Combining Fine- and Coarse-Grained Classifiers for Diabetic Retinopathy Detection

Visual artefacts of early diabetic retinopathy in retinal fundus images are usually small in size, inconspicuous, and scattered all over retina. Detecting diabetic retinopathy requires physicians to look at the whole image and fixate on some specific regions to locate potential biomarkers of the disease. Therefore, getting inspiration from ophthalmologist, we propose to combine coarse-grained classifiers that detect discriminating features from the whole images, with a recent breed of fine-grained classifiers that discover and pay particular attention to pathologically significant regions. To evaluate the performance of this proposed ensemble, we used publicly available EyePACS and Messidor datasets. Extensive experimentation for binary, ternary and quaternary classification shows that this ensemble largely outperforms individual image classifiers as well as most of the published works in most training setups for diabetic retinopathy detection. Furthermore, the performance of fine-grained classifiers is found notably superior than coarse-grained image classifiers encouraging the development of task-oriented fine-grained classifiers modelled after specialist ophthalmologists.Comment: Pages 12, Figures

High prognostic value of measurable residual disease detection by flow cytometry in chronic lymphocytic leukemia patients treated with front-line fludarabine, cyclophosphamide, and rituximab, followed by three years of rituximab maintenance

It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10-4. Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3 years of follow-up. Bone marrow (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated vs. unmutated OS: 85.7% alive at 7.2 years vs. 79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies

La sustitución C>A en el NT 46 en la región 3’ UTR (Alfa Complex Protected Region) del gen ALFA 1 de globina ¿mutación o polimorfismo?

PC-048 Antecedentes: Las regiones no traducidas [UnTranslated Region (UTR)] desempeñan un papel crucial en la regulación postranscripcional de la expresión génica, incluida la modulación del transporte de ARNm fuera del núcleo, la eficacia de la traducción, la localización subcelular y la estabilidad. La estabilidad del ARNm es un factor decisivo para el desarrollo y funcionamiento normal de los glóbulos rojos. En el caso del ARNm de a-globina, los principales determinantes de la estabilidad se localizan en el extremo 3’ UTR; en concreto, se han identificado 3 áreas discontinuas ricas en citosina (C) ubicadas entre los nucleótidos (nt) 25 y 70 corriente abajo del codon de parada. Estas áreas ricas en C son responsables de atraer a una ribonucleoproteína (RNP) llamada a-globina poli (C) de unión o a-complejo proteína (aCP) para estabilizar la molécula de ARNm. Wagoner et al. demostraron a través del análisis in vitro que cualquier mutación en estos elementos ricos en C dificulta la unión del ARNm de a-globina con el aCP y desestabiliza al ARNm. Objetivos: Presentamos 15 pacientes con la sustitución C>A en el extremo 3’UTR del gen a1 de globina, localizada en la región del complejo a (aCP), la cual podría causar a-talasemia no deleción al afectar a la estabilidad postranscripcional (estabilidad del ARNm) o tratarse de un polimorfismo. Métodos: Se han estudiado 15 pacientes pertenecientes a 12 familias, todas de origen español excepto dos, una procedente de Rumanía y otra de Marruecos. Las edades estuvieron comprendidas entre 2 y 67 años. Todos fueron estudiados por presentar microcitosis e hipocromía sin ..

Border effects among Catalan dialects

In this study, we investigate which factors influence the linguistic distance of Catalan dialectal pronunciations from standard Catalan. We use pronunciations from three regions where the northwestern variety of the Catalan language is spoken (Catalonia, Aragon and Andorra). In contrast to Aragon, Catalan has an official status in both Catalonia and Andorra, which likely influences standardization. Because we are interested in the potentially large range of differences that standardization might promote, we examine 357 words in Catalan varieties and in particular their pronunciation distances with respect to the standard. In order to be sensitive to differences among the words, we fitted a generalized additive mixed-effects regression model to this data. This allows us to examine simultaneously the general (i.e. aggregate) patterns in pronunciation distance and to detect those words that diverge substantially from the general pattern. The results revealed higher pronunciation distances from standard Catalan in Aragon than in the other regions. Furthermore, speakers in Catalonia and Andorra, but not in Aragon, showed a clear standardization pattern, with younger speakers having dialectal pronunciations closer to the standard than older speakers. This clearly indicates the presence of a border effect within a single country with respect to word pronunciation distances. Since a great deal of scholarship focuses on single segment changes, we compare our analysis to the analysis of three segment changes that have been discussed in the literature on Catalan. This comparison revealed that the pattern observed at the word pronunciation level was supported by two of the three cases examined. As not all individual cases conform to the general pattern,

Comparison of Pheochromocytoma-Specific Morbidity and Mortality among Adults with Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy

Importance: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. Objective: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. Design, Setting, and Participants: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Exposures: Total or cortical-sparing adrenalectomy. Main Outcomes and Measures: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Results: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Conclusions and Relevance: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma

Escala MPN-SAF TSS o MPN-10 de calidad de vida en Policitemia Vera

Poster [PC-240] Introducción: Los síntomas clínicos en las neoplasias mieloproliferativas crónicas suponen un gran impacto en la calidad de vida de estos pacientes. Desde 2.013 la escala MPN-SAF TSS (“The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score”), compuesta por 10 ítems (astenia, saciedad temprana, malestar abdominal, inactividad, problemas al concentrarse, sudoración nocturna, prurito, dolor óseo, fiebre y pérdida de peso), permite una evaluación cuantificable y comparativa de los síntomas. Métodos: Estudio descriptivo y prospectivo de pacientes en seguimiento ambulatorio en el Servicio de Hematología (HUMS) diagnosticados de Policitemia Vera según criterios OMS 2016. Periodo de estudio: Enero 2018-Mayo 2018. Variables analizadas: demográficas, clínicas, hematimétricas y puntuación global e individual por ítems de escala MPNSAF TSS. Puntuación por ítem entre 0 (ausente) y 10 (lo peor posible). Puntuación total posible: 100 puntos. Paciente: alto riesgo: =60 años y episodio trombótico. Paciente: bajo riesgo: <60 años sin episodio previo trombótico. Resultados: Se han estudiado un total de 48 pacientes cuya media de edad fue de 71, 3 años (rango 46-94). La situación hematimétrica de los pacientes en el momento de la encuesta fue la siguiente: la media de Hemoglobina (Hb) y Hematocrito (Hto): 15, 10 g/dL y 46, 47% respectivamente (1 presentaba anemia (Hb =12 g/dL y Hto =38%) y 17 eritrocitosis (Hb =16 g/dL y Hto =48%). Media de leucocitosis: 8, 25.10³/µL (solo 1 presentaba neutropenia) y media de plaquetas: 287. 10³/µL (3 presentaban trombopenia (=130. 10³/µL y 6 trombocitosis (=400. 10³/µL). Del total de pacientes un 43% presentaban esplenomegalia. 34 pacientes pertenecían al grupo de alto riesgo (32 con tratamiento citorreductor) y 14 al de bajo riesgo (8 con flebotomías), todos ellos con tratamiento antiagregante asociado. La mediana global de la escala MPN-SAF TSS fue 17 (rango 2-58). Dentro del grupo de alto riesgo 26 pacientes (76, 47%) se encontraban dentro del primer cuartil (0-25 puntos), 4 pacientes (11, 76%) dentro del segundo cuartil (25-50 puntos), 4 (11, 76%) dentro del tercer cuartil (50-75 puntos) y ninguno superaba los 75 puntos. Dentro del grupo de bajo riesgo, 10 pacientes (71, 42%) dentro del primer cuartil y 4 (28, 57%) dentro del segundo. La puntuación media de cada uno de los síntomas y el porcentaje de pacientes que superaba los 5 puntos en cada ítem fue: “fatiga” 3, 96 (56, 25%), “dolor óseo” 3, 19 (29, 17%), “saciedad precoz” 2, 35 (33, 33%), “problemas de concentración” 2, 35 (27, 08%), “sudoración nocturna” 2, 40 (27, 08%), “malestar abdominal” 1, 50 (18, 75%), “prurito” 1, 65 (12, 05%), “pérdida de peso” 0, 50 (6, 25%) y “fiebre” 0, 10 (0%). La fatiga fue el síntoma más prevalente, tanto en pacientes de alto y bajo riesgo. Conclusiones: La escala MPN-SAF TSS permite una evaluación concisa, válida y precisa de la carga de síntomas, demostrando que gran parte de estos pacientes presentan una calidad de vida mejorable a pesar de presentar estabilidad hematimétrica. Esta herramienta permite detectar sintomatología no previsible analíticamente y dirigir la entrevista clínica y, así, poder llevar a cabo un plan de tratamiento personalizado y dirigido de los síntomas

In vivo pharmacological evaluations of novel olanzapine analogues in rats: a potential new avenue for the treatment of schizophrenia

Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4′-methylpiperazin-1′-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n = 8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n = 12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis

Perfil de pacientes hematológicos atendidos en un servicio de urgencias hospitalario

Poster [PC-355] Introducción: Durante los últimos años existe un aumento progresivo en la demanda de asistencia en los servicios de urgencias hospitalarios (SUH), tanto generales como pediátricos. Los pacientes hematológicos presentan numerosos episodios clínicos que precisan valoración clínica urgente y dada la facilidad de acceso a los SUH emplean este medio. Métodos: Estudio descriptivo observacional de las urgencias en pacientes con patología hematológica atendidas en el Servicio de Urgencias del Hospital Universitario Miguel Servet de Zaragoza (Hospital de tercer nivel). Periodo de estudio (Enero 2017-Diciembre 2017). Criterios de inclusión: Paciente: s con diagnóstico hematológico según la clasificación CIE-9 en el informe de alta de urgencias. Grupo de pacientes adultos (> 14 años): atendidos en el Hospital General, y grupo de pacientes pediátricos (< 14 años): atendidos en el Hospital Infantil. Variables analizadas: edad, sexo, grupo de patología y nivel de triaje. Datos recogidos a través del registro derivado de la Base de Datos generada por el aplicativo informático “Puesto Clínico Hospitalario de Urgencias”, que da soporte a la actividad asistencial de los servicios de urgencias hospitalarios de Aragón. Se obtuvo autorización correspondiente del centro y del SUH para el acceso a los datos informáticos. Resultados: Muestra total de 2193 pacientes: 1928 en el grupo de adultos y 265 en el grupo pediátrico. En el grupo de adultos la edad media de consulta en SUH fue de 71, 4 años (DE: 18.10), siendo el subgrupo de 81-90 años el que más frecuentemente acude (31.74%). En la población infantil la edad media de consulta fue de 6, 39 años (DE: 4.54), siendo entre los 0-2 años la edad que más frecuenta Urgencias (19.62%). Respecto a la distribución según sexo, el 55% de las consultas son realizadas por mujeres y el 45% por hombres. Sin embargo, en la población infantil el 52% de las consultas son realizadas por niños y el 48% por niñas. En el análisis según grupo de enfermedad: el grupo pediátrico consulta más frecuentemente por enfermedades de hemostasia (47.17%), mientras que los adultos consultan más por enfermedades de serie roja (61.28%). En ambos grupos, las consultas realizadas en Urgencias son de gran complejidad con una prioridad elevada de asistencia. El 93% de la patología en adultos y el 71% de la patología infantil hematológica es triada con niveles I-III de urgencia y tiempos asistenciales reducidos. Conclusiones: El comportamiento de las enfermedades hematológicas varía en función de la edad, el sexo y el tipo de enfermedad. La patología hematológica tiene un gran impacto dentro de los servicios de urgencias hospitalarios, dado que estos pacientes presentan un perfil complejo que requerirá diagnóstico y tratamiento rápido por la gravedad del tipo de complicaciones que asocian. En consonancia con la población envejecida, los pacientes que más demandan la atención en Urgencias y de forma repetida, son adultos muy mayores (81-90 años) pudiéndose plantear circuitos de asistencia urgente diferentes para estos pacientes

Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2\u2009cm; P\u20091.5\u2009cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8\u2009cm vs 652.8\u2009cm (94% vs 85% by 10 years; P\u2009=\u20090.020; 80% vs 50% at 10 years; P\u2009=\u20090.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8\u2009cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs

2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field