227;o de c&#233;lulas inflamat&#243;rias&#44; ativam a neurotransmiss&#227;o colin&#233;rgica&#44; e por melhorar a permeabilidade vascular&#46; Eles tamb&#233;m aumentam o transporte mucociliar&#44; levam &#224; redu&#231;&#227;o da inflama&#231;&#227;o pulmonar&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> A resposta a BD depende&#44; em parte&#44; da prote&#237;na do <span class="elsevierStyleItalic">RTFC</span>&#44; que interage com a prote&#237;na do ADRB2 para promover broncodilata&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> A espirometria &#233; o principal m&#233;todo de avaliar a fun&#231;&#227;o pulmonar&#44; a gravidade e a progress&#227;o da doen&#231;a&#44; bem como a resposta a BD&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Inflama&#231;&#227;o neutrof&#237;lica intensa e baixa hiperreactividade br&#244;nquica s&#227;o caracter&#237;sticas comumente observadas na FC&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> Ademais&#44; a resposta das variantes gen&#233;ticas aos BD &#233; pouco conhecida&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Pode&#8208;se destacar o papel da <span class="elsevierStyleItalic">IL&#8208;8</span> no componente neutrof&#237;lico da doen&#231;a pulmonar na FC&#46; Os genes que podem estar associados &#224; gravidade da FC e possivelmente &#224; resposta a BD foram relatados aqui e na literatura cient&#237;fica de todo o mundo&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1&#44;10&#8211;12</span></a> O gene da <span class="elsevierStyleItalic">IL&#8208;8</span> deve ser destacado&#44; pois ele tem influ&#234;ncia direta sobre a inflama&#231;&#227;o pulmonar e pode ser eficaz na resposta a BD&#46; Portanto&#44; este estudo comparou as variantes gen&#233;ticas da <span class="elsevierStyleItalic">IL&#8208;8</span> rs4073&#44; rs2227306 e rs2227307 com a resposta a BD em pacientes com FC&#44; com o uso da espirometria&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Material e m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Pacientes</span><p id="par0025" class="elsevierStylePara elsevierViewall">Foi conduzido um estudo transversal com 186 pacientes com FC&#44; selecionados em dois centros universit&#225;rios de refer&#234;ncia &#40;Faculdade de Medicina de S&#227;o Jos&#233; do Rio Preto e Universidade de Campinas&#41; para tratamento de FC&#44; de 2013 a 2015&#46; O estudo foi aprovado pelo Comit&#234; de &#201;tica em Pesquisa da Universidade Estadual de Campinas&#44; S&#227;o Paulo&#44; Brasil &#40;n&#176; 528&#47;2008&#41;&#46; Todos os participantes foram informados sobre o estudo e assinaram o Documento de Consentimento Informado&#46; Para os pacientes com menos de 18 anos&#44; o Consentimento Informado foi assinado pelo pai&#47;m&#227;e ou guardi&#227;o&#46; O estudo seguiu as recomenda&#231;&#245;es da Declara&#231;&#227;o de Helsinque&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">O diagn&#243;stico de FC foi confirmado pela presen&#231;a de duas concentra&#231;&#245;es alteradas de s&#243;dio e cloreto no suor &#40;n&#237;vel de cloreto acima de 60 mEq&#47;L&#41;&#46; Al&#233;m disso&#44; nenhum paciente foi submetido a teste inicial de tripsinog&#234;nio imunorreativo &#40;IRT&#41;&#46; Em um grupo de 91 pacientes&#44; houve duas muta&#231;&#245;es no gene do <span class="elsevierStyleItalic">RTFC</span> pertencentes &#224;s classes I&#44; II e&#47;ou III &#40;associadas &#224; maior gravidade da doen&#231;a&#44; devido &#224; aus&#234;ncia ou n&#227;o funcionalidade da prote&#237;na do <span class="elsevierStyleItalic">RTFC</span>&#41;&#59;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> 60 pacientes n&#227;o apresentaram muta&#231;&#227;o identificada do gene do <span class="elsevierStyleItalic">RTFC</span> ou apresentaram duas muta&#231;&#245;es que pertencem &#224;s classes IV&#44; V ou VI&#59; e 35 pacientes apresentaram uma muta&#231;&#227;o no gene do <span class="elsevierStyleItalic">RTFC</span> que pertence &#224;s classes I&#44; II ou III e uma muta&#231;&#227;o n&#227;o identificada ou pertencente &#224;s classes IV&#44; V ou VI &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Vari&#225;veis cl&#237;nicas</span><p id="par0035" class="elsevierStylePara elsevierViewall">As seguintes vari&#225;veis foram analisadas&#58; escores cl&#237;nicos &#40;Shwachman&#8208;Kulczycki&#44; Kanga e Bhalla&#41;&#59; &#237;ndice de massa corporal &#40;IMC&#41; de pacientes com mais de 18 anos&#44; com a f&#243;rmula IMC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>peso&#47;altura&#59;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> a vers&#227;o 3&#46;0&#46;1 do programa Anthro &#40;Organiza&#231;&#227;o Mundial de Sa&#250;de &#91;OMS&#93;&#44; 2006&#41; foi usada para crian&#231;as com menos de cinco anos e a vers&#227;o 1&#46;0&#46;2 do programa Anthro Plus &#40;Organiza&#231;&#227;o Mundial de Sa&#250;de &#91;OMS&#93;&#44; 2007&#41; foi usada para crian&#231;as de cinco anos a adolescentes de 18 anos&#59; idade do paciente e idade na &#233;poca do diagn&#243;stico&#59; primeiro sintoma cl&#237;nico &#40;um sintoma geral&#44; sintomas pulmonares e digestivos&#41;&#59; per&#237;odo at&#233; a primeira coloniza&#231;&#227;o por <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> mucoide &#40;PAM&#41;&#59; microrganismos identificados na cultura de escarro de rotina &#40;<span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; <span class="elsevierStyleItalic">Achromobacter xylosoxidans</span>&#44; <span class="elsevierStyleItalic">Burkolderia cepacia</span> e <span class="elsevierStyleItalic">Staphylococcus aureus</span> mucoides e n&#227;o mucoides&#41;&#59; satura&#231;&#227;o de oxig&#234;nio no sangue arterial transcut&#226;nea &#40;SaO<span class="elsevierStyleInf">2</span>&#41;&#59; espirometria e comorbidades &#40;p&#243;lipos nasais&#44; osteoporose&#44; &#237;leo meconial&#44; <span class="elsevierStyleItalic">diabetes mellitus</span> e insufici&#234;ncia pancre&#225;tica&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">A espirometria foi feita em pacientes com mais de sete anos&#44; com o espir&#244;metro CPFS&#47;D &#40;MedGraphics&#44; Saint Paul&#44; Minnesota&#44; EUA&#41;&#46; Os dados foram registrados pela vers&#227;o 3&#46;8B do <span class="elsevierStyleItalic">software</span> PF BREEZE para Windows 95&#47;98&#47;NT &#40;American Thoracic Society&#41; e avaliados em percentagem de valores preditivos para&#58; capacidade vital for&#231;ada &#40;&#37; de CVF&#41;&#44; volume expirat&#243;rio for&#231;ado no 1&#176; segundo da CVF &#40;VEF<span class="elsevierStyleInf">1</span>&#41;&#44; propor&#231;&#227;o VEF<span class="elsevierStyleInf">1</span>&#47;CVF&#44; fluxo expirat&#243;rio for&#231;ado a 25&#37; da CVF &#40;FEF<span class="elsevierStyleInf">25&#37;</span>&#41;&#44; fluxo expirat&#243;rio for&#231;ado a 50&#37; da CVF &#40;FEF<span class="elsevierStyleInf">50&#37;</span>&#41;&#44; fluxo expirat&#243;rio for&#231;ado a 75&#37; da CVF &#40;FEF<span class="elsevierStyleInf">75&#37;</span>&#41;&#44; fluxo expirat&#243;rio for&#231;ado entre 25&#37; e 75&#37; da CVF &#40;FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#41;&#44; fluxo expirat&#243;rio for&#231;ado m&#225;ximo &#40;FEF<span class="elsevierStyleInf">max</span>&#41; e volume de reserva expirat&#243;ria &#40;VRE&#41;&#46; Os dados da espirometria s&#227;o mostrados em percentual do valor preditivo de acordo com as equa&#231;&#245;es de Polgar e Promadhat &#40;1971&#41;&#59; Pereira et al&#46; &#40;2007&#41; e Duarte et al&#46; &#40;2007&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">14&#8211;16</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Todos os pacientes submetidos a espirometria fizeram o teste antes e 15 minutos ap&#243;s administra&#231;&#227;o dos BD &#91;albutrol&#8211;C<span class="elsevierStyleInf">13</span>H<span class="elsevierStyleInf">21</span>NO<span class="elsevierStyleInf">3</span> &#40;400 mg&#41;&#93;&#46; Os pacientes em terapia com BD foram orientados a interromper a medica&#231;&#227;o oito horas antes da espirometria&#44; caso estivessem em tratamento com BD de curta a&#231;&#227;o&#44; e 48 horas antes&#44; caso estivessem em tratamento com BD de a&#231;&#227;o prolongada&#46; A mudan&#231;a no percentual p&#243;s&#8208;BD foi usada na an&#225;lise estat&#237;stica&#46; Os crit&#233;rios de resposta a BD&#44; definidos como aumento de &#62; 12&#37; e 200 mL de VEF1 inicial&#44; foram usados como o segundo modelo para avaliar a associa&#231;&#227;o entre as variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> e a resposta a BD&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Extra&#231;&#227;o do DNA e genotipagem</span><p id="par0050" class="elsevierStylePara elsevierViewall">O DNA gen&#244;mico foi extra&#237;do de amostras de sangue perif&#233;rico com o m&#233;todo padr&#227;o fenol&#8208;clorof&#243;rmio e quantificado por espectrofot&#244;metro GE NanoVue&#8482; &#40;GE Healthcare Biosciences&#44; Pittsburgh&#44; EUA&#41;&#46; Neste estudo&#44; a concentra&#231;&#227;o final da amostra foi estabelecida em 50 ng&#47;&#956;L&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">As muta&#231;&#245;es do <span class="elsevierStyleItalic">RTFC</span> foram analisadas por rea&#231;&#227;o em cadeia da polimerase &#40;PCR&#41; &#40;F508del&#41; ap&#243;s digest&#227;o enzim&#225;tica &#40;G542X&#44; R1162X&#44; R553X&#44; G551D e N1303 K&#41;&#46; Outras muta&#231;&#245;es no gene do <span class="elsevierStyleItalic">RTFC</span> podem ser identificadas por sequenciamento ou com o uso do m&#233;todo SALSA MPLA &#40;Amplifica&#231;&#227;o de M&#250;ltiplas Sondas Dependentes de Liga&#231;&#227;o&#41; Kit P091&#8208;C1 CFTR&#8208;MRC&#8208;Holland S4X&#44; 2183A &#62; G&#44; 1717&#8208;G &#62; A&#44; I618 T com MegaBace1000<span class="elsevierStyleSup">&#174;</span> &#40;GE Healthcare Biosciences&#44; Pittsburgh&#44; EUA&#41; e ABI3500 &#40;Biossistemas Aplicados &#8211; Thermo Fisher Scientific&#44; S&#227;o Paulo&#44; Brasil&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">As variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> foram analisadas por PCR ap&#243;s digest&#227;o com enzimas de restri&#231;&#227;o&#46; Para a variante rs4073&#44; foram usados os iniciadores 5&#8217;&#8208;CCA TCA TGA TAG CAT CTG TA&#8208;3&#8242; e 5&#8242;&#8208;CCA CAA TTT GGT GAA TTA TTA A&#8208;3&#8242; e a enzima de restri&#231;&#227;o <span class="elsevierStyleItalic">AseI</span>&#59; para a variante rs2227306&#44; foram usados os iniciadores 5&#8242;&#8208;CTC TAA CTC TTT ATA TAG GAA TT&#8208;3&#8242; e 5&#8242;&#8208;GAT TGA TTT TAT CAA CAG GCA&#8208;3&#8242;&#44; bem como a enzima de restri&#231;&#227;o <span class="elsevierStyleItalic">EcoRI</span>&#59; e para a variante rs2227307&#44; foram usados os iniciadores 5&#8242;&#8208;TAA AGG TTT GAT CAA TAT AGA&#8208;3&#8242; e 5&#8242;&#8208;CTT CCT TCT AAT TCCA ATA TG&#8208;3&#8242;&#44; bem como a enzima de restri&#231;&#227;o <span class="elsevierStyleItalic">ScrFI</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">18&#44;19</span></a> Os produtos da restri&#231;&#227;o enzim&#225;tica foram submetidos a eletroforese em gel de poliacrilamida a 12&#37;&#44; ou gel de agarose a 4&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">18&#44;19</span></a> e corados com gel Red<span class="elsevierStyleSup">&#174;</span>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">An&#225;lise estat&#237;stica</span><p id="par0065" class="elsevierStylePara elsevierViewall">Foi feita com a vers&#227;o 22&#46;0 do SPSS &#40;SPSS Inc&#46;&#44; Chicago&#44; EUA&#41;&#46; Foi usada a vers&#227;o 3&#46;1&#46;9&#46;2<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> do <span class="elsevierStyleItalic">software</span> GPower para calcular o poder da amostra&#44; considerou&#8208;se o gen&#243;tipo das variantes analisadas e adotou&#8208;se o poder para valor acima de 80&#37;&#46; As condi&#231;&#245;es a seguir foram aplicadas para calcular o poder da amostra&#58; &#40;teste de an&#225;lise da vari&#226;ncia no lugar do teste de Kruskal&#8208;Wallis&#44; considerou&#8208;se que a an&#225;lise de vari&#226;ncia &#233; um teste mais forte&#41; tamanho do efeito<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;25&#44; &#945;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#44; poder<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;80&#44; grau de liberdade do numerador<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44; n&#250;mero de grupos<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#44; n&#176; ideal<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>158&#59; &#40;teste de Mann&#8208;Whitney&#8211;bicaudal&#41; tamanho do efeito<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;5&#44; &#945;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#44; poder<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;80&#44; propor&#231;&#227;o de atribui&#231;&#227;o N2&#47;N1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44; n&#176; ideal&#8211;134&#59; &#40;teste &#967;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a>&#41; tamanho do efeito<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;3&#44; &#945;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#44; poder<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;80&#44; grau de liberdade<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44; n&#176; ideal<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>108&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Os testes de Mann&#8208;Whitney e Kruskal&#8208;Wallis foram usados para compara&#231;&#227;o entre diferentes gen&#243;tipos e os grupos de variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> e a resposta a BD&#46; Em caso de diferen&#231;as significativas entre os grupos do teste de Kruskal&#8208;Wallis&#44; foram feitas identifica&#231;&#227;o e avalia&#231;&#227;o adicionais das diferen&#231;as entre os gen&#243;tipos com o <span class="elsevierStyleItalic">software</span> para Windows MedCalc<span class="elsevierStyleSup">&#174;</span>&#44; vers&#227;o 16&#46;1 &#40;MedCalc<span class="elsevierStyleSup">&#174;</span> Software&#44; Ostend&#44; B&#233;lgica&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">O teste &#967;2 e o teste exato de Fisher foram usados para compara&#231;&#227;o entre os diferentes gen&#243;tipos e grupos de variantes do gene da IL&#8208;8 e a resposta a BD definidos como um aumento de &#62; 12&#37; e 200 mL de VEF1 inicial&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Para a identifica&#231;&#227;o de muta&#231;&#245;es no gene do <span class="elsevierStyleItalic">RTFC</span>&#44; os pacientes foram analisados com base em dois contextos&#58; &#40;<span class="elsevierStyleItalic">RTFC</span>&#8208;A&#41; todos os pacientes com FC&#44; independentemente das muta&#231;&#245;es do gene &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>186 pacientes&#41;&#59; &#40;<span class="elsevierStyleItalic">RTFC</span>&#8208;B&#41; pacientes com duas muta&#231;&#245;es pertencentes &#224;s classes I&#44; II e&#47;ou III &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>91 pacientes&#41;&#46; Quanto &#224;s variantes&#44; foram adotados quatro modelos de an&#225;lise&#58; &#40;i&#41; codominante &#40;teste de Kruskal&#8208;Wallis&#41;&#59; &#40;ii&#41; recessivo &#40;teste de Mann&#8208;Whitney&#41;&#59; &#40;iii&#41; dominante &#40;teste de Mann&#8208;Whitney&#41;&#59; &#40;iv&#41; superdominante &#40;teste de Mann&#8208;Whitney&#41;&#44; aplicados em associa&#231;&#227;o &#224;s vari&#225;veis cl&#237;nicas&#46; Para todas as an&#225;lises&#44; o valor alfa foi estabelecido em 0&#44;05&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Para an&#225;lise do equil&#237;brio de Hardy&#8208;Weinberg &#40;HWE&#41; foi usado o <span class="elsevierStyleItalic">software</span> Online Encyclopedia for Genetic Epidemiology Studies &#40;OEGE&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">O teste da taxa de falsa descoberta &#40;FDR&#41; foi aplicado para corrigir a compara&#231;&#227;o m&#250;ltipla de testes&#46; A FDR &#233; uma abordagem ao problema de m&#250;ltiplas compara&#231;&#245;es&#46; Em vez de controlar a chance de qualquer falso&#44; os controles da FDR controlam a propor&#231;&#227;o esperada de falsos positivos entre os resultados significativos&#46; O limite da FDR &#233; determinado a partir da distribui&#231;&#227;o do valor de p observado e&#44; assim&#44; &#233; adaptativo ao valor de sinal nos dados&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> O valor de p &#40;p&#41; e o valor de p corrigido &#40;p<span class="elsevierStyleSup">c</span>&#41; foram mostrados no manuscrito&#46; A an&#225;lise de desequil&#237;brio de liga&#231;&#227;o foi feita na vers&#227;o 4&#46;2 do <span class="elsevierStyleItalic">software</span> Haploview&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Resultados</span><p id="par0095" class="elsevierStylePara elsevierViewall">Os dados cl&#237;nicos e laboratoriais dos pacientes com FC s&#227;o descritos na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46; A descri&#231;&#227;o do gen&#243;tipo e da frequ&#234;ncia de alelos das variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> encontra&#8208;se na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#46; A <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> mostra os dados com valores de p e valor de p corrigido para associa&#231;&#227;o das variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span>&#44; consideraram&#8208;se os quatros modelos de an&#225;lise propostos e o gen&#243;tipo do gene do <span class="elsevierStyleItalic">RTFC</span>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">A variante rs2227307 n&#227;o foi associada &#224; resposta a BD em nenhum dos modelos estudados&#59; ao passo que a variante rs2227306 foi associada a FEF<span class="elsevierStyleInf">50&#37;</span> para pacientes com gen&#243;tipo CC &#40;modelo dominante&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;083&#41; e gen&#243;tipo CT &#40;modelo superdominante&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;033&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;083&#41; no grupo <span class="elsevierStyleItalic">RTFC</span>&#8208;B &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>D e E&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Deve&#8208;se enfatizar de modo especial a variante rs4073&#44; associada &#224;s vari&#225;veis de espirometria&#58; FEV<span class="elsevierStyleInf">1</span>&#44; propor&#231;&#227;o VEF<span class="elsevierStyleInf">1</span>&#47;CVF&#44; FEF<span class="elsevierStyleInf">50&#37;</span>&#44; FEF<span class="elsevierStyleInf">75&#37;</span> e FEF<span class="elsevierStyleInf">25&#8208;75&#37;&#46;</span> A menor resposta a BD foi observada para gen&#243;tipo TT &#40;modelo dominante&#41; e pacientes do grupo <span class="elsevierStyleItalic">RTFC</span>&#8208;B a VEF<span class="elsevierStyleInf">1</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>A&#41;&#44; FEF<span class="elsevierStyleInf">50&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a> C&#41;&#44; FEF<span class="elsevierStyleInf">75&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>G&#41; e FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a> K&#41;&#46; O mesmo foi observado para o grupo <span class="elsevierStyleItalic">RTFC</span>&#8208;A para FEF<span class="elsevierStyleInf">75&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>H&#41; e FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>L&#41;&#46; Na an&#225;lise codominante&#44; o gen&#243;tipo TT apresentou menor resposta a BD para VEF<span class="elsevierStyleInf">75&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>F&#41; e FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a> J&#41;&#44; respectivamente para os grupos <span class="elsevierStyleItalic">RTFC</span>&#8208;A e <span class="elsevierStyleItalic">RTFC</span>&#8208;B&#46; Para o indicador VEF<span class="elsevierStyleInf">1</span>&#47;CVF&#44; o gen&#243;tipo AT nos pacientes do grupo <span class="elsevierStyleItalic">RTFC</span>&#8208;B mostrou menor resposta a BD &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>B&#41;&#46; Por fim&#44; nos pacientes dos grupos <span class="elsevierStyleItalic">RTFC</span>&#8208;A e <span class="elsevierStyleItalic">RTFC</span>&#8208;B&#44; respectivamente&#44; o gen&#243;tipo AA &#40;modelo recessivo&#41; para rs4073 mostrou maior resposta a BD para FEF<span class="elsevierStyleInf">75&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>I&#41; e FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a> M&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">A distribui&#231;&#227;o de hapl&#243;tipos para as variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> &#233; apresentada na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Para compara&#231;&#227;o entre as variantes do gene da IL&#8208;8 e a resposta a BD definida como aumento de &#62; 12&#37; e 200 mL de VEF1 inicial&#44; n&#227;o foi encontrada associa&#231;&#227;o positiva &#40;p &#62; 0&#44;05&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discuss&#227;o</span><p id="par0120" class="elsevierStylePara elsevierViewall">Mostramos anteriormente a influ&#234;ncia das diferentes variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> sobre a gravidade cl&#237;nica da FC&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Al&#233;m disso&#44; este estudo mostra a associa&#231;&#227;o das diferentes variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> e sua modula&#231;&#227;o &#224; resposta a BD&#44; avalia o impacto do medicamento sobre a fun&#231;&#227;o pulmonar&#46; A variabilidade das respostas aos BD &#233; determinada por v&#225;rios fatores&#44; como inflama&#231;&#227;o e obstru&#231;&#227;o pulmonar&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> bact&#233;rias<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> e sintomas pulmonares&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> bem como genes modificadores&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> Contudo&#44; at&#233; agora&#44; nenhum estudo investigou o papel da <span class="elsevierStyleItalic">IL&#8208;8</span> como mediador pr&#243;&#8208;inflamat&#243;rio de FC e sua rela&#231;&#227;o aos BD e se as variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> podem explicar a resposta individual aos BD na FC&#46; Acredita&#8208;se que os beta&#8208;2 agonistas de curta e longa dura&#231;&#227;o podem ser ben&#233;ficos para pacientes com FC e com hiperresponsividade br&#244;nquica positiva&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Em doen&#231;as pulmonares progressivas&#44; foram avaliados diferentes marcadores e o uso dos BD parece fornecer melhor resposta ao FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#44; em compara&#231;&#227;o com outros marcadores&#44; o que indica envolvimento de vias a&#233;reas de menor calibre na FC&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> Nosso estudo&#44; em concord&#226;ncia com a literatura de refer&#234;ncia&#44; encontrou uma associa&#231;&#227;o da variante rs4073 para o marcador FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> nos modelos dominante &#40;para os grupos <span class="elsevierStyleItalic">RTFC</span>&#8208;A e <span class="elsevierStyleItalic">RTFC</span>&#8208;B&#41;&#44; codominante &#40;grupo <span class="elsevierStyleItalic">RTFC</span>&#8208;B&#41; e recessivo &#40;grupo <span class="elsevierStyleItalic">RTFC</span>&#8208;B&#41;&#46; Houve melhoria em diversos outros marcadores de espirometria para rs4073&#44; como VEF<span class="elsevierStyleInf">1</span>&#44; VEF<span class="elsevierStyleInf">1</span>&#47;CVF e FEF<span class="elsevierStyleInf">50&#37;</span> e FEF<span class="elsevierStyleInf">75&#37;</span>&#44; o que mostra impacto sobre os padr&#245;es de respira&#231;&#227;o dos pacientes&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">O estudo de Hillian et al&#46; encontrou uma associa&#231;&#227;o das variantes rs2227307 e rs4073 do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> e a gravidade da doen&#231;a pulmonar&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> Nesse estudo&#44; os pacientes foram divididos em duas coortes&#58; &#40;1&#41; pacientes homozigotos F508del&#59; &#40;2&#41; pacientes com outros gen&#243;tipos do gene do <span class="elsevierStyleItalic">RTFC</span>&#46; Na coorte 1&#44; as variantes rs4073&#44; rs2227306 e rs2227543 n&#227;o foram associadas a doen&#231;a pulmonar e a variante rs22227307 mostrou associa&#231;&#227;o&#44; independentemente do sexo&#46; Na coorte 2&#44; as variantes rs4073 e rs2227306 foram associadas a gravidade da doen&#231;a pulmonar em homens&#46; Assim&#44; o sexo do paciente&#44; o gen&#243;tipo do gene do <span class="elsevierStyleItalic">RTFC</span> e os genes modificadores podem modular a gravidade da doen&#231;a pulmonar&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> Nesse estudo&#44; o gen&#243;tipo rs2227307 n&#227;o teve impacto sobre a variabilidade da resposta a BD&#46; Isso sugere que&#44; apesar de esse gen&#243;tipo estar associado a doen&#231;a pulmonar em pacientes homozigotos F508del&#44; sua resposta a BD n&#227;o &#233; relevante&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">O alvo dos BD &#233; a prote&#237;na ADRB2&#44; expressa no m&#250;sculo liso das vias a&#233;reas&#46; As variantes de ADRB2 est&#227;o associadas &#224; resposta &#224; medica&#231;&#227;o&#46; Essa prote&#237;na foi amplamente estudada em asma e ainda muito raramente em FC&#46; A efic&#225;cia da resposta a BD e aos corticosteroides inalat&#243;rios no manejo de inflama&#231;&#227;o das vias a&#233;reas em asma est&#225; confirmada e depende das variantes Arg16Gly &#40;rs1042713&#59; c&#46;46A<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&#41; e Glu27Gln &#40;rs1042714&#59; c&#46;79C<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&#41; do gene <span class="elsevierStyleItalic">ADRB2</span>&#46;&#91;29&#93; A variante Gln27Glu concede resist&#234;ncia &#224; prote&#237;na ADRB2 na resposta a BD&#46; Os alelos 46&#42;G e 79&#42;G protegem contra asma&#44; reduzem o risco em 27&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> As variantes do alelo G induzem altera&#231;&#245;es na regula&#231;&#227;o do receptor&#44; devido ao aumento da susceptibilidade &#224; degrada&#231;&#227;o de prote&#237;nas&#46; Este estudo constatou que as variantes Arg16Gly e Gln27Glu do gene <span class="elsevierStyleItalic">ADRB2</span> influenciam a respostas aos BD na FC&#46; Na espirometria e em outros marcadores de gravidade&#44; a variante Arg16Gly mostrou associa&#231;&#227;o positiva&#44; ao contr&#225;rio da variante Gln27Glu&#46; O gen&#243;tipo Arg&#47;Arg da variante Arg16Gly foi associado a melhores valores de VEF<span class="elsevierStyleInf">1</span> e FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#46; A resposta a BD nas an&#225;lises de hapl&#243;tipo foi positiva na aus&#234;ncia dos gen&#243;tipos Gly16Gly e Glu27Glu para a propor&#231;&#227;o VEF<span class="elsevierStyleInf">1</span>&#47;CVF&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">As variantes de ADRB2&#44; capacidade de difus&#227;o dos pulm&#245;es para&#160;mon&#243;xido de carbono&#44; condut&#226;ncia da membrana capilar alveolar&#44; volume sangu&#237;neo na capilar alveolar e SaO<span class="elsevierStyleInf">2</span>&#44; foram avaliadas na resposta a BD em 18 pacientes e 20 controles saud&#225;veis&#44; antes e depois da administra&#231;&#227;o de salbutamol &#40;30&#44; 60 e 90 minutos&#41;&#46; Os indiv&#237;duos saud&#225;veis n&#227;o apresentaram altera&#231;&#245;es nos marcadores avaliados para a variante Glu27Glu&#46; Contudo&#44; na FC&#44; essa variante influenciou a resposta a BD&#58; a melhor resposta encontrada na presen&#231;a de pelo menos um alelo 27Glu&#46; Houve uma diferen&#231;a de difus&#227;o pulmonar e SaO<span class="elsevierStyleInf">2</span> perif&#233;rica de acordo com a varia&#231;&#227;o do gene <span class="elsevierStyleItalic">ADRB2</span> na posi&#231;&#227;o 27 e a dosagem do medicamento deve ser prescrita de acordo com essa varia&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">A maior parte dos estudos foca nas variantes do gene ADRB2 na resposta a BD&#46; Contudo&#44; este estudo demonstra que&#44; mesmo indiretamente&#44; as variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> e possivelmente em outros genes&#44; que modulam a resposta pulmonar inflamat&#243;ria&#44; podem potencializar ou diminuir o efeito dos BD e&#44; ainda&#44; influenciar a resposta ao medicamento&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Com rela&#231;&#227;o ao HWE&#44; conforme discutido anteriormente por nosso grupo&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> duas variantes &#40;rs4073 e rs2227306&#41; n&#227;o estavam em equil&#237;brio&#46; Devemos lembrar que o HWE pressup&#245;e uma popula&#231;&#227;o ideal&#44; sem a interfer&#234;ncia de fatores evolucion&#225;rios&#46; Contudo&#44; em genes envolvidos em controle de imunidade&#44; inflama&#231;&#227;o e infec&#231;&#227;o&#44; o desequil&#237;brio do HWE parecer estar associado de forma secund&#225;ria aos mecanismos de sele&#231;&#227;o que favoreceram um alelo espec&#237;fico que pode trazer uma resposta mais efetiva&#46; O desequil&#237;brio n&#227;o invalida o estudo de associa&#231;&#227;o&#44; pois os grupos fazem parte da mesma popula&#231;&#227;o&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Limita&#231;&#245;es do estudo&#58; &#40;i&#41; banco de dados transversal &#40;a resposta a BD foi avaliada em um &#250;nico momento&#41;&#59; &#40;ii&#41; h&#225; v&#225;rios dados ausentes&#44; se levarmos em considera&#231;&#227;o os problemas para obter as informa&#231;&#245;es nos registros&#59; &#40;iii&#41; caso a resposta a BD seja diferente com base no VEF<span class="elsevierStyleInf">1</span> de base&#44; principalmente em indiv&#237;duos saud&#225;veis&#59; &#40;iv&#41; poss&#237;veis vari&#225;veis de confus&#227;o com rela&#231;&#227;o aos resultados&#44; como gravidade da doen&#231;a&#44; terapias atuais&#44; ades&#227;o &#224; medica&#231;&#227;o e esfor&#231;o adequado no teste de fun&#231;&#227;o pulmonar&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">As variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> &#40;rs2227306 e especialmente rs4073&#41; podem estar associadas &#224; resposta a BD durante a espirometria&#46; Esse medicamento pode ser uma op&#231;&#227;o para o tratamento da doen&#231;a&#44; na maior parte do tempo em pacientes com vias a&#233;reas de menor calibre&#46; Devem&#8208;se conduzir estudos que envolvam dose e combina&#231;&#245;es de medicamentos para determinar o melhor tratamento de acordo com o gen&#243;tipo do paciente com FC&#44; o gene do <span class="elsevierStyleItalic">RTFC</span>&#44; bem como os genes modificadores&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Financiamento</span><p id="par0165" class="elsevierStylePara elsevierViewall">FALM&#58; Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo &#40;Fapesp&#41;&#44; em apoio &#224;s pesquisas n&#176; 2011&#47;12939&#8208;4&#44; n&#176; 2011&#47;18845&#8208;1&#44; n&#176; 2015&#47;12183&#8208;8 e n&#176; 2015&#47;12858&#8208;5&#59; Fundo de Apoio &#224; Pesquisa&#44; ao Ensino e &#224; Extens&#227;o da Universidade Estadual de Campinas&#44; em apoio &#224; pesquisa n&#176; 0648&#47;2015&#59; JDR&#58; Fapesp&#44; em apoio &#224;s pesquisas n&#176; 2011&#47;18845&#8208;1 e n&#176; 2015&#47;12183&#8208;8&#46; LLF&#58; Fapesp&#44; em apoio &#224; pesquisa n&#176; 2013&#47;19052&#8208;0&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflitos de interesse</span><p id="par0170" class="elsevierStylePara elsevierViewall">Os autores declaram n&#227;o haver conflitos de interesse&#46;</p></span></span>"
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            0 => "<span class="elsevierStyleItalic">CFTR</span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Interleukin 8 protein promotes inflammatory responses&#44; even in airways&#46; The presence of interleukin 8 gene variants causes altered inflammatory responses and possibly varied responses to inhaled bronchodilators&#46; Thus&#44; this study analyzed the interleukin 8 variants &#40;rs4073&#44; rs2227306&#44; and rs2227307&#41; and their association with the response to inhaled bronchodilators in cystic fibrosis patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Analysis of interleukin 8 gene variants was performed by restriction fragment length polymorphism of polymerase chain reaction&#46; The association between spirometry markers and the response to inhaled bronchodilators was evaluated by Mann&#8208;Whitney and Kruskal&#8208;Wallis tests&#46; The analysis included all cystic fibrosis patients&#44; and subsequently patients with two mutations in the cystic fibrosis transmembrane conductance regulator gene belonging to classes I to III&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">This study included 186 cystic fibrosis patients&#46; There was no association of the rs2227307 variant with the response to inhaled bronchodilators&#46; The rs2227306 variant was associated with FEF<span class="elsevierStyleInf">50&#37;</span> in the dominant group and in the group with two identified mutations in the cystic fibrosis transmembrane conductance regulator gene&#46; The rs4073 variant was associated with spirometry markers in four genetic models&#58; co&#8208;dominant &#40;FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> and FEF<span class="elsevierStyleInf">75&#37;</span>&#41;&#44; dominant &#40;FEV<span class="elsevierStyleInf">1</span>&#44; FEF<span class="elsevierStyleInf">50&#37;</span>&#44; FEF<span class="elsevierStyleInf">75&#37;</span>&#44; and FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#41;&#44; recessive &#40;FEF<span class="elsevierStyleInf">75&#37;</span> and FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#41;&#44; and over&#8208;dominant &#40;FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">This study highlighted the importance of the rs4073 variant of the interleukin 8 gene&#44; regarding response to inhaled bronchodilators&#44; and of the assessment of mutations in the cystic fibrosis transmembrane conductance regulator gene&#46;</p></span>"
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        "resumen" => "<span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Objetivo</span><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">A prote&#237;na interleucina 8 promove respostas inflamat&#243;rias&#44; o que inclui sua atua&#231;&#227;o nas vias a&#233;reas&#46; A presen&#231;a de variantes no gene da interleucina 8 causa respostas inflamat&#243;rias alteradas e possivelmente respostas variadas ao uso de broncodilatadores inalat&#243;rios&#46; Assim&#44; este estudo analisou as variantes da interleucina 8 &#40;rs4073&#44; rs2227306&#44; rs2227307&#41; e sua associa&#231;&#227;o &#224; resposta a broncodilatadores inalat&#243;rios em pacientes com fibrose c&#237;stica&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">M&#233;todos</span><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Foi feita an&#225;lise das variantes gen&#233;ticas da interleucina 8 por <span class="elsevierStyleItalic">restriction fragment length polymorphism</span> da rea&#231;&#227;o em cadeia da polimerase&#46; A associa&#231;&#227;o entre os marcadores da espirometria e a resposta a broncodilatadores inalat&#243;rios foi feita pelos testes de Mann&#8208;Whitney e Kruskal&#8208;Wallis&#46; A an&#225;lise incluiu todos os pacientes com fibrose c&#237;stica e posteriormente pacientes com duas muta&#231;&#245;es no gene <span class="elsevierStyleItalic">cystic fibrosis transmembrane conductance regulator</span> pertencentes &#224;s Classes I a II&#46;</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Resultados</span><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Este estudo incluiu 186 pacientes com fibrose c&#237;stica&#46; N&#227;o houve associa&#231;&#227;o da variante rs2227307 &#224; resposta a broncodilatadores inalat&#243;rios&#46; A variante rs2227306 foi associada a FEF<span class="elsevierStyleInf">50&#37;</span> no grupo dominante e no grupo com duas muta&#231;&#245;es identificadas no gene <span class="elsevierStyleItalic">cystic fibrosis transmembrane conductance regulator</span>&#46; A variante rs4073 foi associada a marcadores da espirometria em quatro modelos gen&#233;ticos&#58; codominante &#40;FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> e FEF<span class="elsevierStyleInf">75&#37;</span>&#41;&#44; dominante &#40;VEF<span class="elsevierStyleInf">1</span>&#44; FEF<span class="elsevierStyleInf">50&#37;</span>&#44; FEF<span class="elsevierStyleInf">75&#37;</span> e FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#41;&#44; recessivo &#40;FEF<span class="elsevierStyleInf">75&#37;</span> e FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#41; e overdominante &#40;VEF<span class="elsevierStyleInf">1</span>&#47;CVF&#41;&#46;</p></span> <span id="abst0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclus&#245;es</span><p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Este estudo destaca&#44; principalmente&#44; a import&#226;ncia da variante rs4073 do gene da interleucina 8&#44; na resposta a broncodilatadores inalat&#243;rios&#44; concomitantemente ao gen&#243;tipo das muta&#231;&#245;es no gene <span class="elsevierStyleItalic">cystic fibrosis transmembrane conductance regulator</span>&#46;</p></span>"
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mediana de 10&#44;50 &#40;varia&#231;&#227;o de &#8722;28 a 89&#41;&#46; E&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">50&#37;</span> &#224; variante rs2227306&#44; modelo superdominante e grupo <span class="elsevierStyleItalic">RTFC</span>&#8208;B &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;033&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;083&#41;&#46; &#40;CC<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#59; m&#233;dia de 6&#44;06<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&#44;27&#59; mediana de 4 &#40;varia&#231;&#227;o de &#8722;20 a 55&#41;&#46; &#40;CT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>23&#59; m&#233;dia de 19&#44;96<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>26&#44;43&#59; mediana de 19 &#40;varia&#231;&#227;o de &#8722;28 a 89&#41;&#46; F&#46; Associa&#231;&#227;o do fluxo expirat&#243;rio for&#231;ado de 75&#37; &#40;FEF<span class="elsevierStyleInf">75&#37;</span>&#41; da CVF &#224; variante rs4073&#44; modelo codominante independentemente das muta&#231;&#245;es identificadas no gene do <span class="elsevierStyleItalic">RTFC</span> &#40;grupo RTFC&#8208;A&#41; &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;044&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;058&#41;&#46; 1 &#8800; 3&#46; &#40;AA&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&#59; m&#233;dia de 29&#44;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>39&#44;98&#59; mediana de 30 &#40;varia&#231;&#227;o de &#8722;47 a 142&#41;&#46; &#40;AT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#59; m&#233;dia de 24&#44;81<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>53&#44;57&#59; mediana de 14 &#40;varia&#231;&#227;o de &#8722;58 a 235&#41;&#46; &#40;TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&#59; m&#233;dia de 9&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>36&#44;95&#59; mediana de 2&#44;5 &#40;varia&#231;&#227;o de &#8722;35 a 119&#41;&#46; G&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">75&#37;</span> &#224; variante rs4073&#44; modelo dominante e grupo <span class="elsevierStyleItalic">RTFC</span>&#8208;B &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;024&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;096&#41;&#46; &#40;AA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#59; m&#233;dia de 33<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>55&#44;23&#59; mediana de &#40;varia&#231;&#227;o de &#8722;27 a 235&#41;&#46; &#40;TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#59; m&#233;dia de 5&#44;43<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>35&#44;93&#59; mediana de 2 &#40;varia&#231;&#227;o de &#8722;35 a 119&#41;&#46; H&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">75&#37;</span> &#224; variante rs4073&#44; modelo dominante e grupo <span class="elsevierStyleItalic">RTFC&#8208;A</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;034&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;058&#41;&#46; &#40;AA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AT&#41; &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>70&#59; m&#233;dia de 26&#44;86<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>48&#44;34&#59; mediana de 18 &#40;varia&#231;&#227;o de &#8722;58 a 235&#41;&#46; &#40;TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&#59; m&#233;dia de 9&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>36&#44;95&#59; mediana de 2&#44;5 &#40;varia&#231;&#227;o de &#8722;35 a 119&#41;&#46; I&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">75&#37;</span> &#224; variante rs4073&#44; modelo recessivo e grupo <span class="elsevierStyleItalic">RTFC&#8208;A</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;040&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;058&#41;&#46; &#40;AA&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&#59; m&#233;dia de 29&#44;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>39&#44;98&#59; mediana de 30 &#40;varia&#231;&#227;o de &#8722;47 a 142&#41;&#46; &#40;AT<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>70&#59; m&#233;dia de 18&#44;54<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>47&#44;95&#59; mediana de 10 &#40;varia&#231;&#227;o de &#8722;58 a 235&#41;&#46; J&#46; Associa&#231;&#227;o do FEF entre 25 e 75&#37; &#40;FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#41; da CVF &#224; variante rs4073&#44; modelo codominante e grupo <span class="elsevierStyleItalic">RTFC&#8208;B</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;012&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;024&#41;&#46; TT &#8800; AA e AT&#46; &#40;AA&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#59; m&#233;dia de 25&#44;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#44;14&#59; mediana de 30 &#40;varia&#231;&#227;o de &#8722;21 a 57&#41;&#46; &#40;AT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>29&#59; m&#233;dia de 18&#44;38<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>29&#44;04&#59; mediana de 14 &#40;varia&#231;&#227;o de &#8722;33 a 117&#41;&#46; &#40;TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#59; m&#233;dia de 2&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#44;74&#59; mediana de 0 &#40;varia&#231;&#227;o de &#8722;51 a 65&#41;&#46; K&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#224; variante rs4073&#44; modelo dominante e grupo <span class="elsevierStyleItalic">RTFC&#8208;B</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;007&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;024&#41;&#46; &#40;AA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ATT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#59; m&#233;dia de 20&#44;13<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;64&#59; mediana de 18&#44;50 &#40;varia&#231;&#227;o de &#8722;33 a 117&#41;&#46; &#40;TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>23&#59; m&#233;dia de 2&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#44;74&#59; mediana de 0 &#40;varia&#231;&#227;o de &#8722;51 a 65&#41;&#46; L&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#224; variante rs4073&#44; modelo dominante e grupo <span class="elsevierStyleItalic">RTFC&#8208;A</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;029&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;100&#41;&#46; &#40;AA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>82&#59; m&#233;dia de 15&#44;48<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;20&#59; mediana de 15 &#40;varia&#231;&#227;o de &#8722;40 a 117&#41;&#46; &#40;TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#59; m&#233;dia de 5&#44;94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;33&#59; mediana de 0 &#40;varia&#231;&#227;o de &#8722;51 a 76&#41;&#46; M&#46; Associa&#231;&#227;o do FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span> &#224; variante rs4073&#44; modelo recessivo e grupo <span class="elsevierStyleItalic">RTFC&#8208;B</span> &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;047&#59; p<span class="elsevierStyleSup">c</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;063&#41;&#46; &#40;AA&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#59; m&#233;dia de 25&#44;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#44;14&#59; mediana de 30 &#40;varia&#231;&#227;o de &#8722;21 a 57&#41;&#46; &#40;AT<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>TT&#41; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#59; 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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X&#47;P205S&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X&#47;R334 W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3120<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>A&#47;L206 W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">622&#8208;2A<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&#47;711<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">R1162X&#47;&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X&#47;I618 T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;F508del&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="22" align="left" valign="top">Pacientes com duas muta&#231;&#245;es do <span class="elsevierStyleItalic">RTFC</span> pertencentes &#224;s classes I&#44; II e&#47;ou III<br><span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>Muta&#231;&#245;es G2<br>&#40;grupo <span class="elsevierStyleItalic">CFTR&#8208;B</span>&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;G542X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;N1303 K&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;R1162X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;R553X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;1584&#8208;18672pbA<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;c&#46;1717&#8208;1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3120<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>A&#47;R1066 C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;2183AA<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;2184insA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Duplica&#231;&#227;o do &#233;xon F508del&#47;6B a 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;G85E&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;S549R &#40;T<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;S4X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X&#47;2183AA<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">G542X&#47;R1162X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">A561E&#47;A561E&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;R1066 C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">R1070Q&#59; S466X&#47;G542X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">F508del&#47;1812&#8208;1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2183AA<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&#47;2183AA<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3120<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>A&#47;3120<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">CVF&#44; capacidade vital for&#231;ada&#59; FEF<span class="elsevierStyleInf">25&#37;</span>&#44; fluxo expirat&#243;rio for&#231;ado a 25&#37; da CVF&#59; FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&#44; m&#233;dio do fluxo expirat&#243;rio for&#231;ado entre 25&#37; e 75&#37; da CVF&#59; FEF<span class="elsevierStyleInf">50&#37;</span>&#44; fluxo expirat&#243;rio for&#231;ado a 50&#37; da CVF&#59; FEF<span class="elsevierStyleInf">75&#37;</span>&#44; fluxo expirat&#243;rio for&#231;ado a 75&#37; da CVF&#59; FEF<span class="elsevierStyleInf">max</span>&#44; fluxo expirat&#243;rio for&#231;ado m&#225;ximo&#59; SaO<span class="elsevierStyleInf">2</span>&#44; satura&#231;&#227;o de oxig&#234;nio no sangue arterial&#59; VEF<span class="elsevierStyleInf">1</span>&#44; volume expirat&#243;rio for&#231;ado no 1&#176; segundo da CVF&#59; VRE&#44; volume de reserva expirat&#243;ria&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Os dados da espirometria s&#227;o mostrados em percentual de valor preditivo&#46; Todos os pacientes avaliados s&#227;o descritos&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Vari&#225;veis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Distribui&#231;&#227;o<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sexo &#40;masculino&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">92&#47;186 &#40;49&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Idade &#40;meses&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">159&#59; 38&#44;23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>114&#44;03&#59; 3 &#40;0 a 720&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Diagn&#243;stico &#40;meses&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">171&#59; 87&#44;90<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>158&#44;39&#59; 20 &#40;0 a 833&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">In&#237;cio dos sintomas digestivos &#40;meses&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">140&#59; 41&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>112&#44;61&#59; 3 &#40;0 a 720&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">In&#237;cio dos sintomas pulmonares &#40;meses&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">156&#59; 46&#44;33<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>123&#44;64&#59; 6 &#40;0 a 720&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">&#205;ndice de massa corporal</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">178&#59; 17&#44;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;08&#59; 16&#44;28 &#40;6&#44;5 a 35&#44;67&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Polipose nasal &#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28&#47;162 &#40;17&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diabetes mellitus <span class="elsevierStyleItalic">&#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&#47;164 &#40;19&#44;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Osteoporose &#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#47;162 &#40;15&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Insufici&#234;ncia pancre&#225;tica &#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">130&#47;162 &#40;80&#44;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">&#205;leo meconial &#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23&#47;162 &#40;14&#44;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">1&#170;</span> Pseudomonas aeruginosa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">121&#59; 103&#44;03<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>171&#44;74&#59; 31 &#40;0 a 872&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">P&#46; aeruginosa mucoide <span class="elsevierStyleItalic">&#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">74&#47;173 &#40;42&#44;8&#37;&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">P&#46; aeruginosa <span class="elsevierStyleItalic">n&#227;o mucoide &#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">99&#47;173 &#40;57&#44;2&#37;&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Achromobacter xylosoxidans <span class="elsevierStyleItalic">&#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#47;174 &#40;9&#44;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Burkolderia cepacia <span class="elsevierStyleItalic">&#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#47;174 &#40;14&#44;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Staphylococcus aureus <span class="elsevierStyleItalic">&#40;presen&#231;a&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">131&#47;174 &#40;75&#44;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">SaO</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">2</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">159&#59; 94&#44;87<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;28&#59; 96 &#40;66 a 99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Escore de Bhalla</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">113&#59; 8&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#44;77&#59; 8 &#40;0 a 25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Escore de Kanga</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">118&#59; 18&#44;78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#44;82&#59; 17&#44;5 &#40;10 a 40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Escore de Shwachman&#8208;Kulczycki</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">143&#59; 65&#44;97<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#44;78&#59; 65 &#40;20 a 95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">CVF</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">142&#59; 72&#44;13<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23&#44;86&#59; 77 &#40;19 a 126&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">141&#59; 60&#44;99<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>25&#44;75&#59; 63 &#40;17 a 116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">VEF</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleItalic">&#47;CVF</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">144&#59; 79&#44;08<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;99&#59; 81 &#40;39 a 113&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">FEF</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">25&#37;</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">119&#59; 61&#44;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>31&#44;71&#59; 60 &#40;7 a 138&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">FEF</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">50&#37;</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">119&#59; 46&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>31&#44;25&#59; 40 &#40;3 a 126&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">FEF</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">75&#37;</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">116&#59; 36&#44;32<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>28&#44;77&#59; 27&#44;5 &#40;4 a 142&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">FEF</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">25&#8208;75&#37;</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">140&#59; 47&#44;16<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>32&#44;51&#59; 39 &#40;5 a 150&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">FEF</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">Max</span></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">114&#59; 75&#44;54<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>25&#44;59&#59; 73&#44;5 &#40;25 a 137&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">VRE</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">112&#59; 80&#44;96<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>52&#44;39&#59; 69 &#40;3 a 248&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Resposta a broncodilatador inalat&#243;rio</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CVF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">117&#59; 1&#44;74<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#44;19&#59; 1 &#40;&#8722;17 a 32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">117&#59; 3&#44;51<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#44;0&#59; 3 &#40;&#8722;12 a 48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>VEF<span class="elsevierStyleInf">1</span>&#47;CVF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">111&#59; 2&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#44;43&#59; 2 &#40;&#8722;19 a 32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FEF<span class="elsevierStyleInf">25&#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">99&#59; 9&#44;99<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>24&#44;41&#59; 5 &#40;&#8722;45 a 110&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FEF<span class="elsevierStyleInf">50&#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">99&#59; 13&#44;08<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>26&#44;06&#59; 9 &#40;&#8722;41 a 114&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FEF<span class="elsevierStyleInf">75&#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">99&#59; 20&#44;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>46&#44;47&#59; 16 &#40;&#8722;64 a 235&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FEF<span class="elsevierStyleInf">25&#8208;75&#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">99&#59; 12&#44;28<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;77&#59; 9&#44;5 &#40;&#8722;51 a 117&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FEF<span class="elsevierStyleInf">Max</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">116&#59; 2&#44;63<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;48&#59; 3 &#40;&#8722;42 a 69&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>VRE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100&#59; 23&#44;04<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>101&#44;08&#59; 0 &#40;&#8722;90 a 670&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "notaPie" => array:3 [
            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Os dados com distribui&#231;&#227;o categ&#243;rica s&#227;o apresentados da seguinte forma&#58; n&#176; de vari&#225;veis&#47;n&#176; total &#40;percentual&#41;&#59; os dados com distribui&#231;&#227;o num&#233;rica s&#227;o apresentados da seguinte forma&#58; tamanho da amostra&#59; m&#233;dia<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>desvio padr&#227;o&#59; mediana &#40;m&#237;nimo a m&#225;ximo&#41;&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Os valores ausentes para primeira <span class="elsevierStyleItalic">P&#46; aeruginosa</span> correspondem a pacientes com fibrose c&#237;stica que nunca apresentaram cultura positiva para <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Um paciente com fibrose c&#237;stica apresentou cultura positiva para <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#44; com valores negativos para IgG espec&#237;fico do ant&#237;geno <span class="elsevierStyleItalic">P&#46; aeruginosa</span> e o paciente foi exclu&#237;do para estimativa de frequ&#234;ncia&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">An&#225;lise descritiva dos marcadores cl&#237;nicos e laboratoriais de pacientes com fibrose c&#237;stica</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Tabela 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">fa&#44; frequ&#234;ncia absoluta&#59; <span class="elsevierStyleItalic">IL&#8208;8</span>&#44; interleucina 8&#59; &#37;&#44; percentual&#59; &#967;<span class="elsevierStyleSup">2</span>&#44; qui&#8208;quadrado&#46;</p>"
          "tablatextoimagen" => array:2 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Gen&#243;tipo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N&#250;mero &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Alelo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N&#250;mero &#40;fa&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#967;<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Valor de p<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">rs4073</td><td class="td" title="table-entry  " align="left" valign="top">AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54 &#40;29&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">187 &#40;0&#44;51&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">3&#44;94</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">&#60; 0&#44;05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">79 &#40;42&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">183 &#40;0&#44;49&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52 &#40;28&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">370&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">185&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">rs2227306</td><td class="td" title="table-entry  " align="left" valign="top">CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70 &#40;38&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">211 &#40;0&#44;57&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">8&#44;21</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">&#60; 0&#44;05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">71 &#40;38&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">157 &#40;0&#44;43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;23&#44;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">368&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">184&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">rs2227307</td><td class="td" title="table-entry  " align="left" valign="top">GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31 &#40;17&#44;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">139 &#40;0&#44;39&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">1&#44;48</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;05</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">77 &#40;43&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">217 &#40;0&#44;61&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70 &#40;39&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">356&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">178&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1580260.png"
              ]
            ]
            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">rs4073&#47;rs2227306&#47;rs2227307&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequ&#234;ncia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentual &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CC GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CC GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CC TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CT GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CT GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA CT TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA TT GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA TT GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA TT TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT CC GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT CC TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT CT GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT CT TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT TT GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT TT GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT TT TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CC GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CC GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CC TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CT GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CT GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT CT TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT TT GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT TT GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT TT TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">177&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">&#967;<span class="elsevierStyleSup">2</span> e valores de p fazem refer&#234;ncia ao c&#225;lculo de equil&#237;brio de Hardy&#8208;Weinberg&#46; Os dados significativos s&#227;o mostrados em negrito&#46; Houve uma fraca correla&#231;&#227;o entre as variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> nos pacientes com fibrose c&#237;stica inscritos no estudo&#46; N&#227;o h&#225; desequil&#237;brio de liga&#231;&#227;o&#46;</p>"
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          "pt" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Distribui&#231;&#227;o de gen&#243;tipos&#44; alelos e hapl&#243;tipo das variantes do gene da <span class="elsevierStyleItalic">IL&#8208;8</span> &#40;rs4073&#44; rs2227306 e rs2227307&#41; em pacientes com fibrose c&#237;stica</p>"
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Informação do artigo

ISSN: 22555536
Idioma original: Português

DOI:10.1016/j.jpedp.2017.07.002

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2023 Julho	15	11	26
2023 Junho	13	8	21
2023 Maio	24	15	39
2023 Abril	16	4	20
2023 Mar�o	30	16	46
2023 Fevereiro	28	12	40
2023 Janeiro	20	17	37
2022 Dezembro	40	27	67
2022 Novembro	29	36	65
2022 Outubro	37	45	82
2022 Setembro	20	33	53
2022 Agosto	27	49	76
2022 Julho	25	48	73
2022 Junho	23	38	61
2022 Maio	30	39	69
2022 Abril	37	40	77
2022 Mar�o	30	41	71
2022 Fevereiro	22	33	55
2022 Janeiro	12	28	40
2021 Dezembro	13	22	35
2021 Novembro	22	16	38
2021 Outubro	13	25	38
2021 Setembro	10	11	21
2021 Agosto	5	12	17
2021 Julho	3	4	7
2021 Junho	8	11	19
2021 Maio	8	10	18
2021 Abril	15	15	30
2021 Mar�o	8	10	18
2021 Fevereiro	7	8	15
2021 Janeiro	6	5	11
2020 Dezembro	8	8	16
2020 Novembro	10	14	24
2020 Outubro	6	5	11
2020 Setembro	12	16	28
2020 Agosto	6	10	16
2020 Julho	11	12	23
2020 Junho	2	8	10
2020 Maio	8	16	24
2020 Abril	15	54	69
2020 Mar�o	4	16	20
2020 Fevereiro	8	9	17
2020 Janeiro	7	11	18
2019 Dezembro	8	6	14
2019 Novembro	12	5	17
2019 Outubro	11	20	31
2019 Setembro	9	11	20
2019 Agosto	12	15	27
2019 Julho	12	8	20
2019 Junho	4	9	13
2019 Maio	5	10	15
2019 Abril	15	8	23
2019 Mar�o	8	11	19
2019 Fevereiro	4	5	9
2019 Janeiro	5	4	9
2018 Dezembro	4	10	14
2018 Novembro	18	3	21
2018 Outubro	18	9	27
2018 Setembro	7	7	14
2018 Maio	5	1	6
2018 Abril	19	2	21
2018 Mar�o	20	4	24
2018 Fevereiro	26	4	30
2018 Janeiro	30	19	49
2017 Dezembro	249	16	265
2017 Novembro	68	19	87
2017 Outubro	6	4	10
2017 Setembro	7	0	7

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