array:23 [ "pii" => "S2173579423001500" "issn" => "21735794" "doi" => "10.1016/j.oftale.2023.09.002" "estado" => "S300" "fechaPublicacion" => "2023-11-01" "aid" => "2156" "copyright" => "Sociedad Española de Oftalmología" "copyrightAnyo" => "2023" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Arch Soc Esp Oftalmol. 2023;98:627-32" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S2173579423001512" "issn" => "21735794" "doi" => "10.1016/j.oftale.2023.07.007" "estado" => "S300" "fechaPublicacion" => "2023-11-01" "aid" => "2157" "copyright" => "Sociedad Española de Oftalmología" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Arch Soc Esp Oftalmol. 2023;98:633-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Comparative analysis of the quality of life among different retinal diseases" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "633" "paginaFinal" => "639" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Análisis comparativo de la calidad de vida en diferentes patologías de la retina" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 494 "Ancho" => 2917 "Tamanyo" => 165525 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Results of each domain of the NEI VFQ-25 survey of the different retinal diseases studied.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">DME: diabetic macular edema; RVO: retinal vein occlusion; PM: pathologic myopia; nAMD: neovascular age-related macular degeneration; CSC: central serous chorioretinopathy; BEVA: best eye visual acuity; WEVA: worst eye visual acuity in letters in the Early Treatment Diabetic Retinopathy Scale (ETDRS).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J.I. Fernández-Vigo, D. Blanco-Darriba, H. Etxabe-Avila, E. Montolío-Marzo, P. Robles-Amor, M.J. Escobar-Moreno, B. Burgos-Blasco" "autores" => array:7 [ 0 => array:2 [ "nombre" => "J.I." "apellidos" => "Fernández-Vigo" ] 1 => array:2 [ "nombre" => "D." "apellidos" => "Blanco-Darriba" ] 2 => array:2 [ "nombre" => "H." "apellidos" => "Etxabe-Avila" ] 3 => array:2 [ "nombre" => "E." "apellidos" => "Montolío-Marzo" ] 4 => array:2 [ "nombre" => "P." "apellidos" => "Robles-Amor" ] 5 => array:2 [ "nombre" => "M.J." "apellidos" => "Escobar-Moreno" ] 6 => array:2 [ "nombre" => "B." "apellidos" => "Burgos-Blasco" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0365669123001715" "doi" => "10.1016/j.oftal.2023.07.015" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0365669123001715?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173579423001512?idApp=UINPBA00004N" "url" => "/21735794/0000009800000011/v3_202311101354/S2173579423001512/v3_202311101354/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2173579423001421" "issn" => "21735794" "doi" => "10.1016/j.oftale.2023.08.009" "estado" => "S300" "fechaPublicacion" => "2023-11-01" "aid" => "2152" "copyright" => "Sociedad Española de Oftalmología" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Arch Soc Esp Oftalmol. 2023;98:619-26" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Cost-utility model of new intravitreous units vs. current patient journey model in Spain" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "619" "paginaFinal" => "626" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Análisis coste-utilidad del modelo de unidad de terapia intravítrea (UTI) frente a la administración tradicional de terapia intravítrea" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2628 "Ancho" => 3175 "Tamanyo" => 353832 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Tornado diagram of the univariate sensitivity analysis.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C. Martín-Saborido, J. Zarranz-Ventura, J.J. Escobar-Barranco, G. Garay-Aramburu, A. García-Layana, J. Donate-López, C. Blanch, M. Abraldes" "autores" => array:9 [ 0 => array:2 [ "nombre" => "C." "apellidos" => "Martín-Saborido" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Zarranz-Ventura" ] 2 => array:2 [ "nombre" => "J.J." "apellidos" => "Escobar-Barranco" ] 3 => array:2 [ "nombre" => "G." "apellidos" => "Garay-Aramburu" ] 4 => array:2 [ "nombre" => "A." "apellidos" => "García-Layana" ] 5 => array:2 [ "nombre" => "J." "apellidos" => "Donate-López" ] 6 => array:2 [ "nombre" => "C." "apellidos" => "Blanch" ] 7 => array:2 [ "nombre" => "M." "apellidos" => "Abraldes" ] 8 => array:1 [ "colaborador" => "on behalf of the UTI group" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0365669123001600" "doi" => "10.1016/j.oftal.2023.08.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0365669123001600?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173579423001421?idApp=UINPBA00004N" "url" => "/21735794/0000009800000011/v3_202311101354/S2173579423001421/v3_202311101354/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "A fluorophotometric comparison of anterior chamber riboflavin delivery via corneal application and fornix instillation" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "627" "paginaFinal" => "632" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "K.C. Iselin, L.M. Bachmann, M.A. Thiel, F. Sanak, P.B. Baenninger, C. Kaufmann" "autores" => array:6 [ 0 => array:3 [ "nombre" => "K.C." "apellidos" => "Iselin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "L.M." "apellidos" => "Bachmann" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M.A." "apellidos" => "Thiel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "F." "apellidos" => "Sanak" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "P.B." "apellidos" => "Baenninger" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:4 [ "nombre" => "C." "apellidos" => "Kaufmann" "email" => array:1 [ 0 => "claude.kaufmann@luks.ch" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Departamento de Oftalmología, Hospital Cantonal de Lucerna, Lucerna, Switzerland" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Medignition, Zurich, Switzerland" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Comparación fluorofotométrica de la administración de riboflavina en la cámara anterior mediante aplicación corneal e instilación en el fórnix" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1297 "Ancho" => 2091 "Tamanyo" => 144463 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0170" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Fluorophotometric scans after riboflavin application to the cornea (top row) and into the fornix (bottom row) at baseline (A, C) and after 15<span class="elsevierStyleHsp" style=""></span>min (B, D), demonstrating the increasing fluorescence signal of the corneal peak and of the anterior chamber plateau.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Corneal cross-linking (CXL) requires considerable personnel and space resources solely through the riboflavin impregnation of the cornea.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In his landmark paper on safety aspects of CXL, Spoerl states that riboflavin drops have to be repeatedly instilled onto the cornea during a period of at least 30<span class="elsevierStyleHsp" style=""></span>min or until a riboflavin flare can be detected in the anterior chamber.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Delegating this time-consuming application to patients would therefore represent a considerable gain in efficiency.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Nonetheless, several aspects need be considered before this treatment step can be handed over to patients, including the modified application route. While medical personnel apply the riboflavin drops directly to the cornea, the current standard recommendations for the self-application of eye drops specify the lower fornix as the site of administration.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> However, the extent and dynamics of corneal riboflavin impregnation after drop application into the inferior fornix are not known.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Fluorophotometry is a suitable tool for answering this question. It represents an established non-contact method for studying the pharmacokinetics of fluorescent molecules in the anterior sections of the eye.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> It also appears to be a viable method to study riboflavin concentrations on human corneas in simulated CXL treatments <span class="elsevierStyleItalic">in vitro</span>.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">With the long-term goal of riboflavin self-application in transepithelial CXL, we therefore set out to investigate whether riboflavin application in the fornix is non-inferior to direct application to the cornea itself with regard to the resulting fluorophotometric anterior chamber riboflavin concentrations.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Material and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">In a prospective single centre trial on healthy volunteers, riboflavin concentrations in the anterior chamber were compared between two drop application sites: cornea and fornix. The study was confined to the measurement of riboflavin concentrations and no actual CXL was performed. The study protocol was approved by the Ethics Committee Northwest and Central Switzerland (ID: 2019-01655) and all participants provided informed consent.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Regarding the power calculation of this non-inferiority study, we assumed that riboflavin would be detected in the anterior chamber (as an indirect sign for sufficient corneal riboflavin impregnation) in all subjects receiving riboflavin eye drops on the cornea. We considered it acceptable if at least 78% percent of subjects receiving riboflavin into the fornix would have riboflavin detected in the anterior chamber. The 78% represented the lower boundary of the binomial exact 90% confidence interval at 60<span class="elsevierStyleHsp" style=""></span>min. Conversely, we defined the non-inferiority margin to be 22%. When accepting a one-sided alpha error of five percent, the total number of participants for each of the two sites at 60<span class="elsevierStyleHsp" style=""></span>min would be 12. For practical reasons we decided to enrol 18 subjects for the measurements at 30<span class="elsevierStyleHsp" style=""></span>min to ensure that at least 12 subjects would be available for the measurements performed at 60<span class="elsevierStyleHsp" style=""></span>min of riboflavin exposure.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Clinical staff members of our eye clinic with unremarkable slit lamp findings, full visual acuity and normal intraocular pressure were offered to participate. Each volunteer selected one of his or her eyes as the study eye, which was measured throughout the observation period. Exclusion criteria included epilepsy (owing to the flickering light of the fluorophotometer), corneal opacities (to avoid optical scattering phenomena), or any ocular disease or current ocular medication. In the order of recruitment, volunteers were assigned to one of the two groups (corneal application or fornical application) and a measurement duration (30 or 60<span class="elsevierStyleHsp" style=""></span>min) was suggested. However, depending on personal preferences or time constraints, they could choose different sites or times if desired. Recruitment was terminated when both groups included 18 eyes of 18 volunteers, of which 6 eyes were measured during 30<span class="elsevierStyleHsp" style=""></span>min and 12 eyes during 60<span class="elsevierStyleHsp" style=""></span>min, respectively.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Fluorescence measurements were performed following the manufacturer's instructions with a Fluorotron<span class="elsevierStyleSup">TM</span> Master FM-2 fluorophotometer (OcuMetrics Inc., Mountain View, CA) equipped with an anterior segment adapter (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The apparatus is fitted with an optical illuminating path in the range of 420−490<span class="elsevierStyleHsp" style=""></span>nm and an optical pick-up path in the range of 530−630<span class="elsevierStyleHsp" style=""></span>nm, which jointly scan individual points along the visual axis of the eye. The photon counts at each point are then converted into a concentration of fluorescence in ng/mL, thereby creating a riboflavin concentration profile across cornea and anterior chamber.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">All participants were treated with the Peschke®TE riboflavin formulation (Peschke Trade GmbH, Huenenberg, Switzerland), which is designed for transepithelial CXL and contains 0.25% riboflavin, hypromellose, benzalkonium chloride, disodium hydrogenphosphate, sodium dihydrogenphosphate, sodium chloride and water for injection.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Fluorescence measurements were taken at baseline and 5, 15, 30<span class="elsevierStyleHsp" style=""></span>min on all volunteers (and 45 & 60<span class="elsevierStyleHsp" style=""></span>min in those followed for 60<span class="elsevierStyleHsp" style=""></span>min) during application of a single drop of riboflavin every two minutes by the principal investigator using a Lasik drain but without specula or silicone rings. Evaluation included anterior chamber and corneal riboflavin concentrations (averaged from triplicates), plus anterior segment slit lamp evaluation.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Summaries of continuous variables are given as means<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD. Riboflavin concentrations were compared between groups using non-parametric methods. Exploratory analyses examined the relationship between riboflavin exposure duration and anterior chamber concentrations at different times, using Stata 16.0 (StataCorp, College Station, TX).</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0060" class="elsevierStylePara elsevierViewall">A total of 36 eyes from 36 participants were enrolled (18 in the cornea group, 18 in the fornix group); one candidate was excluded due to corneal scars and replaced. Mean age was 36.3 years (SD 10.3) and 31.8 years (SD 7.0), respectively (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.140); gender ratio of women:men was 10:8 and 12:6, respectively (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.494). The number of data provided by the participants at different points in time was as follows: <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>18 for measurements up to 30<span class="elsevierStyleHsp" style=""></span>min, and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>12 for measurements after 45 and 60<span class="elsevierStyleHsp" style=""></span>min; this applied to both application sites.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The temporal pattern of the measured riboflavin concentrations is presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. At baseline, there were no significant differences between groups for autofluorescence measured in anterior chamber and cornea: anterior chamber values were 16.7<span class="elsevierStyleHsp" style=""></span>ng/mL (SD 5.5) and 14.6<span class="elsevierStyleHsp" style=""></span>ng/mL (SD 4.6) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.221), corneal values were 138.8<span class="elsevierStyleHsp" style=""></span>ng/mL (SD 25.8) and 141.3<span class="elsevierStyleHsp" style=""></span>ng/mL (SD 29.1) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.786). After initiating drop application, both groups experienced a marked surge at the initial post-treatment measurement taken after five minutes (for an example see <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The anterior chamber concentrations were slightly higher in the cornea application group, although not significantly different except at 60<span class="elsevierStyleHsp" style=""></span>min. Since the measurements after 60<span class="elsevierStyleHsp" style=""></span>min also showed the highest standard deviations, this could represent a statistical outlier. After 60<span class="elsevierStyleHsp" style=""></span>min, the slit lamp examination in the cornea group showed two cases of severe stippling with correspondingly unrealistically high readings due to corneal stray phenomena. The two cases were therefore excluded from the analysis. Fluorophotometric signals of the cornea showed an even sharper increase regardless of site and plateaued after 15<span class="elsevierStyleHsp" style=""></span>min at around 75 times baseline without significant variation between groups.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0070" class="elsevierStylePara elsevierViewall">This study shows that riboflavin application in the fornix is non-inferior to direct application to the cornea itself with regard to the resulting fluorophotometric anterior chamber riboflavin concentrations. This was evidenced by the lack of statistical difference in riboflavin concentrations measured in the anterior chamber between the two groups over the course of observation (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Differences between the two application sites were conceivable assuming that corneally applied drops penetrate mainly via the corneal route and fornically applied drops mainly via the conjunctival/scleral route.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> For hydrophilic molecules such as riboflavin (octanol-water partition coefficient <span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf">OW</span> of −1.46), the epithelia represent the most critical barriers,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> since the available pathways are restricted to the water-filled paracellular pores.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> With a molecular weight of 376<span class="elsevierStyleHsp" style=""></span>Da and a molecular radius of about 4<span class="elsevierStyleHsp" style=""></span>Å, riboflavin is just small enough to pass through the tight junctions of the corneal epithelium (upper limits: about 500<span class="elsevierStyleHsp" style=""></span>Da or 5.5<span class="elsevierStyleHsp" style=""></span>Å)<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> but finds less resistance in the conjunctival epithelium due to the wider intercellular pores.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The downstream sclera is even more permeable for hydrophilic molecules than the conjunctiva,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> so that under physiological conditions riboflavin finds higher transmissivity via the conjunctival/scleral route than the corneal route.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Conversely, there are sufficient parallels between the application sites such that the comparable riboflavin concentrations appear plausible. First, the epithelial permeability of the cornea could have been brought into line with the conjunctival permeability by the benzalkonium chloride contained in the riboflavin formulation,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> which loosens tight junctions. Second, further similarities between the two application routes include identical clearance mechanisms (blinking, wash out by tears, nasolacrimal drainage)<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and an identical first barrier to be overcome by the riboflavin molecules, the three-layer tear film.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Recent methods for the investigation of riboflavin impregnation of the human corneal stroma include techniques such as high-performance liquid chromatography,<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> modified RGB cameras,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and two-photon microscopy.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17,18</span></a> While analytical chemical methods are naturally associated with the destruction of the substance under investigation, the optical methods mentioned above have the disadvantage, at least for the time being, that they are not yet suitable for clinical use. In contrast, the Fluorotron™ Master used for the present study had previously been employed for fluorophotometric analyses <span class="elsevierStyleItalic">in vivo</span>: Using a similar setting with healthy volunteers, Dinslage and colleagues compared the corneal and anterior chamber concentrations of two different, topically applied fluorescein formulations.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The limitation of one drop may be one of the reasons why the maximum concentrations observed were ten times lower than those obtained in the present study, where riboflavin was replenished continually. Two conference abstracts described fluorophotometric analyses conducted on CXL patients, yet without quantitative data on riboflavin concentrations.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,21</span></a> In contrast, Iselin et al. simulated riboflavin impregnation of human corneas in an <span class="elsevierStyleItalic">ex vivo</span> model and found concentrations to be four to twenty times higher than the present study.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This discrepancy may be attributed to the use of de-epithelialized, oedematous corneas.</p><p id="par0085" class="elsevierStylePara elsevierViewall">This study extended the use of fluorophotometry to measure riboflavin concentrations in healthy individuals, leading to a clear answer for the initial question. However, it is important to note that there are some limitations. First, we studied the fluorescence signals without considering errors in detail. Fluorophotometry is prone to instrument errors, which can amplify or reduce each other at high concentrations. Absorption and quenching reduce the signal, while reflection and scattering increase it.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Adherent to our clinical protocol, one drop of riboflavin every two min was applied without a wash off before measurements. Thus, the fluorescence signal of the cornea reflects not only stromal riboflavin impregnation but is also likely affected by reflection from the precorneal riboflavin film and epithelial staining. Reassuringly, the concentration derived from the corneal signal was similar to those measured in two independent analytical chemistry studies which simulated transepithelial riboflavin impregnation on human corneas <span class="elsevierStyleItalic">in vitro</span> using high-performance liquid chromatography.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> Second, due to device design, fluorescence measurement is restricted to the visual axis, precluding statements about locally varying corneal riboflavin concentrations. This restriction to the visual axis could also explain why the concentration of riboflavin molecules penetrating via the inferior fornical route was only just not statistically significantly different from the concentration of molecules penetrating via the central corneal route after the initial 5<span class="elsevierStyleHsp" style=""></span>min (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><p id="par0090" class="elsevierStylePara elsevierViewall">Third, allocation of participants took place without randomization in a strict sense. However, comparability between groups was ensured by excluding potential influencing characteristics and including only unremarkable eyes. Both groups went through an identical data collection protocol with digital output which prevented observer bias.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Following the present work on application routes, further studies with suitable patients can now be conducted towards to the clinically relevant long-term goal of riboflavin self-administration. Since progressive keratectasia typically occurs in young adulthood, patients are likely to have the necessary cognitive and manual abilities to comprehend instructions and carry out drop self-application. Options to further increase corneal riboflavin impregnation in this setting include using a scleral contact lens filled with riboflavin or inserting a Merocel sponge into the lower fornix, which expands the riboflavin reservoir and causes microabrasion of the corneal epithelium when blinking.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,23</span></a> To further investigate the effect of potential sources of error in fluorophotometry, a comparison of the fluorophotometrically determined concentration values with those measured using an analytical reference method from anterior chamber aspirates would enable the derivation of correction factors and a more precise assessment of intracameral riboflavin concentration.</p><p id="par0100" class="elsevierStylePara elsevierViewall">The implication of the present work for current clinical practice concerns the riboflavin application time. The recommendation of Spoerl that riboflavin should be applied for 30<span class="elsevierStyleHsp" style=""></span>min or even longer in the absence of detectable riboflavin in the anterior chamber,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> can be weakened in the sense that a 30-minute application is sufficient. Our data suggest that extending the application time to 45 or 60<span class="elsevierStyleHsp" style=""></span>min does not result in higher riboflavin concentrations and thus provides no additional benefit.</p><p id="par0105" class="elsevierStylePara elsevierViewall">In conclusion, this study found that applying riboflavin drops in the inferior fornix was non-inferior to applying it directly to the cornea, based on fluorophotometric measurements of the resulting anterior chamber riboflavin concentrations. This indicates that self-application of riboflavin is feasible in terms of corneal riboflavin impregnation and that CXL treatments could possibly be carried out in a less personnel-intensive manner.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Funding</span><p id="par0110" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres2008249" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1720619" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2008248" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] 4 => array:2 [ "identificador" => "abst0045" "titulo" => "Clinical trial register number" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1720620" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-02-20" "fechaAceptado" => "2023-08-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1720619" "palabras" => array:4 [ 0 => "Cross-linking" 1 => "Riboflavin" 2 => "Fluorophotometry" 3 => "Fluorotron™ Master" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1720620" "palabras" => array:4 [ 0 => "Cross-linking" 1 => "Riboflavina" 2 => "Fluorofotometría" 3 => "Fluorotron™ Master" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">We investigated whether riboflavin self-administration by patients could be a feasible option for corneal cross-linking, given the considerable resources required to impregnate the cornea with riboflavin. We analysed whether administering riboflavin in the inferior fornix (the site of self-administration) results in non-inferior riboflavin concentrations as when applied directly on the cornea (the site of administration by medical personnel).</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">We conducted a prospective study to evaluate riboflavin concentrations at six time-points (baseline, 5, 15, 30, 45 and 60<span class="elsevierStyleHsp" style=""></span>min) in 18 healthy volunteers for each of two application sites: cornea and fornix. Anterior chamber riboflavin (Peschke® TE 0.25%) concentrations were measured by fluorophotometry (Fluorotron™ Master FM-2).</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">For the two application sites cornea and fornix, participants did not differ in terms of age and sex. At baseline, the autofluorescence in the anterior chamber was 16.7<span class="elsevierStyleHsp" style=""></span>ng/mL (SD 5.5) and 14.6<span class="elsevierStyleHsp" style=""></span>ng/mL (SD 4.6) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.221). After 30<span class="elsevierStyleHsp" style=""></span>min, anterior chamber fluorescein concentrations had risen to 55.1<span class="elsevierStyleHsp" style=""></span>ng/mL (SD 25.5) and 46.1<span class="elsevierStyleHsp" style=""></span>ng/mL (SD 25.1) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.293) without a further relevant increase by 60<span class="elsevierStyleHsp" style=""></span>min.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">This study found that applying riboflavin drops in the inferior fornix was non-inferior to applying it directly to the cornea, based on fluorophotometric measurements of anterior chamber riboflavin concentrations. This suggests that self-application of riboflavin is feasible in terms of corneal riboflavin impregnation.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción y objetivos</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Investigamos si la auto-administración de riboflavina por parte de los pacientes podría ser una opción viable para el cross-linking corneal, teniendo en cuenta los importantes recursos necesarios para la impregnación de la córnea con riboflavina. Analizamos si administrar la riboflavina en el fornix inferior (lugar de auto-administración) resulta en concentraciones de riboflavina no inferiores a cuando se aplica directamente en la córnea (lugar de administración por personal médico).</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y métodos</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Realizamos un estudio prospectivo para evaluar las concentraciones de riboflavina en seis puntos de tiempo (basal, 5, 15, 30, 45 y 60<span class="elsevierStyleHsp" style=""></span>min) en 18 voluntarios para cada uno de los dos lugares de aplicación: córnea y fornix. Las concentraciones de riboflavina (Peschke® TE 0.25%) en la cámara anterior fueron medidas por fluorofotometría (Fluorotron™ Master FM-2).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">En los dos lugares de aplicación, córnea y fórnix, se observó una autofluorescencia de 16,7<span class="elsevierStyleHsp" style=""></span>ng/mL (DE 5,5) y 14,6<span class="elsevierStyleHsp" style=""></span>ng/mL (DE 4,6) al inicio de la serie de mediciones (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>,221). Después de 30<span class="elsevierStyleHsp" style=""></span>min, las concentraciones de fluorescencia en la cámara anterior habían aumentado a 55,1<span class="elsevierStyleHsp" style=""></span>ng/mL (DE 25,5) y 46,1<span class="elsevierStyleHsp" style=""></span>ng/mL (DE 25,1) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>,293) sin un aumento relevante adicional a los 60<span class="elsevierStyleHsp" style=""></span>minutos.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Este estudio encontró que la aplicación de gotas de riboflavina en el fornix inferior fue no inferior a la aplicación directa en la córnea, según las mediciones fluorométricas de las concentraciones de riboflavina en la cámara anterior. Sugiere que la auto-administración de riboflavina es viable en términos de impregnación corneal de riboflavina.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Clinical trial register number</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleInterRef" id="intr0005" href="https://clinicaltrials.gov/ct2/show/NCT04062435">https://clinicaltrials.gov/ct2/show/NCT04062435</span></p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] 4 => array:2 [ "identificador" => "abst0045" "titulo" => "Clinical trial register number" ] ] ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 721 "Ancho" => 1007 "Tamanyo" => 73318 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0165" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Measuring setup showing the optical head of the Fluorotron<span class="elsevierStyleSup">TM</span> Master FM-2 with adjustment knobs for focus, chin rest, right/left eye adjustment, alignment window and scan button. For the measurements the room was completely darkened and the participants were covered with a lightproof black cloth.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1297 "Ancho" => 2091 "Tamanyo" => 144463 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0170" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Fluorophotometric scans after riboflavin application to the cornea (top row) and into the fornix (bottom row) at baseline (A, C) and after 15<span class="elsevierStyleHsp" style=""></span>min (B, D), demonstrating the increasing fluorescence signal of the corneal peak and of the anterior chamber plateau.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0175" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">SD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>standard deviation.</p>" "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cornea</th><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Fornix</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " rowspan="2" align="center" valign="middle" scope="col"><span class="elsevierStyleItalic">P</span>-value</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean (ng/mL) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SD \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mean (ng/mL) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SD \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anterior chamber concentration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.223 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5<span class="elsevierStyleHsp" style=""></span>min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.055 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15<span class="elsevierStyleHsp" style=""></span>min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.245 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30<span class="elsevierStyleHsp" style=""></span>min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.293 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45<span class="elsevierStyleHsp" style=""></span>min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.102 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60<span class="elsevierStyleHsp" style=""></span>min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">.027</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cornea concentration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">138.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">141.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.786 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5<span class="elsevierStyleHsp" style=""></span>min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10271.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5097.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8840.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6898.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.484 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; 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entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60<span class="elsevierStyleHsp" style=""></span>min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11441.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9038.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14184.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10833.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.508 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3334624.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mean riboflavin concentrations at the cornea and the anterior chamber measured at different application sites and time points. <span class="elsevierStyleItalic">P</span>-values are provided for the comparison between application sites. 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Journal Information
Original article
A fluorophotometric comparison of anterior chamber riboflavin delivery via corneal application and fornix instillation
Comparación fluorofotométrica de la administración de riboflavina en la cámara anterior mediante aplicación corneal e instilación en el fórnix