array:23 [
  "pii" => "S1579212908600713"
  "issn" => "15792129"
  "doi" => "10.1016/S1579-2129(08)60071-3"
  "estado" => "S300"
  "fechaPublicacion" => "2008-01-01"
  "aid" => "60071"
  "copyright" => "Sociedad Española de Neumología y Cirugía Torácica (SEPAR)"
  "copyrightAnyo" => "2008"
  "documento" => "article"
  "crossmark" => 0
  "subdocumento" => "fla"
  "cita" => "Arch Bronconeumol. 2008;44:402-7"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:2 [
    "total" => 2426
    "formatos" => array:3 [
      "EPUB" => 119
      "HTML" => 1650
      "PDF" => 657
    ]
  ]
  "itemSiguiente" => array:18 [
    "pii" => "S1579212908600725"
    "issn" => "15792129"
    "doi" => "10.1016/S1579-2129(08)60072-5"
    "estado" => "S300"
    "fechaPublicacion" => "2008-01-01"
    "aid" => "60072"
    "copyright" => "Sociedad Española de Neumología y Cirugía Torácica (SEPAR)"
    "documento" => "article"
    "crossmark" => 0
    "subdocumento" => "fla"
    "cita" => "Arch Bronconeumol. 2008;44:408-12"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 3007
      "formatos" => array:3 [
        "EPUB" => 109
        "HTML" => 2174
        "PDF" => 724
      ]
    ]
    "en" => array:10 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Original Articles</span>"
      "titulo" => "Assessment of Differential Lung Function by Electrical Impedance Tomography"
      "tienePdf" => "en"
      "tieneTextoCompleto" => 0
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "408"
          "paginaFinal" => "412"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "J&#46; Bruno de Lema, Ernesto Serrano, Teresa Feixas, N&#250;ria Calaf, Mar&#237;a del Valle Camacho, Pere J&#46; Riu, Pere Casan"
          "autores" => array:7 [
            0 => array:2 [
              "nombre" => "J&#46;"
              "apellidos" => "Bruno de Lema"
            ]
            1 => array:2 [
              "nombre" => "Ernesto"
              "apellidos" => "Serrano"
            ]
            2 => array:2 [
              "nombre" => "Teresa"
              "apellidos" => "Feixas"
            ]
            3 => array:2 [
              "nombre" => "N&#250;ria"
              "apellidos" => "Calaf"
            ]
            4 => array:2 [
              "nombre" => "Mar&#237;a"
              "apellidos" => "del Valle Camacho"
            ]
            5 => array:2 [
              "nombre" => "Pere J&#46;"
              "apellidos" => "Riu"
            ]
            6 => array:2 [
              "nombre" => "Pere"
              "apellidos" => "Casan"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212908600725?idApp=UINPBA00003Z"
    "url" => "/15792129/0000004400000008/v1_201305150357/S1579212908600725/v1_201305150357/en/main.assets"
  ]
  "itemAnterior" => array:18 [
    "pii" => "S1579212908600701"
    "issn" => "15792129"
    "doi" => "10.1016/S1579-2129(08)60070-1"
    "estado" => "S300"
    "fechaPublicacion" => "2008-01-01"
    "aid" => "60070"
    "copyright" => "Sociedad Espa&#241;ola de Neumolog&#237;a y Cirug&#237;a Tor&#225;cica &#40;SEPAR&#41;"
    "documento" => "simple-article"
    "crossmark" => 0
    "subdocumento" => "edi"
    "cita" => "Arch Bronconeumol. 2008;44:399-401"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 2287
      "formatos" => array:3 [
        "EPUB" => 97
        "HTML" => 1518
        "PDF" => 672
      ]
    ]
    "en" => array:8 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>"
      "titulo" => "Chronic Obstructive Pulmonary Disease and Lung Cancer"
      "tienePdf" => "en"
      "tieneTextoCompleto" => 0
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "399"
          "paginaFinal" => "401"
        ]
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Esther Barreiro"
          "autores" => array:1 [
            0 => array:2 [
              "nombre" => "Esther"
              "apellidos" => "Barreiro"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212908600701?idApp=UINPBA00003Z"
    "url" => "/15792129/0000004400000008/v1_201305150357/S1579212908600701/v1_201305150357/en/main.assets"
  ]
  "en" => array:13 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Original Articles</span>"
    "titulo" => "Contribution of Exhaled Nitric Oxide Measurements to Abbreviated Bronchial Challenge Test Protocols"
    "tieneTextoCompleto" => 0
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "402"
        "paginaFinal" => "407"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Amparo Lloris Bayo, Miguel Perpi&#241;&#225; Tordera, Encarnaci&#243;n Mart&#237;nez P&#233;rez, Vicente Maci&#225;n Gisbert"
        "autores" => array:4 [
          0 => array:3 [
            "nombre" => "Amparo"
            "apellidos" => "Lloris Bayo"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor1"
              ]
            ]
          ]
          1 => array:2 [
            "nombre" => "Miguel"
            "apellidos" => "Perpi&#241;&#225; Tordera"
          ]
          2 => array:2 [
            "nombre" => "Encarnaci&#243;n"
            "apellidos" => "Mart&#237;nez P&#233;rez"
          ]
          3 => array:2 [
            "nombre" => "Vicente"
            "apellidos" => "Maci&#225;n Gisbert"
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:1 [
            "entidad" => "Servicio de Neumolog&#237;a&#44; Hospital Universitario La Fe&#44; Valencia&#44; Spain E-mail&#58; amparolloris&#64;yaho"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor1"
            "etiqueta" => "&#42;"
            "correspondencia" => "Correspondence&#58; Dr A&#46; Lloris Bayo Servicio de Neumolog&#237;a&#44; Hospital Universitario La Fe Avda&#46; Campanar&#44; 21 46009 Valencia&#44; Spain"
          ]
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Key words"
          "identificador" => "xpalclavsec155338"
          "palabras" => array:4 [
            0 => "Exhaled nitric oxide"
            1 => "Bronchial challenge test"
            2 => "Receiver operating characteristic &#40;ROC&#41; curves"
            3 => "Exaggerated bronchoconstriction"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec155337"
          "palabras" => array:4 [
            0 => "&#211;xido n&#237;trico exhalado"
            1 => "Prueba de provocaci&#243;n bronquial"
            2 => "Curvas de eficacia diagn&#243;stica"
            3 => "Broncoconstricci&#243;n excesiva"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:1 [
        "resumen" => "<span class="elsevierStyleSectionTitle">Objective</span><p class="elsevierStyleSimplePara elsevierViewall">The bronchial challenge test is commonly used to diagnose asthma but it is a tedious&#44; time-consuming procedure&#46; Although in recent years&#44; several shortened methods have been proposed&#44; it has been shown that they can give rise to exaggerated bronchoconstriction&#46; The aims of the present study were <span class="elsevierStyleItalic">a&#41;</span> to determine the frequency of exaggerated bronchoconstriction in patients with asthma following the application of a shortened bronchial challenge test&#44; and <span class="elsevierStyleItalic">b&#41;</span> to determine if the fraction of exhaled nitric oxide &#40;FE<span class="elsevierStyleInf">NO</span>&#41; can be used to predict the onset of exaggerated bronchoconstriction&#46;</p> <span class="elsevierStyleSectionTitle">Patients and methods</span><p class="elsevierStyleSimplePara elsevierViewall">We performed a prospective study of 210 patients with asthma in whom FE<span class="elsevierStyleInf">NO</span> levels were measured in accordance with the abbreviated protocol recommended by the European Respiratory Society &#40;ERS&#41;&#46; Exaggerated bronchoconstriction was defined as a decrease of more than 20&#37; in forced expiratory volume in 1 second after the first challenge&#44; after a skipped dose&#44; or after administration of saline&#46; A receiver operating characteristic &#40;ROC&#41; curve was generated to determine the best FE<span class="elsevierStyleInf">NO</span> cutoff value for predicting exaggerated bronchoconstriction&#46; The pretest probability of developing exaggerated bronchoconstriction was also calculated using Bayes&#39; theorem&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p class="elsevierStyleSimplePara elsevierViewall">The frequency of exaggerated bronchoconstriction in our series was 30&#37;&#46; Patients who developed exaggerated bronchoconstriction had significantly higher FE<span class="elsevierStyleInf">NO</span> levels than those who did not &#40;32&#46;6 vs 16&#46;2 parts per billion &#91;ppb&#93;&#41;&#46; The chosen FE<span class="elsevierStyleInf">NO</span> cutoff of 19&#46;5 ppb had a sensitivity of 80&#37;&#44; a specificity of 77&#37;&#44; and a negative predictive value of 88&#37;&#46; The area under the ROC curve was 0&#46;83 &#40;95&#37; confidence interval&#44; 0&#46;77&#8211;0&#46;89&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p class="elsevierStyleSimplePara elsevierViewall">The abbreviated bronchial challenge test recommended by the ERS led to exaggerated bronchoconstriction in 30&#37; of the patients studied&#46; FE<span class="elsevierStyleInf">NO</span> measurements could possibly be used to identify patients at increased risk of exaggerated bronchoconstriction&#46; The shortened challenge test can be performed safely in individuals with a FE<span class="elsevierStyleInf">NO</span> of &#60;19&#46;5 ppb&#46;</p>"
      ]
      "es" => array:1 [
        "resumen" => "<span class="elsevierStyleSectionTitle">Objetivo</span><p class="elsevierStyleSimplePara elsevierViewall">La prueba de provocaci&#243;n bronquial es un procedimiento habitual en el diagn&#243;stico del asma&#44; pero su realizaci&#243;n resulta larga y tediosa&#46; Por ello se han propuesto m&#233;todos que acortan su duraci&#243;n&#46; Sin embargo&#44; en los &#250;ltimos a&#241;os se ha se&#241;alado que dichos m&#233;todos pueden dar lugar a broncoconstricciones excesivas &#40;BE&#41;&#46; Los objetivos del presente estudio han sido&#58; a&#41; determinar la frecuencia de BE en pacientes con asma tras la aplicaci&#243;n del m&#233;todo abreviado de la prueba de provocaci&#243;n bronquial&#44; y b&#41; cuantificar si la determinaci&#243;n de &#243;xido n&#237;trico en aire exhalado &#40;ONE&#41; puede predecir la aparici&#243;n de BE&#46;</p> <span class="elsevierStyleSectionTitle">Pacientes y m&#233;todos</span><p class="elsevierStyleSimplePara elsevierViewall">Se ha realizado un estudio prospectivo sobre 210 asm&#225;ticos a quienes se determin&#243; el ONE y se realiz&#243; una prueba de provocaci&#243;n bronquial siguiendo el protocolo abreviado de la European Respiratory Society &#40;ERS&#41;&#46; Se defini&#243; BE como una ca&#237;da superior al 20&#37; del volumen espiratorio forzado en el primer segundo tras la primera dosis&#44; despu&#233;s de suprimir una dosis o tras el diluyente&#46; Se construy&#243; una curva de eficacia diagn&#243;stica para determinar el mejor punto de corte del ONE para predecir BE y se calcul&#243; la probabilidad preprueba de presentar BE&#44; siguiendo el teorema de Bayes&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p class="elsevierStyleSimplePara elsevierViewall">La frecuencia de BE en nuestra serie fue del 30&#37;&#46; Hubo diferencias significativas en el ONE&#44; siendo la concentraci&#243;n m&#225;s elevada en el grupo que present&#243; BE &#40;32&#44;6 frente a 16&#44;2 ppb&#41;&#46; El punto de corte de ONE elegido fue 19&#44;5 ppb&#44; con una sensibilidad del 80&#37;&#44; especificidad del 77&#37; y valor predictivo negativo del 88&#37;&#46; El &#225;rea bajo la curva de eficacia diagn&#243;stica fue de 0&#44;83 &#40;intervalo de confianza del 95&#37;&#44; 0&#44;77&#8211;0&#44;89&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p class="elsevierStyleSimplePara elsevierViewall">La prueba de provocaci&#243;n bronquial abreviada que recomienda la ERS da lugar a un 30&#37; de BE&#46; La determinaci&#243;n de ONE podr&#237;a identificar a los pacientes con mayor probabilidad de presentar BE&#46; Una concentraci&#243;n de ONE inferior a 19&#44;5 ppb permite realizar la prueba de provocaci&#243;n bronquial abreviada con seguridad&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:1 [
        "nota" => "<p class="elsevierStyleNotepara">This study was partly funded by a grant from the Instituto de Salud Carlos III &#40;PI05&#47;0583&#41;&#46;</p>"
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:1 [
          "bibliografiaReferencia" => array:21 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Standardization of bronchial inhalation challenge procedures"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H Chai"
                            1 => "RS Farr"
                            2 => "LA Froeligh"
                            3 => "DA Mathison"
                            4 => "JA McLean"
                            5 => "RR Rosenthal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "1975"
                        "volumen" => "56"
                        "paginaInicial" => "323"
                        "paginaFinal" => "327"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1176724"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bronchial reactivity to inhaled histamine&#58; a method and clinical survey"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "DW Cockcroft"
                            1 => "DN Killian"
                            2 => "JJA Mellon"
                            3 => "FE Hargreave"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Allergy"
                        "fecha" => "1977"
                        "volumen" => "7"
                        "paginaInicial" => "235"
                        "paginaFinal" => "243"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/908121"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Airway responsiveness&#58; standardized challenge testing with pharmacological&#44; physical and sensitizing stimuli in adults&#46; Report Working Party Standardization of Lung Function Tests&#46; European Community for Steel and Coal&#46; Official Statement of the European Respiratory Society"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "PJ Sterk"
                            1 => "LM Fabbri"
                            2 => "PH Quanjer"
                            3 => "DW Cockcroft"
                            4 => "PM O&#39;Byrne"
                            5 => "SD Anderson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "1993"
                        "volumen" => "16"
                        "paginaInicial" => "53"
                        "paginaFinal" => "83"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "EF Juniper"
                            1 => "DW Cockcroft"
                            2 => "FE Hargreave"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:5 [
                        "edicion" => "2nd ed&#46;"
                        "titulo" => "Histamine and methacholine inhalation tests&#58; tidal breathing method-laboratory procedure and standardization"
                        "fecha" => "1994"
                        "editorial" => "AB Draco"
                        "editorialLocalizacion" => "Lund"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methacholine challenge testing&#58; safety of low starting FEV1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "RJ Martin"
                            1 => "JS Wanger"
                            2 => "CG Irvin"
                            3 => "BB Bartelson"
                            4 => "RM Cherniak"
                            5 => "the Asthma Clinical Research Network &#40;ACRN&#41;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "1997"
                        "volumen" => "112"
                        "paginaInicial" => "53"
                        "paginaFinal" => "56"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9228357"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A survey of the current use and methods of analysis of bronchoprovocational challenges"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "GC Scott"
                            1 => "SR Braun"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "1991"
                        "volumen" => "100"
                        "paginaInicial" => "322"
                        "paginaFinal" => "328"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1864101"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Use and safety of a shortened histamine challenge test in an occupational study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "AM Kremer"
                            1 => "TM Pal"
                            2 => "M Oldenziel"
                            3 => "M Kerkof"
                            4 => "JGR De Monchy"
                            5 => "B Rijken"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "1995"
                        "volumen" => "8"
                        "paginaInicial" => "737"
                        "paginaFinal" => "741"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7656944"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Frequency and determinants of exaggerated bronchoconstriction during shortened methacholine challenge tests in epidemiological and clinical set-ups"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "S Troyanov"
                            1 => "JL Malo"
                            2 => "A Cartier"
                            3 => "D Gautrin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2000"
                        "volumen" => "16"
                        "paginaInicial" => "9"
                        "paginaFinal" => "14"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10933078"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methacholine inhalation challenge&#58; a shorter&#44; cheaper and safe approach"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "G Izbicki"
                            1 => "E Bar-Yishay"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2001"
                        "volumen" => "17"
                        "paginaInicial" => "46"
                        "paginaFinal" => "51"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11307754"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Guidelines for methacholine and exercise challenge testing-1999"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "American Thoracic Society"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.161.1.ats11-99"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2000"
                        "volumen" => "161"
                        "paginaInicial" => "309"
                        "paginaFinal" => "329"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10619836"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Airway hyperresponsiveness"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "PM O&#39;Byrne"
                            1 => "MD Inman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2003"
                        "volumen" => "123"
                        "paginaInicial" => "411S"
                        "paginaFinal" => "416S"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12629006"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Exhaled nitric oxide in asthma&#58; from bench to bedside"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "CA Bates"
                            1 => "PE Silkoff"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2003"
                        "volumen" => "111"
                        "paginaInicial" => "256"
                        "paginaFinal" => "262"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12589342"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "titulo" => "ATS&#47;ERS Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide&#44; 2005"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.200406-710ST"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2005"
                        "volumen" => "171"
                        "paginaInicial" => "912"
                        "paginaFinal" => "930"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15817806"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Las curvas ROC en la evaluaci&#243;n de las pruebas diagn&#243;sticas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "MJ Burge&#241;o"
                            1 => "JL Garc&#237;a Bastos"
                            2 => "JM Gonz&#225;lez Buitrago"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Med Clin &#40;Barc&#41;"
                        "fecha" => "1995"
                        "volumen" => "104"
                        "paginaInicial" => "661"
                        "paginaFinal" => "670"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gu&#237;a espa&#241;ola para el manejo del asma &#40;GEMA&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V Plaza Moral"
                            1 => "FJ &#193;lvarez Guti&#233;rrez"
                            2 => "P Cas&#225;n Clar&#224;"
                            3 => "N Cobos Barroso"
                            4 => "A L&#243;pez Vi&#241;a"
                            5 => "MA Llauger Rossell&#243;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2003"
                        "volumen" => "39"
                        "numero" => "Supl 5"
                        "paginaInicial" => "3"
                        "paginaFinal" => "42"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Methacholine challenge&#58; test-shortening procedures"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "DW Cockcroft"
                            1 => "DD Marciniuk"
                            2 => "TS Hurst"
                            3 => "DJ Cotton"
                            4 => "KF Laframboise"
                            5 => "BD McNab"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2001"
                        "volumen" => "120"
                        "paginaInicial" => "1857"
                        "paginaFinal" => "1860"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11742913"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Correlation between exhaled nitric oxide&#44; sputum eosinophils&#44; and methacholine responsiveness in patients with mild asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A Jatakanon"
                            1 => "S Lim"
                            2 => "SA Kharitonov"
                            3 => "KF Chung"
                            4 => "PJ Barnes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Thorax"
                        "fecha" => "1998"
                        "volumen" => "53"
                        "paginaInicial" => "91"
                        "paginaFinal" => "95"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9624291"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Combined use of exhaled nitric oxide and airway hyperresponsiveness in characterizing asthma in a large population study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "AH Henriksen"
                            1 => "T Lingaas Holmen"
                            2 => "M Sue Chu"
                            3 => "L Bjermer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2002"
                        "volumen" => "15"
                        "paginaInicial" => "849"
                        "paginaFinal" => "855"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10853848"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Exhaled nitric oxide measurements&#58; clinical application and interpretation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "DR Taylor"
                            1 => "MW Pijnenburg"
                            2 => "AD Smith"
                            3 => "JC De Jongste"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/thx.2005.056093"
                      "Revista" => array:6 [
                        "tituloSerie" => "Thorax"
                        "fecha" => "2006"
                        "volumen" => "61"
                        "paginaInicial" => "817"
                        "paginaFinal" => "827"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16936238"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hiperrespuesta bronquial en el asma&#46; Patogenia y medici&#243;n"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M Perpi&#241;&#225; Tordera"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2004"
                        "volumen" => "40"
                        "numero" => "Supl 5"
                        "paginaInicial" => "8"
                        "paginaFinal" => "13"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16137451"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Asthma&#58; defining of the persistent adult phenotypes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "SE Wenzel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(06)69290-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2006"
                        "volumen" => "368"
                        "paginaInicial" => "804"
                        "paginaFinal" => "813"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16935691"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/15792129/0000004400000008/v1_201305150357/S1579212908600713/v1_201305150357/en/main.assets"
  "Apartado" => null
  "PDF" => "https://static.elsevier.es/multimedia/15792129/0000004400000008/v1_201305150357/S1579212908600713/v1_201305150357/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212908600713?idApp=UINPBA00003Z"
]
Share
Journal Information
Vol. 44. Issue 8.
Pages 402-407 (January 2008)
Share
Share
Download PDF
More article options
Vol. 44. Issue 8.
Pages 402-407 (January 2008)
Original Articles
Full text access
Contribution of Exhaled Nitric Oxide Measurements to Abbreviated Bronchial Challenge Test Protocols
Visits
4408
Amparo Lloris Bayo*, Miguel Perpiñá Tordera, Encarnación Martínez Pérez, Vicente Macián Gisbert
Servicio de Neumología, Hospital Universitario La Fe, Valencia, Spain E-mail: amparolloris@yaho
This item has received
Article information
Objective

The bronchial challenge test is commonly used to diagnose asthma but it is a tedious, time-consuming procedure. Although in recent years, several shortened methods have been proposed, it has been shown that they can give rise to exaggerated bronchoconstriction. The aims of the present study were a) to determine the frequency of exaggerated bronchoconstriction in patients with asthma following the application of a shortened bronchial challenge test, and b) to determine if the fraction of exhaled nitric oxide (FENO) can be used to predict the onset of exaggerated bronchoconstriction.

Patients and methods

We performed a prospective study of 210 patients with asthma in whom FENO levels were measured in accordance with the abbreviated protocol recommended by the European Respiratory Society (ERS). Exaggerated bronchoconstriction was defined as a decrease of more than 20% in forced expiratory volume in 1 second after the first challenge, after a skipped dose, or after administration of saline. A receiver operating characteristic (ROC) curve was generated to determine the best FENO cutoff value for predicting exaggerated bronchoconstriction. The pretest probability of developing exaggerated bronchoconstriction was also calculated using Bayes' theorem.

Results

The frequency of exaggerated bronchoconstriction in our series was 30%. Patients who developed exaggerated bronchoconstriction had significantly higher FENO levels than those who did not (32.6 vs 16.2 parts per billion [ppb]). The chosen FENO cutoff of 19.5 ppb had a sensitivity of 80%, a specificity of 77%, and a negative predictive value of 88%. The area under the ROC curve was 0.83 (95% confidence interval, 0.77–0.89).

Conclusions

The abbreviated bronchial challenge test recommended by the ERS led to exaggerated bronchoconstriction in 30% of the patients studied. FENO measurements could possibly be used to identify patients at increased risk of exaggerated bronchoconstriction. The shortened challenge test can be performed safely in individuals with a FENO of <19.5 ppb.

Key words:
Exhaled nitric oxide
Bronchial challenge test
Receiver operating characteristic (ROC) curves
Exaggerated bronchoconstriction
Objetivo

La prueba de provocación bronquial es un procedimiento habitual en el diagnóstico del asma, pero su realización resulta larga y tediosa. Por ello se han propuesto métodos que acortan su duración. Sin embargo, en los últimos años se ha señalado que dichos métodos pueden dar lugar a broncoconstricciones excesivas (BE). Los objetivos del presente estudio han sido: a) determinar la frecuencia de BE en pacientes con asma tras la aplicación del método abreviado de la prueba de provocación bronquial, y b) cuantificar si la determinación de óxido nítrico en aire exhalado (ONE) puede predecir la aparición de BE.

Pacientes y métodos

Se ha realizado un estudio prospectivo sobre 210 asmáticos a quienes se determinó el ONE y se realizó una prueba de provocación bronquial siguiendo el protocolo abreviado de la European Respiratory Society (ERS). Se definió BE como una caída superior al 20% del volumen espiratorio forzado en el primer segundo tras la primera dosis, después de suprimir una dosis o tras el diluyente. Se construyó una curva de eficacia diagnóstica para determinar el mejor punto de corte del ONE para predecir BE y se calculó la probabilidad preprueba de presentar BE, siguiendo el teorema de Bayes.

Resultados

La frecuencia de BE en nuestra serie fue del 30%. Hubo diferencias significativas en el ONE, siendo la concentración más elevada en el grupo que presentó BE (32,6 frente a 16,2 ppb). El punto de corte de ONE elegido fue 19,5 ppb, con una sensibilidad del 80%, especificidad del 77% y valor predictivo negativo del 88%. El área bajo la curva de eficacia diagnóstica fue de 0,83 (intervalo de confianza del 95%, 0,77–0,89).

Conclusiones

La prueba de provocación bronquial abreviada que recomienda la ERS da lugar a un 30% de BE. La determinación de ONE podría identificar a los pacientes con mayor probabilidad de presentar BE. Una concentración de ONE inferior a 19,5 ppb permite realizar la prueba de provocación bronquial abreviada con seguridad.

Palabras clave:
Óxido nítrico exhalado
Prueba de provocación bronquial
Curvas de eficacia diagnóstica
Broncoconstricción excesiva
Full text is only aviable in PDF
References
[1]
H Chai, RS Farr, LA Froeligh, DA Mathison, JA McLean, RR Rosenthal, et al.
Standardization of bronchial inhalation challenge procedures.
J Allergy Clin Immunol, 56 (1975), pp. 323-327
[2]
DW Cockcroft, DN Killian, JJA Mellon, FE Hargreave.
Bronchial reactivity to inhaled histamine: a method and clinical survey.
Clin Allergy, 7 (1977), pp. 235-243
[3]
PJ Sterk, LM Fabbri, PH Quanjer, DW Cockcroft, PM O'Byrne, SD Anderson, et al.
Airway responsiveness: standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report Working Party Standardization of Lung Function Tests. European Community for Steel and Coal. Official Statement of the European Respiratory Society.
Eur Respir J, 16 (1993), pp. 53-83
[4]
EF Juniper, DW Cockcroft, FE Hargreave.
Histamine and methacholine inhalation tests: tidal breathing method-laboratory procedure and standardization, 2nd ed., AB Draco, (1994),
[5]
RJ Martin, JS Wanger, CG Irvin, BB Bartelson, RM Cherniak, the Asthma Clinical Research Network (ACRN).
Methacholine challenge testing: safety of low starting FEV1.
Chest, 112 (1997), pp. 53-56
[6]
GC Scott, SR Braun.
A survey of the current use and methods of analysis of bronchoprovocational challenges.
Chest, 100 (1991), pp. 322-328
[7]
AM Kremer, TM Pal, M Oldenziel, M Kerkof, JGR De Monchy, B Rijken.
Use and safety of a shortened histamine challenge test in an occupational study.
Eur Respir J, 8 (1995), pp. 737-741
[8]
S Troyanov, JL Malo, A Cartier, D Gautrin.
Frequency and determinants of exaggerated bronchoconstriction during shortened methacholine challenge tests in epidemiological and clinical set-ups.
Eur Respir J, 16 (2000), pp. 9-14
[9]
G Izbicki, E Bar-Yishay.
Methacholine inhalation challenge: a shorter, cheaper and safe approach.
Eur Respir J, 17 (2001), pp. 46-51
[10]
American Thoracic Society.
Guidelines for methacholine and exercise challenge testing-1999.
Am J Respir Crit Care Med, 161 (2000), pp. 309-329
[11]
PM O'Byrne, MD Inman.
Airway hyperresponsiveness.
Chest, 123 (2003), pp. 411S-416S
[12]
CA Bates, PE Silkoff.
Exhaled nitric oxide in asthma: from bench to bedside.
J Allergy Clin Immunol, 111 (2003), pp. 256-262
[13]
ATS/ERS Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.
Am J Respir Crit Care Med, 171 (2005), pp. 912-930
[14]
MJ Burgeño, JL García Bastos, JM González Buitrago.
Las curvas ROC en la evaluación de las pruebas diagnósticas.
Med Clin (Barc), 104 (1995), pp. 661-670
[15]
V Plaza Moral, FJ Álvarez Gutiérrez, P Casán Clarà, N Cobos Barroso, A López Viña, MA Llauger Rosselló, et al.
Guía española para el manejo del asma (GEMA).
Arch Bronconeumol, 39 (2003), pp. 3-42
[16]
DW Cockcroft, DD Marciniuk, TS Hurst, DJ Cotton, KF Laframboise, BD McNab, et al.
Methacholine challenge: test-shortening procedures.
Chest, 120 (2001), pp. 1857-1860
[17]
A Jatakanon, S Lim, SA Kharitonov, KF Chung, PJ Barnes.
Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma.
Thorax, 53 (1998), pp. 91-95
[18]
AH Henriksen, T Lingaas Holmen, M Sue Chu, L Bjermer.
Combined use of exhaled nitric oxide and airway hyperresponsiveness in characterizing asthma in a large population study.
Eur Respir J, 15 (2002), pp. 849-855
[19]
DR Taylor, MW Pijnenburg, AD Smith, JC De Jongste.
Exhaled nitric oxide measurements: clinical application and interpretation.
Thorax, 61 (2006), pp. 817-827
[20]
M Perpiñá Tordera.
Hiperrespuesta bronquial en el asma. Patogenia y medición.
Arch Bronconeumol, 40 (2004), pp. 8-13
[21]
SE Wenzel.
Asthma: defining of the persistent adult phenotypes.

This study was partly funded by a grant from the Instituto de Salud Carlos III (PI05/0583).

Copyright © 2008. Sociedad Española de Neumología y Cirugía Torácica (SEPAR)
Archivos de Bronconeumología
Article options
Tools

Are you a health professional able to prescribe or dispense drugs?