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ResumenObjetivoEstablecer un diagnóstico etiológico de la ceguera de Jorge Luis Borges basado en los datos clínicos obtenidos de su obra poética.Material y métodosSe integró un caso clínico basado en la revisión de su obra literaria (poemas, conferencias, entrevistas) y biográfica (referencias históricas y fotografías). Se compararon los datos clínicos con las causas de ceguera crónica más comunes y se establecieron diagnósticos diferenciales. Se seleccionó la causa de ceguera crónica más compatible con la clínica establecida y se determinó un diagnóstico presuntivo.ResultadosDe los 6 diagnósticos diferenciales más importantes de la ceguera crónica (maculopatía senil, retinopatía diabética, glaucoma, cataratas, retinosis pigmentaria y miopía degenerativa), se estableció que la miopía degenerativa es la etiología más probable de la ceguera de Jorge Luis Borges según la compatibilidad de cada entidad con la obra poética.ConclusionesPese a que la miopía degenerativa es la etiología más probable de la ceguera de Jorge Luis Borges, no es posible descartar por completo otras oftalmopatías sin una exploración física adecuada. Se cumple el objetivo solo en el marco presuntivo.AbstractObjectiveDetermine the etiological diagnosis of Jorge Luis Borges blindness based on the clinical data obtained from his poetic work.Material and methodsA clinical case was structured based in the revision of his literary work (poems, speeches, interviews) and biographical references (historic references and photography). The clinical data was compared with the most common causes of chronic blindness and several differential diagnosis were established. The most compatible cause of chronic blindness related with the clinical data was selected and instituted as presumptive diagnosis.ResultsOf the six most important differential diagnosis of chronic blindness (Senile Macular Degeneration, Diabetic Retinopathy, Glaucoma, Cataract, Retinitis Pigmentosa and Pathological Myopia) it was determined that the most probable etiology of Jorge Luis Borges blindness is Pathological Myopia by comparing each pathological entity with his poetic work.ConclusionsAlthough Pathologic Myopia is the most plausible etiology of Jorge Luis Borges blindness, it is not possible to completely discard other ophthalmopthy without an appopriate physical examination. The objective of the investigation is fulfill in a presumptive framework.

Inherited retinal dystrophies (IRDs) are a broad group of neurodegenerative disorders associated with reduced or deteriorating visual system. In the retina, cells are under constant oxidative stress, leading to elevated reactive oxygen species (ROS) generation that induces mitochondrial dysfunction and alteration of the mitochondrial network. This mitochondrial dysfunction combined with mutations in mitochondrial DNA and nuclear genes makes photoreceptors and retinal ganglion cells more susceptible to cell death. In this minireview, we focus on mitochondrial dynamics and their contribution to neuronal degeneration underlying IRDs, with particular attention to Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA), and propose targeting cell resilience and mitochondrial dynamics modulators as potential therapeutic approaches for retinal disorders.

Diabetes mellitus in a serious public health problem worldwide that it is rising. Diabetic retinopathy is acomplication of this disease and due to its high prevalence is the main cause of blindness in the economically active population. This review seeks to highlight the importance of early diagnosis and timely and appropriate treatment, both of diabetes mellitus and its associated risk conditions, as well as diabetic retinopathy. La diabetes mellitus en un grave problema de salud pública a nivel mundial que se encuentra en aumento. La retinopatía diabética es una complicación de esta enfermedad y debido a su alta prevalencia es la principal causa de ceguera en la población económicamente activa. En esta revisión se busca resaltar la importancia del diagnóstico precoz y tratamiento oportuno y adecuado, tanto de la diabetes mellitus y las condiciones de riesgo asociadas, como de la retinopatía diabética.

Submitted by Boris Flegr (boris@uerj.br) on 2021-01-06T20:52:39Z No. of bitstreams: 1 Laura Gomes Nunes de Melo Tese completa.pdf: 10719696 bytes, checksum: 8be19f63381164ed95df3ab3a6c36b18 (MD5) Made available in DSpace on 2021-01-06T20:52:39Z (GMT). No. of bitstreams: 1 Laura Gomes Nunes de Melo Tese completa.pdf: 10719696 bytes, checksum: 8be19f63381164ed95df3ab3a6c36b18 (MD5) Previous issue date: 2019-11-27 This study aims to evaluate the prevalence of diabetic retinopathy, its main risk factors and its relationship with cardiovascular disease and inflammatory factors in patients with type 1 diabetes in Brazil. This thesis is based on a multicenter study involving 1760 patients submitted to a questionnaire, laboratory and clinical examinations, including screening for diabetic retinopathy with indirect ophthalmoscopy and further classification into mild, moderate, severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy. Retinopathy was considered as vision threatening in severe nonproliferative, proliferative, and macular edema, and as referable in moderate, severe, proliferative, and macular edema. The results of the thesis were presented in scientific articles. The first article and a letter to the editor, both published, showed a 35% prevalence of diabetic retinopathy, the vision-threatening retinopathy in 12% and referable retinopathy in 18%. The main risk factors related to diabetic retinopathy, regardless of severity grouping were: duration of diabetes, glycated hemoglobin levels and elevated serum uric acid levels. Arterial hypertension was also related to the presence of diabetic retinopathy and the referable form. Chronic kidney disease has been associated with the vision-threatening diabetic retinopathy and the referable form. The third published article demonstrated that the presence of diabetic retinopathy can be considered an indicator of cardiovascular risk. The fourth article submitted demonstrated an association between serum C-reactive protein levels and proliferative diabetic retinopathy, but there was no relationship with the other inflammatory factors investigated (interleukin-6, vascular endothelial growth factor and tumor necrosis factor-⍺). We conclude that the prevalence of diabetic retinopathy in Brazil resembles the worldwide prevalence, as well as the main risk factors that were similar to those already established, except for uric acid, which probably due to its pro-oxidant characteristics, was also related to the presence of diabetic retinopathy. The association of diabetic retinopathy with cardiovascular disease suggests that patients with type 1 diabetes and diabetic retinopathy should be investigated for cardiovascular disease, and fundoscopy can help in identifying patients at risk for this important cause of mortality, especially in patients with diabetes. Regarding inflammatory factors, further studies are needed to evaluate the role of these cytokines in the pathophysiology of proliferative diabetic retinopathy. Este estudo tem como objetivo avaliar a prevalência da retinopatia diabética, seus principais fatores de risco e sua relação com a doença cardiovascular e com fatores inflamatórios, em pacientes com diabetes tipo 1, no Brasil. A tese é baseada no estudo multicêntrico que envolveu 1760 pacientes, submetidos a um questionário padronizado, exames laboratoriais e clínicos, incluindo rastreamento da retinopatia diabética com oftalmoscopia binocular indireta e posterior classificação em retinopatia diabética não proliferativa leve, moderada, severa e retinopatia diabética proliferativa. A retinopatia foi considerada como ameaça `a visão nas formas não proliferativa severa, proliferativa e edema macular, e como referenciável nas formas não proliferativa moderada, severa, proliferativa e presença de edema macular. Os resultados da tese foram apresentados em forma de artigos científicos. O primeiro artigo é uma carta ao editor, ambos publicados, demonstraram uma prevalência da retinopatia diabética em 35%, das formas mais graves da retinopatia, que ameaçam a visão, em 12% e da retinopatia referenciável em 18%. Os principais fatores de risco relacionados com a retinopatia diabética, independente do grupamento pela gravidade, foram: o tempo de duração do diabetes, os níveis de hemoglobina glicada e os níveis séricos elevados de ácido úrico. A hipertensão arterial foi também relacionada `a presença de retinopatia diabética e com a forma referenciável. A doença renal crônica foi associada com as formas mais graves da retinopatia, que ameaçam a visão, e com a forma referenciável. O terceiro artigo publicado demonstrou que a presença da retinopatia diabética pode ser considerada um indicador de risco cardiovascular. O quarto artigo, submetido, revelou uma associação entre os níveis séricos da proteína C reativa com a retinopatia diabética proliferativa, porém não houve relação com os outros fatores inflamatórios pesquisados (interleucina-6, fator de crescimento endotelial vascular e o fator de necrose tumoral-⍺). Concluímos que a prevalência da retinopatia diabética no Brasil se assemelha a prevalência mundial, assim como os principais fatores de risco que foram semelhantes aos já estabelecidos, exceto pelo ácido úrico que provavelmente pelas suas características pró-oxidantes, foi também relacionado a presença da retinopatia diabética. A associação da retinopatia diabética com a doença cardiovascular sugere que os pacientes com diabetes tipo 1 e retinopatia diabética sejam investigados para a doença cardiovascular, podendo a fundoscopia auxiliar na identificação de pacientes sobre risco dessa importante causa de mortalidade principalmente nos pacientes com diabetes. Em relação aos fatores inflamatórios, novos estudos são necessários para avaliar o papel dessas citocinas na fisiopatologia da retinopatia diabética proliferativa.

Background Diabetic retinopathy (DR) is the leading cause of blindness in type 1 Diabetes Mellitus (DM) patients, as a consequence of impaired blood flow in the retina. Optical coherence tomography angiography (OCTA) is a newly developed, non-invasive, retinal imaging technique that permits adequate delineation of the perifoveal vascular network. It allows the detection of paramacular areas of capillary non perfusion and/or enlargement of the foveal avascular zone (FAZ), representing an excellent tool for assessment of DR. The relationship of these microvascular changes with systemic factors such as metabolic control or duration of the disease still needs to be elucidated. Methods Prospective, consecutive, large-scale OCTA study. A complete ocular examination including a comprehensive series of OCTA images of different scan sizes captured with 2 OCT devices (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA, USA, and Triton Deep Range Imaging OCT, Topcon Corp, Topcon, Japan) will be obtained as part of the yearly routine follow up visits in type 1 DM patients seen in the Diabetes Unit of the Endocrinology department which give written informed consent to participate in the project. The aim of this study is to investigate the relationship between OCTA-derived parameters and systemic factors, as metabolic control (Hb1Ac, lipid profile, cholesterol, etc), and other relevant clinical factors as demographics or duration of the disease. Discussion This study is directed to investigate the relationship between the status of the perifoveal vascular network and systemic markers of the disease, and in particular to study whether these changes reflect those occurring elsewhere in the body affected by diabetic microvascular disease, as the kidneys or the brain. If these relationships were demonstrated, early detection of these microvascular changes by OCTA could lead to modifications in the pharmacological management of type 1 diabetic patients, as a way to reduce the risk of future complications in both the eye and other organs. Trial registration ClinicalTrials.gov, trial number NCT03422965.

Objective To perform a cost-utility analysis of diabetic retinopathy (DR) screening strategies from the perspective of the Brazilian Public Healthcare System. Methods A model-based economic evaluation was performed to estimate the incremental costs per quality-adjusted life-year (QALY) gained between three DR screening strategies: (1) the opportunistic ophthalmology referral-based (usual practice), (2) the systematic ophthalmology referral-based, and (3) the systematic teleophthalmology-based. The target population included individuals with type 2 diabetes (T2D) aged 40 years, without retinopathy, followed over a 40-year time horizon. A Markov model was developed with five health states and a 1-year cycle. Model parameters were based on literature and country databases. One-way and probabilistic sensitivity analyses were performed to assess model parameters’ uncertainty. WHO willingness-to-pay (WHO-WTP) thresholds were used as reference (i.e. one and three times the Brazilian per capita Gross Domestic Product of R$32747 in 2018). Results Compared to usual practice, the systematic teleophthalmology-based screening was associated with an incremental cost of R$21445/QALY gained ($9792/QALY gained). The systematic ophthalmology referral-based screening was more expensive (incremental costs = R$4) and less effective (incremental QALY = −0.012) compared to the systematic teleophthalmology-based screening. The probability of systematic teleophthalmology-based screening being cost-effective compared to usual practice was 0.46 and 0.67 at the minimum and the maximum WHO-WTP thresholds, respectively. Conclusion Systematic teleophthalmology-based DR screening for the Brazilian population with T2D would be considered very cost effective compared to the opportunistic ophthalmology referral-based screening according to the WHO-WTP threshold. However, there is still a considerable amount of uncertainty around the results. Electronic supplementary material The online version of this article (10.1007/s40258-019-00528-w) contains supplementary material, which is available to authorized users.

The objective was to investigate the usefulness of the &ldquo, liquid biopsy&rdquo, of aqueous humor (AH) to predict the clinical response after intravitreal injections (IVT) of anti-VEGF agents for treating diabetic macular edema (DME). For this purpose, AH samples obtained during the first anti-VEGF IVT from 31 type two diabetic patients were analyzed. Patients were classified into three groups according to their anti-VEGF response: rapid responders (n = 11), slow responders (n = 11), and non-responders (n = 9). In addition, patients (n = 7) who showed good response to corticosteroids but a delayed or no response to anti-VEGF therapy were analyzed. Levels of 17 different cytokines, chemokines, and growth factors in AH were measured using a multiplex immunoassay. We found higher concentrations of VEGF in rapid responders to anti-VEGF therapy compared to non-responders. In addition, slow responders to anti-VEGF treatment showed higher levels of inflammatory markers than rapid responders, but did not reach statistical significance. Finally, those patients who responded to corticosteroids but not to anti-VEGF therapy showed significantly lower levels of VEGF than patients with rapid response (p = 0.01). In conclusion, &ldquo, of AH could be useful to determine whether the predominant pathogenic event is primarily angiogenic or inflammatory in nature. This approach would allow physicians to select a more rational and cost-effective treatment. Further studies to validate these preliminary results are warranted.

We describe three patients who had previous heart diseases and nonproliferative diabetic retinopathy with clinically significant diabetic macular edema. They underwent unilateral dexamethasone intravitreal implantation. Without ophthalmological treatment in the fellow eye, patients showed marked bilateral improvement in best-corrected visual acuity, optical coherence images, and macular thickness values. These findings provide evidence of the bilateral effect of dexamethasone intravitreal implantation, which may be clinically useful in patients for whom the systemic effects of the drug may affect their general health. RESUMO Descrevemos três pacientes que tiveram doenças cardíacas prévias e retinopatia diabética não proliferativa com edema macular diabético clinicamente significativo. Eles foram submetidos a implante intravítreo de dexametasona unilateral. Sem tratamento oftalmológico no olho contralateral, os pacien tes apresentaram uma melhora bilateral significativa na melhor acuidade visual corrigida, nas imagens de coerência óptica e nos valores da espessura macular. Esses achados fornecem evidências sobre o efeito bilateral do implante intravítreo de dexametasona, que pode ser clinicamente útil em pacientes para os quais os efeitos sistêmicos da droga possam afetar a saúde geral do paciente.

Resumo Objetivo: Determinar a concordância do retinógrafo portátil Pictor Plus, na ausência de midríase, com a retinografia digital e avaliar a sua acurácia como método de rastreio da retinopatia diabética (RD). Métodos: Estudo transversal, mascarado para o observador, avaliando 100 olhos de 51 pacientes diabéticos. Foram realizadas retinografias com o Pictor Plus com e sem midríase, seguidos de retinografia convencional com o retinógrafo IMAGEnet por técnico treinado. As imagens obtidas foram analisadas por oftalmologista especialista em retina e classificadas normais, presença de edema macular diabético, retinopatia não proliferativa (inicial, moderada e grave) e retinopatia proliferativa, além de análise inviável. A concordância entre os resultados foi avaliada via coeficiente Kappa. As imagens foram agrupadas em normais e alteradas e estas em RD de alto risco e RD de baixo risco. Avaliou-se ainda a sensibilidade, especificidade, valores preditivos positivos e negativos, em relação à retinografia convencional. Resultados: Oitenta e nove por cento das imagens foram consideradas viáveis para classificação. Pouco mais de 31% dos olhos avaliados foram considerados como normais pelas três tecnologias. O exame com Pictor na ausência de midríase apresentou altos índices de sensibilidade e especificidade para a classificação normal (92,9% e 93,4%) e RD de alto risco (82,9% e 97,9%) e bons resultados para RD de baixo risco (75,0% e 87,0%). Conclusão: O Pictor Plus apresentou altos níveis de concordância com a retinografia digital ao discriminar exames normais de alterados e portadores de RD de baixo e alto risco. Foram verificadas ainda altas sensibilidade e especificidade desta ferramenta, se comparados à retinografia padrão. Abstract Purpose: Determine the effectiveness of the use a portable handheld fundus camera as a screening method for diabetic retinopathy, compared to regular digital retinography. Methods: This is a cross-sectional, observer-masked study, evaluating 100 eyes of 51 diabetic patients undergoing a routine dilated retinography for diabetic retinopathy. Fundus images pre and post-dilation we captured by Pictor Plus (Volk Optical Inc., Mentor, USA), followed by routine digital retinography by IMAGEnet (Topcon Medical Systems, New Jersey, USA). All exams were performed by a trained technician on the same occasion. The images were analyzed and graded by a masked retina specialist and classified as normal, presence of diabetic macular edema, nonproliferative diabetic retinopathy (initial, moderate and severe) and proliferative diabetic retinopathy. The ungradable images were recorded and excluded from analyses. The agreement between results obtained by the three methods was evaluated via Kappa coefficient. Sensitivity, specificity, positive and negative predictive values in relation to IMAGEnet images were also determined. Results: Images were gradable in 89% of pre-dilation photos. Pictor Plus pre-dilation images had high sensitivity and specificity in identifying normal eyes (92.9% and 93.4%) and in vision-threatening DR (82.9% and 97.9%) both when compared to IMAGEnet results. Conclusion: Pictor can capture retinal images of sufficient quality to screen for DR with and without dilation. Single retinal images obtained using Pictor can identify eyes with vision-threatening DR with high sensitivity and specificity compared to routine IMAGEnet images.

Objective To evaluate indications, results and strategy of retinal exams requested at Primary Care Units. Methods A retrospective study that analyzed the indications and results of retinal exams, in the modalities clinical dilated fundus exams and color fundus photographs. In the following situations, patients were considered eligible for color fundus photographs if visual acuity was normal and ocular symptoms were absent: diabetes mellitus and/or hypertension, in use of drugs with potential retinal toxicity, diagnosis or suspicion of glaucoma, stable and asymptomatic retinopathies, except myopia greater than -3.00 diopters. Results A total of 1,729 patients were evaluated (66% female, age 63.5±15.5 years), and 1,190 underwent clinical dilated fundus exam and 539 underwent color fundus photographs. Diabetes was present in 32.2%. The main indications were diabetes (23.7%) and glaucoma evaluation (23.5%). In 3.4% of patients there was no apparent indication. The main results were a large cup/disc ratio (30.7%) and diabetic retinopathy (13.2%). Exam was normal in 9.6%, detected peripheral changes in 7% and could not be performed in 1%. Considering patients eligible for fundus photographs (22.4%), more than half underwent clinical dilated fundus exams. Conclusion Regarding exam modality, there were no important differences in the distribution of indications or diagnosis. Color fundus photograph is compatible with telemedicine and more cost-effective, and could be considered the strategy of choice in some scenarios. Since there are no clear guidelines for retinal exams indications or the modality of choice, this study may contribute to such standardization, in order to optimize public health resources. RESUMO Objetivo Avaliar as indicações, os resultados e a estratégia de exames de retina solicitados em Unidades Básicas de Saúde. Métodos Estudo retrospectivo no qual foram analisados as indicações e os resultados de exames de retina, nas modalidades mapeamento de retina e retinografia. Em casos de boa acuidade visual e sintomas oculares ausentes, foram considerados elegíveis para avaliação por retinografia: pacientes com diabetes mellitus e/ou hipertensão arterial sistêmica, em uso de medicação com potencial toxicidade retiniana, diagnóstico ou suspeita de glaucoma, e retinopatias estáveis e assintomáticas, exceto miopia maior que -3,00 dioptrias. Resultados Foram avaliados 1.729 pacientes (66% do sexo feminino, idade 63,5±15,5 anos). Destes, 1.190 realizaram mapeamento de retina e 539 realizaram retinografia. Diabetes estava presente em 32,2%. As principais indicações para solicitação do exame foram diabetes (23,7%) e investigação de glaucoma (23,5%). Em 3,4%, não havia indicação aparente. Os principais resultados foram aumento da escavação papilar (30,7%) e retinopatia diabética (13,2%). O exame foi normal em 9,6%; detectou alterações periféricas em 7%; e sua realização foi impossível em 1%. Dos pacientes elegíveis para retinografia (22,4%), mais da metade foi submetida ao mapeamento de retina. Conclusão Não houve diferenças importantes nas distribuições de indicações ou diagnósticos em relação à modalidade de exame. A retinografia, compatível com telemedicina e mais custo-efetiva, pode ser considerada a modalidade de escolha em determinadas situações. Na ausência de consenso quanto às indicações para a solicitação de exames da retina ou sua modalidade, este estudo pode contribuir para tal padronização, de modo a otimizar recursos do sistema público de saúde.

Objective To evaluate indications, results and strategy of retinal exams requested at Primary Care Units. Methods A retrospective study that analyzed the indications and results of retinal exams, in the modalities clinical dilated fundus exams and color fundus photographs. In the following situations, patients were considered eligible for color fundus photographs if visual acuity was normal and ocular symptoms were absent: diabetes mellitus and/or hypertension, in use of drugs with potential retinal toxicity, diagnosis or suspicion of glaucoma, stable and asymptomatic retinopathies, except myopia greater than -3.00 diopters. Results A total of 1,729 patients were evaluated (66% female, age 63.5±15.5 years), and 1,190 underwent clinical dilated fundus exam and 539 underwent color fundus photographs. Diabetes was present in 32.2%. The main indications were diabetes (23.7%) and glaucoma evaluation (23.5%). In 3.4% of patients there was no apparent indication. The main results were a large cup/disc ratio (30.7%) and diabetic retinopathy (13.2%). Exam was normal in 9.6%, detected peripheral changes in 7% and could not be performed in 1%. Considering patients eligible for fundus photographs (22.4%), more than half underwent clinical dilated fundus exams. Conclusion Regarding exam modality, there were no important differences in the distribution of indications or diagnosis. Color fundus photograph is compatible with telemedicine and more cost-effective, and could be considered the strategy of choice in some scenarios. Since there are no clear guidelines for retinal exams indications or the modality of choice, this study may contribute to such standardization, in order to optimize public health resources.

Objectives: To compare the effect of intravitreal Ranibizumab (0.3mg) and Triamicinolone (4mg) on different parameters in spectral domain OCT and their relation to visual acuity of patients with diabetic macular edema. Methods: This study is designed as a prospective randomized study. Patients were randomly divided into 2 groups receiving either Pro re nata intravitreal Ranibizumab (0.3mg) or Triamicinolone acetonide (4mg), to whom Spectral Domain OCT was done as well as best corrected Log MAR visual acuity. Results: 40 patients were included in this study. Comparison and correlation of mean BCVA and mean CMT among and within treatment groups of our study revealed strong and significant relationship between both parameters and showing equal effect of both treatment types regarding them with the consideration that Triamicinolone acetonide treated group (Group B) showed statistically significant lower CMT compared to Ranibizumab treated group (Group A) at three and six months. Also both showed equal effectivity regarding improvement of the photoreceptors integrity and in turn the improvement of the BCVA. Meanwhile the association of CMT and IS/OS integrity was found to be significant only at six months in both groups (p =0.009 in Group A; p =0.031 in Group B). The fading initial effect of a single ranibizumab injection on macular edema can be augmented by following that one injection with two injections of the loading dose. Triamicinolone effect after single injection began to fade at 3 months. Conclusion: Both treatment types had good effect on reduction of CMT and improvement of BCVA and the IS/OS junction with difference in sustainability of their effects due to difference in their pharmacokinetics and need for repeated injections. Resumo Objetivos: Comparar o efeito do ranibizumabe intravítreo (0,3mg) e triacmicinolona (4mg) em diferentes parâmetros do domínio espectral da OCT e sua relação com a acuidade visual de pacientes com edema macular diabético. Métodos: Este estudo foi concebido como um estudo prospectivo randomizado. Os pacientes foram divididos aleatoriamente em 2 grupos que receberam Ranibizumab Pro rata intravitreal (0,3mg) ou acetonido de Triamicinolona (4mg), a quem foi realizada a Spectral Domain OCT, bem como a melhor acuidade visual de Log MAR corrigida. Resultados: Quarenta pacientes foram incluídos neste estudo. A comparação e a correlação da acuidade visual média e CMT média entre e dentro de grupos de tratamento do nosso estudo revelaram uma relação forte e significativa entre ambos os parâmetros e mostrando um efeito igual de ambos os tipos de tratamento, considerando que o grupo tratado com acetonido Triamicinolona (Grupo B) apresentou significância estatística. menor CMT comparado ao grupo tratado com Ranibizumab (Grupo A) aos três e seis meses. Também ambos mostraram igual efetividade em relação à melhoria da integridade dos fotorreceptores e, por sua vez, a melhora do BCVA. Enquanto isso, a associação de CMT e IS / OS integridade foi significativa apenas aos seis meses em ambos os grupos (p = 0,009 no Grupo A; p = 0,031 no Grupo B). O efeito inicial enfraquecido de uma única injeção de ranibizumabe no edema macular pode ser aumentado seguindo-se aquela injeção com duas injeções da dose de ataque. O efeito triamicinolona após injeção única começou a diminuir aos 3 meses. Conclusão: Ambos os tipos de tratamento tiveram bom efeito na redução da CMT e melhora do BCVA e da junção IS / OS com a diferença na sustentabilidade de seus efeitos devido à diferença em sua farmacocinética e necessidade de injeções repetidas.

Introduccion: Los programas de cribado sistematico de retinopatia son efectivos para evitar la ceguera causada por la Diabetes Mellitus (DM). La utilizacion de metodos avanzados de Inteligencia Artificial (IA) posibilitan el analisis automatico de las imagenes, lo que permitiria: Mejorar la atencion: aumentando la capacidad de resolucion de Atencion Primaria (AP) y evitando desplazamientos a los pacientes Optimizar el trabajo de los oftalmologos disminuyendo consultas Mejorar la sostenibilidad del sistema sanitario ante el reto de la cronicidad. El objetivo de este trabajo fue desarrollar un sistema automatico de deteccion de la retinopatia diabetica (RD) en imagenes digitales de retina, evaluar los resultados obtenidos, y analizar el impacto economico de su implantacion en programas de cribado poblacional. Metodos: Se desarrollo un algoritmo innovador basado en metodos avanzados de clasificacion (Deep Learning y Support Vector Machine) que identifica automaticamente las imagenes patologicas de forma eficaz y segura. Un estudio de minimizacion de costes analizo el impacto economico de su implementacion a nivel poblacional. Mediante un modelo de simulacion de eventos discretos se calculo el numero de retinografias de cribado necesarias en un periodo de 10 anos. Resultados: El software discrimina automaticamente retinografias normales y patologicas, mediante un algoritmo innovador configurable en funcion de las necesidades que se determinen, pudiendo alcanzar una sensibilidad de 94% y una especificidad del 96%. El estudio economico muestra que la utilizacion del software podria suponer un ahorro de 270.000 € en el Pais Vasco, donde la prevalencia de la diabetes es del 10%. Seleccionado como uno de los mejores proyectos del Pais Vasco en 2018 por Health 2.0 Basque, ha tenido importante repercusion en prensa y redes sociales. Discusion: El software simplifica el proceso de cribado de RD, ya que detecta imagenes patologicas automaticamente en el mismo momento de la realizacion de la prueba, reduciendo la utilizacion de los circuitos establecidos entre AP y Oftalmologia solo a las pruebas patologicas. Esta simplificacion permite reducir costes. Asimismo, disminuye la variabilidad y los posibles errores humanos, y garantiza la seguridad del paciente y sus datos. Por tanto, es una iniciativa que mejora tanto la calidad de la atencion prestada como la sostenibilidad a largo plazo. En entornos con recursos economicos escasos o falta de profesionales, la aplicacion de esta tecnica ayudaria a detectar la enfermedad ocular y evitar cegueras en pacientes diabeticos. Conclusiones: El software desarrollado facilita el proceso de cribado, de manera que mejora la calidad asistencial y disminuye costes para el sistema sanitario, Lecciones aprendidas: La aplicacion de metodos avanzados de analisis puede mejorar la atencion al paciente, la calidad percibida, la satisfaccion de los profesionales y la eficiencia del sistema sanitario. Limitaciones: El software esta disenado para cribado de RD, a partir de datos de pacientes del programa de Osakidetza. Futuras investigaciones: Construir un modelo para elegir configuraciones y analizar su impacto. Disenar algoritmos complementarios para mejorar la precision del diagnostico y su utilizacion en otras fases de la enfermedad.

Current treatments for diabetic retinopathy (DR) target late stages when vision has already been significantly a ected. Accumulating evidence suggests that neuroinflammation plays a major role in the pathogenesis of DR, resulting in the disruption of the blood-retinal barrier. Suppressors of cytokine signaling (SOCS) are cytokine-inducible proteins that function as a negative feedback loop regulating cytokine responses. On this basis, the aim of the present study was to evaluate the e ect of a SOCS1-derived peptide administered by eye drops (2 weeks) on retinal neuroinflammation and early microvascular abnormalities in a db/db mouse model. In brief, we found that SOCS1-derived peptide significantly reduced glial activation and neural apoptosis induced by diabetes, as well as retinal levels of proinflammatory cytokines. Moreover, a significant improvement of electroretinogram parameters was observed, thus revealing a clear impact of the histological findings on global retinal function. Finally, SOCS1-derived peptide prevented the disruption of the blood-retinal barrier. Overall, our results suggest that topical administration of SOCS1-derived peptide is e ective in preventing retinal neuroinflammation and early microvascular impairment. These findings could open up a new strategy for the treatment of early stages of DR, This study was supported by grants from the Ministerio de Economía y Competitividad (PI16/00541, SAF2015-63696-R, PI14/00386, PI17/01495 and DTS-2017/00203)

Submitted by Biblioteca Escola Superior de Saúde (biblioteca@ess.ipp.pt) on 2020-01-27T16:42:47Z No. of bitstreams: 1 DM_BeatrizRolim_2019_MGO.pdf: 1064446 bytes, checksum: 9b52c578c4260d2d219c1306e08749ad (MD5) Made available in DSpace on 2020-01-27T16:42:47Z (GMT). No. of bitstreams: 1 DM_BeatrizRolim_2019_MGO.pdf: 1064446 bytes, checksum: 9b52c578c4260d2d219c1306e08749ad (MD5) Previous issue date: 2019-07

Los ácidos grasos poliinsaturados omega-3 (PUFA n-3) son ácidos grasos esenciales que deben obtenerse a través de la alimentación o mediante suplementación dietética. La principal fuente nutricional de omega-3 proviene de la ingesta de pescados azules, aceites vegetales y frutos secos, entre otros. El principal precursor del n-3 es el ácido α-linolénico (ALA), que puede ser alargado y desaturado a través de distintas vías metabólicas, dando lugar a sus metabolitos: ácido docosahexaenoico (DHA) y ácido eicosapentaenoico (EPA). Los ácidos grasos omega-3 poseen propiedades antiinflamatorias, antitrombóticas, antiarrítmicas y antiangiogénicas. Además, se ha demostrado que el DHA se expresa altamente en las membranas de las células fotorreceptoras retinianas, encargas de detectar y responder a estímulos luminosos para iniciar el proceso visual. Los múltiples efectos y funciones recogidas en un sinnúmero de artículos científicos sobre el papel del omega-3 en el organismo, nos hace plantear la necesidad de realizar esta revisión bibliográfica para recoger la evidencia científica publicada sobre el uso de omega-3 a nivel visual. Para ello, se ha realizado una recopilación bibliográfica de todos los artículos encontrados referentes a este tema. Obteniendo así que las patologías visuales para las cuales hay evidencia científica del papel de los ácidos grasos n-3 son: ojo seco, degeneración macular asociada a la edad y retinopatía diabética. Se han asociado los omega-3 con una mejora de la estabilidad lagrimal, la disminución en la evaporación lagrimal y un aumento de la secreción lagrimal. Esto se debe a la actividad antiinflamatoria del n-3, a través de su metabolismo a eicosanoides, y el poder inhibidor de prostaglandinas de serie 2, derivadas de los ácidos grasos omega-6. Además, una dieta rica en omega-3 influye en la mejora de la inflamación palpebral (blefaritis) y previene la obstrucción de las glándulas de Meibomio. Asimismo, se han relacionado los omega-3 con patologías retinianas como la DMAE y la retinopatía diabética, por sus marcados efectos antitrombóticos, hipolipidémicos y vasodilatadores, y por su capacidad para inhibir el factor de crecimiento endotelial vascular (disminuyendo la angiogénesis y permeabilidad vascular). Universidad de Sevilla. Grado en Óptica y Optometría

Purpose: To evaluate the usefulness of fundus autofluorescence imaging of diabetic patients without retinopathy to investigate early retinal damage. Methods: Fundus autofluorescence images of patients with type 2 diabetes mellitus without retinopathy (diabetic group) and age-sex matched healthy patients (control group) were recorded with a CX-1 digital mydriatic retinal camera after detailed ophthalmologic examinations. MATLAB 2013a software was used to measure the average pixel intensity and average curve width of the macula and fovea. Results: Fifty-six eyes of 28 patients, as the diabetic group, and 54 eyes of 27 healthy patients, as the control group, were included in this study. The mean aggregation index was 168.32 ± 37.18 grayscale units (gsu) in the diabetic group and 152.27 ± 30.39 gsu in the control group (p=0.014). The mean average pixel intensity value of the fovea was 150.87 ± 35.83 gsu the in diabetic group and as 141.51 ± 31.10 gsu in the control group (p=0.060). The average curve width value was statistically higher in the diabetic group than in the control group (71.7 ± 9.2 vs. 59.4 ± 8.6 gsu, respectively, p=0.03). Conclusion: Fundus autofluorescence imaging analysis revealed that diabetic patients without retinopathy have significant fluorescence alterations. Therefore, a noninvasive imaging technique, such as fundus autofluorescence, may be valuable for evaluation of the retina of diabetic patients without retinopathy. RESUMO Objetivo: Avaliar a utilidade da autofluorescência do fundo de olho de pacientes diabéticos sem retinopatia para investigar lesões precoces na retina. Métodos: Imagens de autofluorescência do fundo de olho de pacientes com diabetes mellitus do tipo 2 sem retinopatia (grupo diabético) e indivíduos saudáveis pareados por idade e sexo (grupo controle) foram registrados com uma câmera retiniana digital midriática CX-1 após exames oftalmológicos detalhados. O software MATLAB 2013a foi usado para medir a intensidade média do pixel e a largura média da curva da mácula e fóvea. Resultados: Cinquenta e seis olhos de 28 pacientes, como o grupo diabético, e 54 olhos de 27 indivíduos saudáveis, como grupo controle, foram incluídos neste estudo. O índice médio de agregação foi de 168,32 ± 37,18 unidades de escala de cinza (gsu) no grupo diabético e em 152,27 ± 30,39 gsu no grupo controle (p = 0,014). O valor médio da intensidade de pixel na fóvea foi de 150,87 ± 35,83 gsu no grupo diabético e de 141,51 ± 31,10 gsu no grupo controle (p=0,060). O valor médio da largura da curva foi estatisticamente maior no grupo diabético do que no grupo controle (71,7 ± 9,2 vs. 59,4 ± 8,6 gsu, respectivamente; p = 0,03). Conclusão: A análise por imagens de autofluorescência de fundo de olho revelou que pacientes diabéticos sem retinopatia apresentam alterações significativas de fluorescência. Portanto, uma técnica de imagem não invasiva, como a autofluorescência de fundo de olho, pode ser valiosa para a avaliação da retina de pacientes diabéticos sem retinopatia.

In order to determine the frequency and severity of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (MD), a cross-sectional descriptive study was conducted in 3,239 patients of the Regional Institute of Ophthalmology in the city of Trujillo, La Libertad region, Peru. After pupil dilation, trained personnel took two photographs of each eye, centered on macula and optic nerve. The frequency of DR was 25.9%, with a higher proportion in men with DR (28.2%) and in those with more than 10 years of MD disease (49.0%). Most patients had mild to moderate non-proliferative diabetic retinopathy (NPDR) (79.3%); 10.1% had severe NPDR, and 9.7% had proliferative DR. We conclude that DR occurs in one in four patients and about 20% in advanced degrees. There is a need to expand screening coverage from the time of diagnosis of DM and to implement preventive measures such as metabolic control and periodic ocular fundus exam. Para determinar la frecuencia y el grado de severidad de retinopatía diabética (RD) en pacientes con diabetes mellitus (DM) tipo 2 se realizó un estudio descriptivo transversal en 3239 pacientes del Instituto Regional de Oftalmología de la ciudad de Trujillo, región La Libertad, Perú. Previa dilatación pupilar, personal entrenado tomó dos fotografías de cada ojo, centrado en mácula y nervio óptico. La frecuencia de RD fue de 25,9 % con mayor proporción en varones con RD (28,2%) y en aquellos con más de 10 años de enfermedad por DM (49,0%). La mayoría de pacientes tuvieron retinopatía diabética no proliferativa (RDNP) leve a moderada (79,3%), el 10,1% tuvo RDNP severa y el 10,6 % RD proliferativa. Concluimos que la RD se presenta en uno de cada cuatro pacientes y alrededor del 20% en grados avanzados. Es preciso ampliarla cobertura de tamizaje desde el momento del diagnóstico de DM e implementar medidas preventivas como el control metabólico y el examen periódico del fondo de ojo.

Purpose: We aimed to evaluate the use of automated quantitative static and dynamic pupillometry in screening patients with type 2 diabetes mellitus and different stages of diabetic retinopathy. Method: 155 patients with type 2 diabetes mellitus (diabetes mellitus group) were included in this study and another 145 age- and sex-matched healthy individuals to serve as the control group. The diabetes mellitus group was divided into three subgroups: diabetes mellitus without diabetic retinopathy (No-diabetic retinopathy), nonproliferative diabetic retinopathy, and proliferative diabetic retinopathy. Static and dynamic pupillometry were performed using a rotating Scheimpflug camera with a topography-based system. Results: In terms of pupil diameter in both static and dynamic pupillometry (p0.05). However, it could be concluded that the proliferative diabetic retinopathy group was significantly different from the rest of the subgroups, No-diabetic retinopathy and nonproliferative diabetic retinopathy groups, in terms of all the static pupillometry measurements (p0.05 for all). Conclusion: This study revealed that the measurements derived from automated pupillometry are altered in patients with type 2 diabetes mellitus. The presence of nonproliferative diabetic retinopathy does not have a negative effect on pupillometry findings, but with proliferative diabetic retinopathy, significant alterations were observed. These results suggest that using automated quantitative pupillometry may be useful in verifying the severity of diabetic retinopathy. RESUMO Objetivos: Procuramos avaliar o uso da pupilometria estática e dinâmica quantitativa automatizada na triagem de pacientes com diabetes mellitus tipo 2 e em diferentes estágios de retinopatia diabética. Métodos: Cento e cinquenta e cinco pacientes com diabetes mellitus tipo 2 (grupo com diabetes mellitus) foram incluídos neste estudo e outros 145 controles saudáveis pareados por idade e sexo para server como grupo controle. O grupo com diabetes mellitus foi dividido em três subgrupos: diabetes mellitus sem retinopatia diabética (retinopatia não diabética), retinopatia diabética não proliferativa e retinopatia diabética proliferativa. A pupilometria estática e dinâmica foi realizada utilizando uma camera rotative Scheimpflug com um sistema baseado em topografia. Resultados: Em termos de diâmetro da pupila, tanto na pupilometria estática quanto na dinâmica (p0,05). No entanto, pode-se concluir que o grupo de retinopatia diabética proliferative foi sugnificativamente diferente do restante dos subgrupos, retinopatia não diabética e retinopatia diabética não proliferativa, em termos de todas as medidas de pupilometris estática (p0,05 para todos). Conclusão: Este estudo revelou que as medidas derivadas da pupilometria automatizada estão alteradas em pacientes com diabetes mellitus tipo 2. A presença de retinopatia diabética não proliferativa não afeta negativamente os achados pupilométricos, mas com a retinopatia diabética proliferative, alterações significativas foram observadas. Estes resultados sugerem que o uso da pupilometria quantitativa automatizada pode ser útil na verificação gravidade da retinopatia diabética.

Submitted by Angela Maria de Oliveira (amolivei@uepg.br) on 2019-09-24T11:43:29Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Diego José Schebelski.pdf: 1645628 bytes, checksum: 0e26d1629ae95908e7d54ed09ff79401 (MD5) Made available in DSpace on 2019-09-24T11:43:29Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Diego José Schebelski.pdf: 1645628 bytes, checksum: 0e26d1629ae95908e7d54ed09ff79401 (MD5) Previous issue date: 2019-05-24 A retinopatia diabética é uma das principais complicações da diabetes mellitus. Não existe tratamento para retinopatia diabética inicial, apenas controle da glicemia e controle de comorbidades. O cilostazol é uma possível alternativa terapêutica. Essa pesquisa teve o objetivo de avaliar o efeito protetor do cilostazol administrado por gavagem no desenvolvimento e evolução de retinopatia diabética em ratos com indução de diabetes mellitus por estreptozotocina intraperitoneal. Foram comparados 4 grupos de 15 animais por 8 semanas. Em dois grupos foi administrado estreptozotocina intraperitoneal para indução de diabetes mellitus e dois grupos foram mantidos normoglicêmicos para controle. Após confirmação da hiperglicemia nesses grupos, um grupo de rato diabético e um grupo sem diabetes passou a recebeu cilostazol oral (30mg/dia) por 8 semanas. Após o período de tratamento os olhos foram removidos e um deles foi destinado para análise histológica. Foram comparadas as espessuras e a contagem de núcleos das camadas da retina. O grupo de ratos diabéticos tratados com cilostazol oral (média de 3 ±1 núcleos em 50 µm de retina) teve perda estatisticamente menor (p

Resumo Objetivo: Avaliar o nível de conhecimento dos pacientes diabéticos, atendidos no Sistema Único de Saúde (SUS) na cidade de Boa Vista/Roraima, acerca da Retinopatia Diabética (RD). Métodos: Trata-se de um estudo transversal, descritivo, de caráter quantitativo, realizado através da aplicação de um questionário semi-estruturado para 150 indivíduos diabéticos, usuários do SUS, da cidade de Boa Vista - RR, durante o ano de 2017. As análises estatísticas foram realizadas utilizando os programas Microsoft Excel e EpiInfo 7®, fixando-se o nível de 5% para a rejeição da hipótese de nulidade. Resultados: Do total amostral pesquisado,76,7% dos indivíduos não possuía nenhum conhecimento sobre a RD, 19,3% tinha algum tipo de conhecimento, mas não possuía a patologia, 2,7% conhecia, possuía a RD e fazia tratamento e 1,3% conhecia, possuía a RD e não se tratava. Quanto a orientação, 40,6% dos participantes nunca recebeu nenhuma informação sobre o risco de perda da visão. Acerca do tipo de Diabetes, 44,7% dos participantes não sabia que tipo possuía, 42% relatou ter DM 2 e 13,3% DM1. Sobre o controle da glicose, 59,4% não conseguia mantê-lo. Foi evidenciada associação entre o controle da glicose e o conhecimento sobre RD, entre o tempo de instalação da DM e o conhecimento sobre RD e entre ter consultado um oftalmologista e conhecer sobre a RD. Conclusão: O nível de conhecimento sobre a RD é muito baixo, fator preocupante por tratar-se de uma das complicações mais importantes do Diabetes. Percebe-se que o sistema de saúde não está sendo eficiente como facilitador deste conhecimento. Abstract Objective: To evaluate the level of knowledge of diabetic patients treated at the Unified Health System (SUS - Sistema Único de Saúde) in the city of Boa Vista / Roraima, about Diabetic Retinopathy (DR). Methods: This is a cross-sectional, descriptive, quantitative study conducted through the application of a semi-structured questionnaire for 150 diabetic individuals, SUS users, from the city of Boa Vista - RR, during the year 2017. Statistical analyzes were performed using the Microsoft Excel and EpiInfo 7® programs, setting the 5% level for the rejection of the null hypothesis. Results: Of the total sample, 76.7% of the individuals did not have any knowledge about DR, 19.3% had some type of knowledge, but did not have the pathology, 2.7% knew, had DR and was receiving treatment, 1,3% knew, had DR and was not receiving treatment. About orientation, 40.6% of the participants never received any information about the risk of vision loss. About the type of Diabetes, 44.7% of the participants did not know what type they had, 42% reported having DM 2 and 13.3% DM1. On glucose control, 59.4% could not maintain it. It was evidenced an association between glucose control and DR knowledge, between the time of DM installation and knowledge about DR, and between having consulted an ophthalmologist and knowing about DR. Conclusion: The level of knowledge about DR is very low, a worrying factor because it is one of the most important complications of diabetes. It is observed that the health system is not being efficient as facilitator of this knowledge.

Purpose: To determine the effect of panretinal photocoagulation on optic disk topographic parameters in non-glaucomatous patients with proliferative diabetic retinopathy. Methods: This was a prospective, single-center, observational study. Thirty-eight eyes of 26 patients with diabetes underwent panretinal photocoagulation for proliferative diabetic retinopathy. Stereoscopic disk photographs and optic nerve head parameters were evaluated using the Zeiss fundus camera and the confocal scanning laser ophthalmoscope (Heidelberg Retinal Tomograph), respectively, at baseline and 12 months after the completion of panretinal photocoagulation. Results: Thirty-eight eyes of 26 patients (15 female) with a mean age of 53.7 (range 26-74) years were recruited. No significant difference was found between the stereo photography determined mean horizontal and vertical cup-to-disk ratio before and after panretinal photocoagulation treatment (p=0.461 and 0.839, respectively). The global values of the optic nerve head parameters analyzed with the HRT3 showed no significant change from baseline to 12 months, including the disk area, cup area, rim area, cup volume, rim volume, cup-to-disk area ratio, linear cup-to-disk ratio, mean cup depth, maximum cup depth, cup shape measure, height variation contour, mean retinal nerve fiber layer thickness, and cross-sectional area. Conclusion: Our results suggest that panretinal photocoagulation does not cause morphological optic disk changes in patients with diabetic proliferative retinopathy after 1 year of follow-up. RESUMO Objetivo: Determinar o efeito da panfotocoagulação retiniana nos parâmetros topográficos do disco óptico em pacientes não glaucomatosos com retinopatia diabética proliferativa. Métodos: Este é um estudo observacional prospectivo e unicêntrico. Trinta e oito olhos de 26 pacientes diabéticos foram submetidos à panfotocoagulação retiniana para retinopatia diabética proliferativa. As estereofotografias e os parâmetros do disco óptico foram avaliados usando o retinógrafo Visucam da Zeiss e o oftalmoscópio confocal de varredura a laser (Heidelberg Retinal Tomograph), respectivamente, no início e 12 meses após a conclusão da panfotocoagulação. Resultados: Trinta e oito olhos de 26 pacientes (15 mulheres) com média de idade de 53,7 anos (intervalo de 26-74) foram recrutados. Nenhuma diferença significativa foi encontrada entre a média horizontal e vertical para relação escavação/disco óptico determinadas pelas estereofotografias antes e após o tratamento com panfotocoagulação retiniana (p=0,461 e 0,839, respectivamente). Os valores globais dos parâmetros do disco óptico analisados com a tomografia de varredura a laser não mostraram nenhuma mudança significativa entre o início até os 12 meses, incluindo disk area, cup area, rim area, cup volume, rim volume, C/D area ratio, linear C/D ratio, mean cup depth, maximum cup depth, cup shape measure, height variation contour, mean retinal nerve fiber layer thickness e cross-sectional area. Conclusão: Nossos resultados sugerem que a panfotocoagulação retiniana não causa alterações morfológicas no disco óptico em pacientes com retinopatia diabética proliferativa após um ano de seguimento.

Purpose: To compare the intravitreal concentrations of cellular mediators involved in neurodegeneration, inflammation, and angiogenesis in patients with proliferative diabetic retinopathy and other vitreoretinal diseases. Methods: A multiplex bead immunoassay was used to measure vitreous levels of pigment epithelium-derived factor, serum amyloid P, C-reactive protein, complement C4, alpha-1 antitrypsin, vascular endothelial growth factor, platelet-derived growth factor-AA, platelet-derived growth factor-BB, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor alpha and beta in patients undergoing 23-gauge vitrectomy for proliferative diabetic retinopathy and other diagnoses (control group). Results: We evaluated 55 patients, of whom 24 had proliferative diabetic retinopathy and 31 had other diagnoses including vitreous hemorrhage, retinal detachment, macular hole, and epiretinal membrane. Patients with proliferative diabetic retinopathy demonstrated increased levels of serum amyloid P (85.49 vs. 31.38 ng/mL); C-reactive protein (59.89 vs. 41.75 ng/mL), vascular endothelial growth factor (2,330.11 vs. 554.25 pg/mL; p

Es indispensable concientizar a la població con diabetes mellitus tipo 2 sobre la importancia de los controles oftalmológicos para detectar tempranamente esta complicación. Objetivo: determinar los factores de riesgo que inciden en la retinopatía diabética en pacientes con diabetes mellitus tipo 2 mayores de 40 años en el establecimiento de salud Carapungo 2, Quito 2018. Metodología: estudio piloto con diseño cuantitativo, documental-bibliográfico, transversal de tipo descriptivo a pacientes de consulta externa de medicina general. Se utilizó la aplicación de una Guía de observación como instrumento y la técnica de investigación fue la observación con 29 ítems. Los factores de riesgo que predominaron en la retinopatía diabética fueron Edad (70%) llevando a las paredes de los capilares se engruesan ligeramente relacionándose con Hipertensión Arterial 40% como principal antecedente patológico personal. Se mostro que el estado nutricional mediante la aplicación Índice Masa Corporal que sobresalió fue el sobrepeso con 60% se identificó que el habito predominante que conlleva a adquirir retinopatía diabética es el consumo de alcohol con 70%. Las consecuencias presentadas a raíz de los factores de riesgo estuvieron enmarcadas por la Hipertensión Arterial y el sobrepeso que conllevaron a la retinopatía diabética y posteriormente a la ceguera.

Submitted by Programa de Pós-Graduação Engenharia Elétrica (ppgee@ifpb.edu.br) on 2019-08-27T12:18:44Z No. of bitstreams: 2 60- Ana Emília Malvino Ferreira da Costa- DETECÇÃO AUTOMÁTICA DE EXSUDATOS E MICROANEURISMAS EM IMAGENS DE RETINOPATIA DIABÉTICA UTILIZANDO O ALGORITMO BIOINSPIRADO NA COLÔNIA ARTIFICIAL DE ABELHAS E PROCESSAMENT.pdf: 32322540 bytes, checksum: 5c2b7d4b5fe8b3d4276aebb1d75e3506 (MD5) AUTORIZAÇÃO_ANA EMÍLIA.pdf: 214255 bytes, checksum: eb5693a92400a6cc3d864767ab4a653e (MD5) Approved for entry into archive by Josinete Nobrega Araujo (josinete@ifpb.edu.br) on 2019-08-28T13:02:01Z (GMT) No. of bitstreams: 2 60- Ana Emília Malvino Ferreira da Costa- DETECÇÃO AUTOMÁTICA DE EXSUDATOS E MICROANEURISMAS EM IMAGENS DE RETINOPATIA DIABÉTICA UTILIZANDO O ALGORITMO BIOINSPIRADO NA COLÔNIA ARTIFICIAL DE ABELHAS E PROCESSAMENT.pdf: 32322540 bytes, checksum: 5c2b7d4b5fe8b3d4276aebb1d75e3506 (MD5) AUTORIZAÇÃO_ANA EMÍLIA.pdf: 214255 bytes, checksum: eb5693a92400a6cc3d864767ab4a653e (MD5) Made available in DSpace on 2019-08-28T13:02:01Z (GMT). No. of bitstreams: 2 60- Ana Emília Malvino Ferreira da Costa- DETECÇÃO AUTOMÁTICA DE EXSUDATOS E MICROANEURISMAS EM IMAGENS DE RETINOPATIA DIABÉTICA UTILIZANDO O ALGORITMO BIOINSPIRADO NA COLÔNIA ARTIFICIAL DE ABELHAS E PROCESSAMENT.pdf: 32322540 bytes, checksum: 5c2b7d4b5fe8b3d4276aebb1d75e3506 (MD5) AUTORIZAÇÃO_ANA EMÍLIA.pdf: 214255 bytes, checksum: eb5693a92400a6cc3d864767ab4a653e (MD5) Previous issue date: 2019-03-22 O diagnóstico da retinopatia diabética, em imagens do fundo do olho, impulsionou o desenvolvimento de algoritmos de processamento que fossem capazes de identificar e classificar patologias automaticamente. As técnicas de processamento digital de imagens, aplicadas a medicina, facilitam a visualização e identificação de patologias a partir de minimização de artefatos indesejáveis nas imagens. O objetivo do presente trabalho consiste em implementar pelo método baseado na colônia artificial de abelhas (Artificial Bee Colony - ABC), para adetecção de exsudatos, e o uso de técnicas de processamento digital de imagens para facilitar nos processos de detecção e classificação das microaneurismas. Como sinais de entrada para os algoritmos, foram utilizadas as imagens do banco de dados da Diaretdb1. Técnicas de pré-processamento foram utilizadas para realizar a exclusão do disco óptico (projeção luminosa decorrente dos exames de fundoscopia), e uma máscara foi proposta para encontrar nas imagens a patologia, com base na forma e tamanho da mesma. Para a avaliação dos algoritmos desenvolvidos foram utilizadas as taxas de sensibilidade, especificidade e acurácia das imagens. Na detecção dos exsudatos os valores coletados após o pos-processamento foram 85% de sensibilidade, 92% de especificidade e 96% de acurácia. Na detecção e classifica ção das microaneurismas, os testes retornaram 75% de sensibilidade, 99% de especificidade e 98% de acurácia. Conforme as imagens resultantes dos processos de detecção, foram identificados 52 pacientes com a presença de exsudatos em comparação com o banco de dados que diagnosticaram 48 pacientes com a doença. O algoritmo de classificação detectou a evidência de microaneurismas em 75 pacientes e o banco de dados diagnosticou a patologia em 71.

Submitted by Cristiane Chim (cristiane.chim@ucpel.edu.br) on 2019-05-28T13:19:20Z No. of bitstreams: 1 Josiara Affonso.pdf: 1138286 bytes, checksum: b82093f6c0278fd62224938e1f1e17f4 (MD5) Made available in DSpace on 2019-05-28T13:19:20Z (GMT). No. of bitstreams: 1 Josiara Affonso.pdf: 1138286 bytes, checksum: b82093f6c0278fd62224938e1f1e17f4 (MD5) Previous issue date: 2019-02-27 The present study aimed to evaluate the resilience and the associated factors in type 2 diabetic patients (DM2) who perform follow-up at a referral clinic in a city in the south of Brazil. The patients who underwent examination to evaluate complications in the target organ - the eye - were evaluated from June 2015 to October 2017, in a reference clinic of a municipality in the south of Brazil. A self-administered questionnaire containing sociodemographic data and patient health was used. The resilience capacity was evaluated by ResilienceScale of Wagnild & Young. A total of 217 patients were evaluated, 57.6% were female, 39.8% were between 56 and 65 years of age, 42.4% completed between 8 and 11 years of study, and 44.2% had a partner level economic variables A and B. Male patients presented higher resilience averages (153.48), when compared to the means obtained by female patients (145,20), p of 0.001. Regarding age, older patients had higher resilience averages when compared to younger patients. The averages were: patients with up to 55 years obtained a mean of 144.66, between 56 and 65 years old 149.69 and above 66 years old 150.80, p of linearity of 0.054. Individuals with severe diabetic retinopathy presented averages above those with moderate RD, mild RD or no RD (respective means: 151.87, 151.71, 144.00 and 146.00 p of linearity 0.023). In the present study, males with severe diabetic retinopathy, hypertensive and older than 65 years had better means of resilience. Therefore, it can be thought that, perhaps, patients with greater impairments had to develop mechanisms of adaptation to life with adverse conditions, to be accustomed to the limitations imposed by comorbidities, such as low visual acuity and even blindness. The study design, however, does not allow us to make causal inferences, since the data were collected simultaneously, however, it is possible to think if resilience can be a factor that contributes to the way the disease will evolve. Perhaps the more resilient patients were more likely to become accustomed to the damage caused by DM, and in doing so they ended up making poorer control, inadequate treatment of complications, which eventually led to more serious complications. There is still much to investigate in this field, this study aims to initiate a debate about these aspects, to reflect on what factors may be involved, and other studies with designs that allow an assessment of causality and with more robust sample sizes are needed to clarify these aspects. O presente estudo teve por objetivo avaliar a resiliência e os fatores associados em pacientes diabéticos tipo 2 que realizaram acompanhamento em uma clínica de referência em cidade do sul do Brasil. Os pacientes que realizaram exame para avaliação de complicações em órgão alvo – o olho - foram avaliados no período de junho 2015 a outubro de 2017, em uma clínica de referência de município no sul do Brasil. Foi utilizado um questionário autoaplicado contendo questões sociodemográficas e sobre a saúde dos pacientes. A capacidade de resiliência foi avaliada pela Resilience Scale de Wagnild & Young. Ao todo 217 pacientes foram avaliados, destes 57,6% são do sexo feminino, 39,8% tinham entre 56 e 65 anos de idade, 42,4% completaram entre 8 e 11 anos de estudo, e 44,2% apresentaram nível sócio econômico A ou B. Pacientes do sexo masculino apresentaram maiores médias de resiliência (153,48 DP=13,43), quando comparadas às médias obtidas pelos pacientes do sexo feminino (145,20 DP=19,83), p = 0,001. No que se refere à idade, os pacientes com mais idade apresentaram médias na escala de resiliência mais elevadas quando comparados aos pacientes com menos idade. As médias foram: pacientes com até 55 anos obtiveram média de 144.66 (DP=21,96), entre 56 e 65 anos 149,69 (DP=15,58) e acima de 66 anos 150,80 (DP=16,25), p de linearidade = 0,054. Indivíduos que apresentam retinopatia diabética grave apresentaram médias superiores aos indivíduos com Retinopatia Diabética (RD) moderada, RD leve ou sem RD (médias respectivas: 151,87 e DP=12,47; 151,71 DP=15,91; 144,00 e DP=21,27 e 146,00e DP=20,21) p de linearidade = 0,023). No presente estudo pacientes homens, com retinopatia diabética grave, hipertensos e com idade superior a 65 anos apresentaram melhores médias de capacidade de resiliência. Diante disso, pode-se pensar que os pacientes com maiores comprometimentos tiveram que desenvolver mecanismos de adaptação à vida com condições adversas, acostumar-se às limitações impostas pelas comorbidades, tais como a baixa acuidade visual e até mesmo a cegueira. O delineamento do estudo, entretanto não nos permite fazer inferências causais, uma vez que os dados foram coletados simultaneamente, contudo, é possível pensar se a resiliência pode ser um fator que contribui para a forma como a doença irá evoluir. Talvez os pacientes mais resilientes tiveram mais facilidade em se acostumar com os prejuízos causados pelo DM e, dessa forma, acabaram por fazer um controle mais pobre, tratamento inadequado das complicações o que acabou por levar a complicações mais graves. Há muito ainda que se investigar nesse campo, esse estudo visa iniciar um debate sobre esses aspectos, refletir sobre quais fatores podem estar implicados, sendo necessário outros estudos com delineamentos que permitam uma avaliação da causalidade e com tamanhos amostrais mais robustos que possam esclarecer esses aspectos.

Purpose: We aimed to compare the aqueous humor total oxidant status, total antioxidant capacity, and levels of interleukin-6 and vascular endothelial growth factor between patients with diabetic retinopathy and controls and to correlate these levels with the DR status. Methods: Patients who underwent cataract surgery were enrolled. The first group (control group) comprised patients without diabetes; the second group comprised diabetic patients without retinopathy; the third group comprised patients with nonproliferative diabetic retinopathy; and the fourth group comprised patients with proliferative diabetic retinopathy. All patients underwent full ophthalmologic examination before cataract surgery. Prior to surgery, samples of aqueous humor sampling were obtained and stored at -80 °C. Total antioxidant capacity, total oxidant status, and levels interleukin-6 and vascular endothelial growth factor were investigated in these samples and correlated with diabetic retinopathy status. Results: This study analyzed 86 pairs of eyes of 86 patients. All groups were statistically similar in age and sex, but the total antioxidant capacity was lowest in patients with proliferative diabetic retinopathy. Moreover, the total oxidant status and levels of vascular endothelial growth factor and interleukin-6 were found to slightly increase according to the retinopathy status. Conclusion: Oxidative stress, interleukin-6, and vascular endothelial growth factor in the aqueous humor seem to play important roles in the pathogenesis of diabetic retinopathy, especially in the proliferative type.

La retinopatia diabètica és una malaltia crònica i una de les principals causes de ceguesa i discapacitat visual en els pacients diabètics. L'examen ocular a través d'imatges de la retina és utilitzat pels metges per detectar les lesions relacionades amb aquesta malaltia. En aquesta tesi, explorem diferents mètodes innovadors per a la classificació automàtica del grau de malaltia utilitzant imatges del fons d'ull. Per a aquest propòsit, explorem mètodes basats en l'extracció i classificació automàtica, basades en xarxes neuronals profundes. A més, dissenyem un nou mètode per a la interpretació dels resultats. El model està concebut de manera modular per a que pugui ser utilitzat en d'altres xarxes i dominis de classificació. Demostrem experimentalment que el nostre model d'interpretació és capaç de detectar lesions de retina a la imatge únicament a partir de la informació de classificació. A més, proposem un mètode per comprimir la representació interna de la informació de la xarxa. El mètode es basa en una anàlisi de components independents sobre la informació del vector d'atributs intern de la xarxa generat pel model per a cada imatge. Usant el nostre mètode d'interpretació esmentat anteriorment també és possible visualitzar aquests components en la imatge. Finalment, presentem una aplicació experimental del nostre millor model per classificar imatges de retina d'una població diferent, concretament de l'Hospital de Reus. Els mètodes proposats arriben al nivell de rendiment de l'oftalmòleg i són capaços d'identificar amb gran detall les lesions presents en les imatges, que es dedueixen només de la informació de classificació de la imatge. La retinopatía diabética es una enfermedad crónica y una de las principales causas de ceguera y discapacidad visual en los pacientes diabéticos. El examen ocular a través de imágenes de la retina es utilizado por los médicos para detectar las lesiones relacionadas con esta enfermedad. En esta tesis, exploramos diferentes métodos novedosos para la clasificación automática del grado de enfermedad utilizando imágenes del fondo de la retina. Para este propósito, exploramos métodos basados en la extracción y clasificación automática, basadas en redes neuronales profundas. Además, diseñamos un nuevo método para la interpretación de los resultados. El modelo está concebido de manera modular para que pueda ser utilizado utilizando otras redes y dominios de clasificación. Demostramos experimentalmente que nuestro modelo de interpretación es capaz de detectar lesiones de retina en la imagen únicamente a partir de la información de clasificación. Además, proponemos un método para comprimir la representación interna de la información de la red. El método se basa en un análisis de componentes independientes sobre la información del vector de atributos interno de la red generado por el modelo para cada imagen. Usando nuestro método de interpretación mencionado anteriormente también es posible visualizar dichos componentes en la imagen. Finalmente, presentamos una aplicación experimental de nuestro mejor modelo para clasificar imágenes de retina de una población diferente, concretamente del Hospital de Reus. Los métodos propuestos alcanzan el nivel de rendimiento del oftalmólogo y son capaces de identificar con gran detalle las lesiones presentes en las imágenes, que se deducen solo de la información de clasificación de la imagen. Diabetic Retinopathy is a chronic disease and one of the main causes of blindness and visual impairment for diabetic patients. Eye screening through retinal images is used by physicians to detect the lesions related with this disease. In this thesis, we explore different novel methods for the automatic diabetic retinopathy disease grade classification using retina fundus images. For this purpose, we explore methods based in automatic feature extraction and classification, based on deep neural networks. Furthermore, as results reported by these models are difficult to interpret, we design a new method for results interpretation. The model is designed in a modular manner in order to generalize its possible application to other networks and classification domains. We experimentally demonstrate that our interpretation model is able to detect retina lesions in the image solely from the classification information. Additionally, we propose a method for compressing model feature-space information. The method is based on a independent component analysis over the disentangled feature space information generated by the model for each image and serves also for identifying the mathematically independent elements causing the disease. Using our previously mentioned interpretation method is also possible to visualize such components on the image. Finally, we present an experimental application of our best model for classifying retina images of a different population, concretely from the Hospital de Reus. The methods proposed, achieve ophthalmologist performance level and are able to identify with great detail lesions present on images, inferred only from image classification information.

Producción Científica, Diabetic retinopathy (DR) is one of the most common causes of visual loss in developed countries. Computer-aided diagnosis systems aimed at detecting DR can reduce the workload of ophthalmologists in screening programs. Nevertheless, a large number of retinal images cannot be analyzed by physicians and automatic methods due to poor quality. Automatic retinal image quality assessment (RIQA) is needed before image analysis. The purpose of this study was to combine novel generic quality features to develop a RIQA method. Several features were calculated from retinal images to achieve this goal. Features derived from the spatial and spectral entropy-based quality (SSEQ) and the natural images quality evaluator (NIQE) methods were extracted. They were combined with novel sharpness and luminosity measures based on the continuous wavelet transform (CWT) and the hue saturation value (HSV) color model, respectively. A subset of non-redundant features was selected using the fast correlation-based filter (FCBF) method. Subsequently, a multilayer perceptron (MLP) neural network was used to obtain the quality of images from the selected features. Classification results achieved 91.46% accuracy, 92.04% sensitivity, and 87.92% specificity. Results suggest that the proposed RIQA method could be applied in a more general computer-aided diagnosis system aimed at detecting a variety of retinal pathologies such as DR and age-related macular degeneration., Ministerio de Ciencia, Innovación y Universidades - Fondo Europeo de Desarrollo Regional (projects RTC-2015-3467-1 and DPI2017-84280-R)

Orientador: Andrei Carvalho Sposito Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: INTRODUÇÃO: A doença arterial coronariana (DAC) aterosclerótica é a principal causa de morte em pacientes com diabetes tipo 2 (DM2) e é proporcional ao escore de cálcio coronariano (ECC). Em paralelo, a retinopatia diabética (RD) é uma complicação microvascular também frequente no DM2, cuja presença tem enorme impacto na qualidade de vida. Dentre as principais vias envolvidas no desenvolvimento e progressão de ambas manifestações micro e macrovasculares é o processo bioquímico de glicação avançada que além disso estimula a calcificação coronariana. Hipoteticamente, esses produtos finais de glicação avançada (AGE) podem atuar como mediador num paralelismo entre ECC e RD como o faz para DAC, servindo por esse meio como método de screening para ambas as complicações do DM2. OBJETIVO: O objetivo desse estudo foi avaliar a presença de associação entre ECC e RD e estimar o efeito de mediação do AGE em pacientes com DM2. MÉTODOS: Foram avaliados, consecutivamente, 198 pacientes, previamente diagnosticados com DM2, com média de idade (59±7 anos), incluindo biomicroscopia de retina, tomografia computadorizada cardíaca e autofluorescência da pele (sAF) para mensuração do AGE. O grau de RD foi classificado como RD não aparente (RDNA), RD não proliferativa (RDNP) e RD proliferativa (RDP). RESULTADO: O aumento gradual de AGE-sAF foi observado entre indivíduos com RDNA (2,7 ± 0,5), RDNP (3,1 ± 0,3) e aqueles com RDP (3,6 ± 0,7; p

Purpose: To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). Design: AQUA was a multicenter, open-label, single-arm, phase 4 study. Participants: Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. Methods: Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. Main outcome measures: The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. Results: A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 μm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was -175.38 μm (SD, 132.62 μm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. Conclusions: Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept.

Agradecimentos: We thank the medical team from the Department of Ophthalmology, Federal University of São Paulo, for the data collection and annotation and Dr. Alexandre Ferreira for suggestions on earlier drafts of this work. We thank José A. Stuchi, Flavio P. Vieira and Diego Lencione, co-founders of Phelcom Technologies for encouraging us in investigation of efficient solutions. We thank Kaggle, the California Healthcare Foundation, and EyePACs for sponsoring a diabetic retinopathy competition and for providing the community with a useful and wide dataset. The Messidor-2 dataset was kindly provided by the LaTIM laboratory (see http://latim.univ-brest.fr/) and the Messidor program partners (see http://messidor.crihan.fr/). We also thank the University of Iowa for providing the reference standard of Messidor-2 dataset. We gratefully acknowledge the support of NVIDIA Corporation with the donation of the GPUs used for this research. Finally, this work was supported in part by Microsoft Research, São Paulo Research Foundation (Fapesp) under the grant #2017/12646-3, the National Council for Scientific Research (CNPq) under grants #311486/2014-2, and 304472/2015-8, Amazon Web Services, CAPES DeepEyes project, CAPES/PNPD, and Google Research. MDA is Director and shareholder of IDx, LLC, Iowa City, and has patents and patent applications, assigned to the University of Iowa, that may compete with the technology that is the subject of this study. IDx, LLC is not associated with the present study and has no interest in the presented methods Abstract: Prior art on automated screening of diabetic retinopathy and direct referral decision shows promising performance; yet most methods build upon complex hand-crafted features whose performance often fails to generalize. We investigate data-driven approaches that extract powerful abstract representations directly from retinal images to provide a reliable referable diabetic retinopathy detector.We gradually build the solution based on convolutional neural networks, adding data augmentation, multi-resolution training, robust feature-extraction augmentation, and a patient-basis analysis, testing the effectiveness of each improvement. The proposed method achieved an area under the ROC curve of 98.2% (95% CI: 97.4-98.9%) under a strict cross-dataset protocol designed to test the ability to generalize - training on the Kaggle competition dataset and testing using the Messidor-2 dataset. With a 5 × 2-fold cross-validation protocol, similar results are achieved for Messidor-2 and DR2 datasets, reducing the classification error by over 44% when compared to most published studies in existing literature. Additional boost strategies can improve performance substantially, but it is important to evaluate whether the additional (computation- and implementation-) complexity of each improvement is worth its benefits. We also corroborate that novel families of data-driven methods are the state of the art for diabetic retinopathy screening. Significance: By learning powerful discriminative patterns directly from available training retinal images, it is possible to perform referral diagnostics without detecting individual lesions CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES Fechado

Introducción: Los programas de cribado sistemático de retinopatía son efectivos para evitar la ceguera causada por la Diabetes Mellitus (DM). La utilización de métodos avanzados de Inteligencia Artificial (IA) posibilitan el análisis automático de las imágenes, lo que permitiría: Mejorar la atención: aumentando la capacidad de resolución de Atención Primaria (AP) y evitando desplazamientos a los pacientes Optimizar el trabajo de los oftalmólogos disminuyendo consultas Mejorar la sostenibilidad del sistema sanitario ante el reto de la cronicidad. El objetivo de este trabajo fue desarrollar un sistema automático de detección de la retinopatía diabética (RD) en imágenes digitales de retina, evaluar los resultados obtenidos, y analizar el impacto económico de su implantación en programas de cribado poblacional. Métodos: Se desarrolló un algoritmo innovador basado en métodos avanzados de clasificación (Deep Learning y Support Vector Machine) que identifica automáticamente las imágenes patológicas de forma eficaz y segura. Un estudio de minimización de costes analizó el impacto económico de su implementación a nivel poblacional. Mediante un modelo de simulación de eventos discretos se calculó el número de retinografías de cribado necesarias en un periodo de 10 años. Resultados: El software discrimina automáticamente retinografías normales y patológicas, mediante un algoritmo innovador configurable en función de las necesidades que se determinen, pudiendo alcanzar una sensibilidad de 94% y una especificidad del 96%. El estudio económico muestra que la utilización del software podría suponer un ahorro de 270.000 € en el País Vasco, donde la prevalencia de la diabetes es del 10%. Seleccionado como uno de los mejores proyectos del País Vasco en 2018 por Health 2.0 Basque, ha tenido importante repercusión en prensa y redes sociales. Discusión: El software simplifica el proceso de cribado de RD, ya que detecta imágenes patológicas automáticamente en el mismo momento de la realización de la prueba, reduciendo la utilización de los circuitos establecidos entre AP y Oftalmología sólo a las pruebas patológicas. Esta simplificación permite reducir costes. Asimismo, disminuye la variabilidad y los posibles errores humanos, y garantiza la seguridad del paciente y sus datos. Por tanto, es una iniciativa que mejora tanto la calidad de la atención prestada como la sostenibilidad a largo plazo. En entornos con recursos económicos escasos o falta de profesionales, la aplicación de esta técnica ayudaría a detectar la enfermedad ocular y evitar cegueras en pacientes diabéticos. Conclusiones: El software desarrollado facilita el proceso de cribado, de manera que mejora la calidad asistencial y disminuye costes para el sistema sanitario, Lecciones aprendidas: La aplicación de métodos avanzados de análisis puede mejorar la atención al paciente, la calidad percibida, la satisfacción de los profesionales y la eficiencia del sistema sanitario. Limitaciones: El software está diseñado para cribado de RD, a partir de datos de pacientes del programa de Osakidetza. Futuras investigaciones: Construir un modelo para elegir configuraciones y analizar su impacto. Diseñar algoritmos complementarios para mejorar la precisión del diagnóstico y su utilización en otras fases de la enfermedad.

Supported by the European Foundation for Study of Diabetes and Sanofi in the Collaborative Clinical Diabetes Research between European and Non-European Countries Programme. DAD received a scholarship from FAPESP (2015/23258-9). PURPOSE. Outer blood retinal barrier breakdown is a neglected feature of diabetic retinopathy (DR). We demonstrated that the agonism of the δ opioid receptor (DOR) by epicatechin preserves the tight junction proteins in ARPE-19 cells under diabetic conditions. Presently, we aimed to evaluate the possible role of the DOR on the maintenance of tight junction of RPE layer and on the early markers of experimental DR. METHODS. DR markers and external retinal tight junction proteins were evaluated in CL57B diabetic mice submitted to intravitreous injection of short hairpin RNA (shRNA)-DOR (108 transducing units [TU]/mL) treated or not with DOR agonist (0.05 g/animal/d of epicatechin in drinking water) for 16 weeks. The presence of DOR in human retina from postmortem eyes from diabetic and nondiabetic donors were also performed. RESULTS. DOR is present in RPE layer and in neuro retina. The treatment with DOR agonist prevented the upregulation of the early markers of retinopathy (glial fibrillary acidic protein, VEGF) and the downregulation of pigment epithelium-derived factor, occludin, claudin-1, and zonula occludens-1 tight junction expressions. The silencing of DOR in retina of diabetic mice partially abolished the protective effects of epicatechin. In human retina specimens, DOR is present throughout the retina, similarly in nondiabetic and diabetic donors. CONCLUSIONS. This set of experiments strongly indicates that the DOR agonism preserves RPE tight junctions and reduces the early markers of retinopathy in model of diabetes. These novel findings designate DOR as a potential therapeutic tool to treat DR with preservation of the RPE tight junction proteins.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia Elétrica, Florianópolis, 2019. O objetivo desse trabalho foi avaliar qual rede neural artificial junto com qual tipo de processamento de imagem seria capaz de identificar corretamente o grau de retinopatia diabética e risco de edema macular em pacientes com diabetes mellitus, de acordo com o diagnóstico dado por três instituições francesas. Para cada entidade foram utilizadas as arquiteturas de rede neural Inception V3 e PNASNet. As imagens do banco de dados passaram por cinco processamentos diferentes, totalizando seis grupos de imagens, um para cada processamento e um para as imagens sem processamento. Foram criadas 12 redes neurais para cada entidade, totalizando 36 redes neurais para cada uma das condições clínicas. Para a comparação do desempenho das diferentes redes foi utilizada a análise de desempenho aplicada a testes-diagnósticos em 60 imagens da retina de pacientes. A avaliação através desses índices alcançou os melhores resultados para a classificação do grau de retinopatia diabética com a rede de arquitetura PNASNet, treinada com as imagens avaliadas pelo Hôpital Lariboisière Paris, após um aprimoramento de contraste e adição de brilho simultâneos, com os seguintes valores de desempenho: sensibilidade de 89,5%, especificidade de 86,4%, valor preditivo positivo de 91,9%, valor preditivo negativo de 82,6% e acurácia de 88,3%. Os melhores resultados para a classificação do nível de risco de edema macular foram obtidos pela rede de arquitetura PNASNet, treinada com as imagens avaliadas pelo LATIM - CHRU de Brest, após um aprimoramento de contraste e adição de brilho simultâneos, com os seguintes valores de desempenho: sensibilidade de 100%, especificidade de 98,1%, valor preditivo positivo de 87,5%, valor preditivo negativo de 100% e acurácia de 98,3%. Abstract: The goal of this work was to evaluate which artificial neural network along with which type of image processing would be able to correctly identify the degree of diabetic retinopathy and risk of macular edema in patients with diabetes mellitus, according to the diagnosis given by three French institutions. For each center were used the Inception V3 and PNASNet neural network architectures. The images in the database went through five different renderings, totaling six groups of images, one for each processing and one for unprocessed images. Twelve neural networks were created for each entity, totaling 36 neural networks for each of the diseases. In order to compare the performance of the different networks, the performance analysis applied to diagnostic tests in 60 patient retinal images was used. The evaluation through these indices achieved the best results for the classification of the degree of diabetic retinopathy with the PNASNet architecture network, trained with the images evaluated by Hôpital Lariboisière Paris, after simultaneous enhancement of contrast and addition of brightness, with the following values of performance: sensitivity of 89.5%, specificity of 86.4%, positive predictive value of 91.9%, negative predictive value of 82.6% and accuracy of 88.3%. The best results for the classification of the risk level of macular edema were obtained by the PNASNet architecture network, trained with the images evaluated by Brest 's LATIM - CHRU after simultaneous enhancement of contrast and brightness addition, with the following performance values: sensitivity of 100%, specificity of 98.1%, positive predictive value of 87.5%, negative predictive value of 100% and accuracy of 98.3%.

Recent studies have shown that retinal neurodegeneration may precede visible vascular changes in diabetic retinopathy (DR). In addition, the relationship of choroidal thickness (CT) with DR stage is not well defined. To assess the inner retinal and choroidal structural changes in type 1 diabetic subjects (T1D), a cross-sectional study was conducted in 242 T1D patients and in 69 age-matched, non-diabetic individuals. The nasal retinal nerve fibre layer (RNFL) thickness was lower in T1D patients without DR (p &lt, 0.001), with mild DR (p &lt, 0.001), and with advanced DR (p &lt, 0.001) compared to control subjects. The ganglion cell layer (GCL) thickness was lower in T1D patients with advanced DR compared to those with mild DR (p = 0.003) and without DR (p &lt, 0.001) and compared to the control subjects (p &lt, 0.001). T1D subjects with no DR and mild DR had higher CT than the control subjects, but the CT in T1D patients with advanced DR was lower (p = 0.038) than that in T1D subjects with mild DR and was not significantly different from that of the control subjects. In conclusion, T1D subjects showed a significant thinning of the nasal RNFL in the early stages of the disease, even before any vascular changes in the retina. A decrease in the GCL thickness during advanced DR stages was observed. Choroidal thickness was higher in T1D subjects without DR and in early DR stages but decreased in advanced stages.

La neurodegeneració és un event precoç en la patogènia de la retinopatia diabètica (RD). De fet, recentment la American Diabetes Association ha definit la RD com una complicació neurovascular teixit-específica, emfatitzant així la importància de la unitat neurovascular en el desenvolupament de la RD. La retina és un teixit que deriva del cervell i disposem d’evidència creixent que indica que els diabètics tipus 2 tenen un major risc de desenvolupar malalties neurodegeneratives com la malaltia d’Alzheimer. Així doncs, sembla raonable postular que els mediadors del procés de neurodegeneració que succeeix al cervell també es troben presents a la retina del pacient diabètic. L’objectiu general d’aquesta tesi doctoral és investigar la relació entre la neurodegeneració a la retina i al cervell i les seves potencials implicacions clíniques i terapèutiques. La primera part d’aquesta tesi doctoral es centra en un seguit d’estudis experimentals per tal d’identificar mediadors de la disfunció de la unitat neurovascular. Amb aquest objectiu, s’ha realitzat un estudi “d’hipòtesi lliure” comparant retines humanes de subjectes no diabètics i diabètics amb i sense activació glial (que és una de les principals característiques de la neurodegeneració). Un dels resultats obtinguts ha estat que diverses vies relacionades amb les malalties neurodegeneratives es troben diferencialment expressades en retines de pacients diabètics i especialment en aquells amb activació glial. Aquesta observació recolza el concepte de que existeix un substrat comú entre els processos neurodegeneratius que succeeixen al cervell i a la retina. A més a més, s’ha observat una disminució en la expressió de diverses proteïnes implicades en el transport axonal i del citoesquelet de l’axó a les retines de donants diabètics amb activació glial. Per altra banda, l’activació glial induïda per la diabetis s’associa a una disregulació del sistema del complement, així com a un increment de les proteïnes que governen el citoesquelet de l’endoteli. Aquests resultats s’han validat per mètodes ortogonals. Aquestes troballes contribueixen no només en la comprensió dels mecanismes implicats en l’increment de la permeabilitat vascular induït per la disfunció de la unitat neurovascular, sinó que podrien tenir potencials implicacions terapèutiques. La segona part d’aquesta tesi doctoral, es basa en una “hipòtesi dirigida” i té l’objectiu d’examinar el paper de l’endotelina-1 en la disfunció neurovascular que succeeix en la RD. Això es fonamenta en el fet de que per mitjà dels receptors ETA l’endotelina-1 indueix dany vascular, mentre que a través dels receptors ETB indueix neurodegeneració. En primer lloc, hem detectat un augment en l’expressió de l’endotelina-1 i els seus receptors (tant ETA i ETB) en les retines de donants diabètics en comparació amb donants no diabètics. En segon lloc, hem pogut demostrar que l’aplicació tòpica de bosentan (que bloqueja els receptors ETA i ETB) prevé la neurodegeneració de la retina induïda per la diabetis en el ratolí db/db. A més, entre els efectes del bosentan hi ha la inhibició de l’activació de les vies induïdes per la diabetis PKC-β, TNF-α i VEGF, fet que explica els beneficis a nivell vascular que ofereix aquest tractament. L’efecte beneficiós dual (neurotròpic i vasculotròpic), així com els resultats de l’estudi farmacocinètic, indiquen que el bosentan pot ésser un excel·lent candidat a explorar en futurs assajos clínics. La tercera part de la tesi és un estudi clínic adreçat a reforçar el concepte de que l’avaluació de la neurodegeneració de la retina podria ser una eina útil per identificar aquells pacients diabètics en risc de desenvolupar demència. En aquest sentit, en un estudi previ vam demostrar que la sensibilitat de la retina avaluada per microperimetria es relacionava amb la neurodegeneració a nivell cerebral i podria ésser un biomarcador útil per identificar aquells pacients diabètics tipus 2 en risc de desenvolupar malaltia d’Alzheimer. En aquest treball hem avaluat si l’estudi de la fixació de la mirada, que és un paràmetre que també pot ser avaluat per microperimetria, s’associa al deteriorament cognitiu. En aquest sentit, estudis previs indiquen que la capacitat per mantenir la mirada fixada en una localització es troba alterada en la malaltia d’Alzheimer. Els nostres resultats mostren que la fixació de la mirada és més inestable a mesura que avança l’estat de deteriorament cognitiu. A més a més, l’avaluació dels paràmetres relacionats amb la fixació millora de forma significativa la sensibilitat de la retina com a test diagnòstic per a diferenciar els pacients diabètics amb deteriorament cognitiu incipient dels normocognitius. Així doncs, la mesura de la sensibilitat de la retina en combinació amb els paràmetres relacionats amb la fixació utilitzant la microperimetria podria ser un mètode fiable per a detectar estadis prodròmics de la demència en la població de diabètics tipus 2. Esperem que aquestes troballes esdevinguin la prova de concepte per a la realització d’un estudi clínic de llarga escala. Aquest treball, contribueix al coneixement dels mediadors de la disfunció neurovascular en etapes inicials de la RD i amplia el coneixement del vincle existent entre la neurodegeneració que succeeix al cervell i a la retina en la població afecta de diabetis mellitus tipus 2. A més a més, les nostres troballes suggereixen futurs candidats com a potencials dianes terapèutiques per al tractament de la RD. Neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). In fact, the American Diabetes Association has recently defined DR as a highly tissue-specific neurovascular complication, thus emphasizing the importance of the neurovascular unit in the development of DR. The retina is a brain-derived tissue and there is growing evidence indicating that type 2 diabetic subjects are more prone to develop neurodegenerative processes such as Alzheimer’s disease. Therefore, it seems reasonable to postulate that the mediators of the neurodegenerative process that occurs in the brain could also be present in the diabetic retina. On this basis, the general objective of this thesis is to investigate the relationship between retinal and brain neurodegeneration and its potential clinical and therapeutic implications. The first part of this thesis focuses on experimental studies addressed to identifying mediators of impairment of the neurovascular unit. For this purpose a proteomic “hypothesis-free” study was performed comparing human retinas from non-diabetic and diabetic donors with and without glial activation (one of the hallmarks of retinal neurodegeneration). The Ingenuity Pathway Analysis revealed that several critical pathways related to brain neurodegenerative diseases were differently expressed in retinas from diabetic patients and in particular in those with glial activation. This observation supports the concept that a common soil exists in the neurodegenerative processes that occur in the retina and the brain. In addition, a downregulation of several proteins involved in axonal transport and the cytoskeleton was found in retinas from diabetic donors with glial activation. Furthermore, diabetes-induced glial activation was associated with a dysregulation of the complement system, as well as an upregulation of the proteins that govern the cytoskeleton changes. These results were confirmed by orthogonal methods. These novel findings contribute not only to our understanding of the mechanisms involved in the vascular leakage induced by neurovascular unit impairment, but could also have potential therapeutic implications. The second part of this doctoral thesis is based on a “driven hypothesis” aimed at examining whether endothelin-1 plays a pivotal role in the neurovascular unit impairment that occurs in DR. This is based on the fact that by means of ETA receptors ET-1 leads to vascular damage and through ETB induces neurodegeneration. We first found an overexpression of both ET-1 and its receptors (ETA and ETB) in the retinas from diabetic donors in comparison with nondiabetic donors. Second, we found that topical administration of bosentan (a blocker of ETA and ETB receptors) prevented retinal neurodegeneration induced by diabetes in the db/db mouse model. In addition, the inhibition of diabetes-induced upregulation of PKC-β, TNF-α and VEGF plays an important role in the beneficial vascular action of bosentan. These dual beneficial effects of bosentan (neurotrophic and vasculotropic) and the pharmacokinetic results point to this drug as an excellent candidate to be tested in clinical trials. The third part of the thesis is a clinical study addressed to reinforcing the concept that the assessment of retinal neurodegeneration could be a useful tool to identify those diabetic subjects at risk of developing dementia. Indeed, in a previous study we demonstrated that retinal sensitivity assessed by fundus-driven microperimetry was related to brain neurodegeneration and could be a useful biomarker for identifying patients with T2D who are at risk of developing Alzheimer’s disease. In the present work, we assessed whether gaze fixation, a parameter that can also be assessed by retinal microperimetry, is associated with cognitive impairment. This is based on previous evidence indicating that the capacity to maintain visual gaze on a single location (fixation) is hampered in Alzheimer’s disease. Our results showed that gaze fixation is more unstable as cognitive impairment progresses. Moreover the assessment of fixational parameters significantly improves retinal sensitivity assessment in differentiating those subjects with mild cognitive impairment from normocognitive diabetic subjects. Therefore, the measurement of retinal sensitivity in combination with parameters of fixation by using microperimetry could be a reliable method for detecting prodromal stages of dementia in the T2D population. Hopefully, these findings will be the proof of concept of a large scale-clinical study. Overall, this work contributes to the knowledge of the mediators of neurovascular unit impairment in the early stages of DR and increases our understanding of the link between retinal and brain neurodegeneration in the setting of the type 2 diabetic population. In addition, our findings suggest further candidates as new potential targets for the treatment of DR.

Producción Científica, Diabetic retinopathy (DR) is the main cause of blindness in the working-age population in developed countries. Digital color fundus images can be analyzed to detect lesions for large-scale screening. Thereby, automated systems can be helpful in the diagnosis of this disease. The aim of this study was to develop a method to automatically detect red lesions (RLs) in retinal images, including hemorrhages and microaneurysms. These signs are the earliest indicators of DR. Firstly, we performed a novel preprocessing stage to normalize the inter-image and intra-image appearance and enhance the retinal structures. Secondly, the Entropy Rate Superpixel method was used to segment the potential RL candidates. Then, we reduced superpixel candidates by combining inaccurately fragmented regions within structures. Finally, we classified the superpixels using a multilayer perceptron neural network. The used database contained 564 fundus images. The DB was randomly divided into a training set and a test set. Results on the test set were measured using two different criteria. With a pixel-based criterion, we obtained a sensitivity of 81.43% and a positive predictive value of 86.59%. Using an image-based criterion, we reached 84.04% sensitivity, 85.00% specificity and 84.45% accuracy. The algorithm was also evaluated on the DiaretDB1 database. The proposed method could help specialists in the detection of RLs in diabetic patients., Ministerio de Ciencia, Innovación y Universidades - Fondo Europeo de Desarrollo Regional (projects DPI2017-84280-R and RTC-2015-3467-1)

BackgroundMacular oedema is a form of diabetic retinopathy that can be treated with photocoagulation. The expected effect of treatment varies, and may depend on the previous characteristics of retinal thickening.ObjectiveTo determine whether the change in retinal thickness after focal photocoagulation for diabetic macular oedema varies due to the presence of anatomical features that may justify a separate assessment.Material and methodsNon-experimental, comparative, retrospective, longitudinal study. The mean percentage change in macular volume was compared in eyes with diabetic macular oedema, 3 weeks after focal photocoagulation. The analysis was stratified according to the presence of central and perifoveal temporal thickening (Mann–Whitney U). A regression analysis was performed to identify the contribution of the anatomical variables before photocoagulation to the change in macular volume.ResultsA total of 72 eyes were evaluated. The mean change of macular volume in the sample was −0.68±3.84%. In the multiple regression analysis, the changes of perifoveal temporal (beta 0.54, p

Purpose: To evaluate choroidal thickness (CT) using spectral domain optical coherence tomography (SD-OCT) imaging at baseline and 6 months after intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with diabetic macular edema (DME). Methods: A retrospective chart review was performed to identify patients with DME who underwent intravitreal injection of anti-VEGF (bevacizumab or ranibizumab) in a pro re nata (PRN) regimen. Subfoveal choroidal thickness was compared between values obtained at baseline and at 6-month follow-up visits. Results: Thirty-nine eyes (15 females, 24 males) from 39 patients were enrolled (mean age, 62.43 ± 8.7 years; range, 44-79 years). Twenty-three and 16 eyes were treated with ranibizumab and bevacizumab respectively. The mean number of anti-VEGF injections was 2.28 ± 1.27 (range, 1-5). Mean nasal, subfoveal, and temporal choroidal thickness (CT) measurements at baseline were 234.10 ± 8.63 µm, 246.89 ± 8.94 µm, and 238.12 ± 8.20 µm, respectively, and those at 6 months post-treatment were 210.46 ± 8.00 µm, 215.66 ± 8.29 µm, and 212.43 ± 8.14 µm, respectively. Significant differences in CT were observed between baseline and the 6-month follow-up at all measured points (p=0.0327). Conclusions: Over a 6-month period, the use of intravitreal anti-VEGF was associated with significant thinning of the choroid in patients with DME. The clinical significance of a thinner choroid in DME is currently unknown; however, it may contribute to long-term adverse effects on choroidal and retinal function, representing an area requiring future investigation.

Background Although photocoagulation reduces the incidence of moderate visual loss in eyes with focal diabetic macular oedema, some eyes may lose some vision after treatment. The proportion of eyes with poor functional response after photocoagulation, and whether any retinal variable is associated with this, is unknown. Objective To determine the proportion of eyes with diabetic macular oedema that have a poor functional response after focal photocoagulation, and their associated features. Material and methods A non-experimental, longitudinal, comparative and retrospective study was conducted. The proportion and 95% confidence intervals (CI) of diabetics with macular oedema that had a poor functional response after focal photocoagulation (any visual loss after 6 weeks) were identified. The means of retinal variables before treatment were compared between eyes with and without a poor functional response using the Student t test for independent means. Results The study included 115 eyes of patients aged 59.3 (SD 9.24) years. Visual acuity was greater than or equal to 0.5 in 63 eyes (54.8%). A total of 33 eyes had a poor functional response after photocoagulation (28.7%, 95% CI: 13.3–44.1). The comparison between retinal variables and visual acuity before treatment did not show any differences between eyes with or without a poor functional response and eyes ( p > 0.05). Conclusion Retinal thickening and visual acuity improved or did not change in 71.3% of eyes with diabetic macular oedema with a single photocoagulation procedure. Retinal variables that are usually evaluated were unable to identify the remaining 28.7%, which could lose vision after that treatment, and would require additional interventions.