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Background & Aims Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population. Methods Multicentre retrospective, cross-sectional, international study of liver cancer patients with SARS-CoV-2 infection registered between February and December 2020. Clinical data at SARS-CoV-2 diagnosis and outcomes were registered. Results Two hundred fifty patients from 38 centres were included, 218 with hepatocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at SARS-CoV-2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow-up of 7.20 (IQR: 1.84–11.24) months, 100 (40%) patients have died, 48% of the deaths were SARS-CoV-2-related. Forty (18.4%) HCC patients died within 30-days. The death rate increase was significantly different according to the BCLC stage (6.10% [95% CI 2.24–12.74], 11.76% [95% CI 4.73–22.30], 20.69% [95% CI 11.35–31.96] and 34.52% [95% CI 17.03–52.78] for BCLC 0/A, B, C and D, respectively; p = .0017). The hazard ratio was 1.45 (95% CI 0.49–4.31; p = .5032) in BCLC-B versus 0/A, and 3.13 (95% CI 1.29–7.62; p = .0118) in BCLC-C versus 0/A in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, and 12 deaths were related to SARS-CoV-2 infection. Conclusions This is the largest cohort of liver cancer patients infected with SARS-CoV-2. It characterizes the 30-day mortality risk of SARS-CoV-2 infected patients with HCC during this period., Spanish Health Ministry; Ricerca Corrente, Grant/Award Number: RC2019/105-01, RC2018/105-01 and RC2017/105-01; European Association for the Study of the Liver (Andrew Burroughs Fellowship); Cancer Treatment and Research Trust (CTRT); Wellcome Trust Strategic Fund, Grant/Award Number: PS3416; Cancer Research UK (CR UK) centre, Grant/Award Number: C9380/A26813, C18342/A23390 and C9380/A18084; Instituto de Salud Carlos III, Grant/Award Number: PI18/0358, PI15/00145, CD18/00126, PI19/00819, FI19/00222, 16-0026, PI044031, PI18/00768, PI18/00542 and PI13/01229; Bristol Myers Squibb and Celgene; Cancer Research UK, Grant/Award Number: RCCPDB-Nov21/100008

BACKGROUND & AIMS Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population. METHODS Multicenter retrospective, cross-sectional, international study of liver cancer patients with SARS-CoV-2 infection registered between February-December 2020. Clinical data at SARS-CoV-2 diagnosis and outcomes were registered. RESULTS Two-hundred-fifty patients from 38 centers were included, 218 with hepatocellular carcinoma (HCC), 32 with intrahepatic cholangiocarcinoma (iCCA). Median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts, respectively. Patients had advanced cancer stage at SARS-CoV-2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow-up of 7.20 [IQR:1.84-11.24] months, 100 (40%) patients have died,48% of the deaths were SARS-CoV-2-related. Forty (18.4%) HCC patients died within 30-days. The death rate increase was significantly different according to the BCLC stage [6.10%(95%CI 2.24-12.74), 11.76%(95%CI 4.73-22.30), 20.69%(95%CI 11.35-31.96), and 34.52%(95%CI 17.03-52.78) for BCLC 0/A, B, C and D respectively; p=0.0017]. The Hazard Ratio was 1.45 (95%CI 0.49-4.31; p=0.5032) in BCLC-B vs 0/A, and 3.13 (95%CI 1.29-7.62; p=0.0118) in BCLC-C vs 0/A in the Competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, 12 deaths related to SARS-CoV-2 infection. CONCLUSIONS This is the largest cohort of liver cancer patients infected with SARS-CoV-2. It characterizes the 30-day mortality risk of SARS-CoV-2 infected patients with HCC during this period.

This document aims to support the final report from the doctoral thesis Historical Reconfiguration of Higher- Distance Education, from a Theoretical, Dialogical, Didactic, Mediated, Perspective, Experienced in the University of Quindío. As a requirement to become a doctor in Educational Sciences. The main objective of this study was focused on reshaping the higher-distance education history from the University of Quindío, taking as a reference the Dialogical Mediated Theory, to provide importance to the academic legacy with a critical and proactive point of view. The methodological scheme was supported in the Historical-Educational investigation, from the Historic Method. To gather relevant information, the study was based on primary sources such as the Historical Interview technique and secondary sources like documentary investigation. After the study application, the following specific objectives of this inquiry were accomplished, Con fines de sustentar el Grado de Doctora en Ciencias de la Educación, se presenta el informe final de la Tesis Doctoral, Reconfiguración Histórica de la Educación Superior a Distancia, desde la perspectiva Teórica Dialógica Didáctica Mediada, experiencia Universidad del Quindío. Para desarrollar la investigación se trazó como telar u objetivo general, reconfigurar la historia de la Educación Superior a Distancia en la Universidad del Quindío, a partir de la Teoría Dialógica Mediada, para otorgar sentido al legado académico y aportar una visión crítica y propositiva. Las urdimbres de orden metodológico se sustentaron en la Investigación Histórico Educativa, desde el Método Histórico. Para tal efecto, esta investigación se apoyó en fuentes primarias, haciendo uso de la técnica Entrevista Histórica, y en fuentes secundarias, mediante el uso de la investigación documental. A partir del estudio se comprobó la hipótesis cualitativa, 1 Introducción ….. 4 Primer eje ….. 6 Capitulo uno …… 6 Naturaleza Ontológica e histórica ….. 32 Capitulo dos ….. 32 Naturaleza Social y Teológica ….. 37 Segundo Eje ….. 39 Capitulo uno ….. 39 Fundamentos conceptuales ….. 52 Capitulo dos ….. 52 Fundamentos Teóricos ….. 79 Capitulo tres …..79 Fundamentos Normativos ….. 114 Tercer Eje ….. 116 Capitulo uno ….. 116 Marco Metodológico ….. 128 Capitulo dos ….. 128 Diseño mitológico ….. 133 Capitulo tres ….. 133 Desarrollo Matriz Metodológica …..257 Capitulo cuatro …..257 Redacción texto histórico de la fase síntesis explicativa ….. 344 Conclusiones ….. 355 Bibliografía, Doctorado, Doctor en Ciencias de la Educación, Informática Educativa

Background NAFLD clinical trials have shown suboptimal results, particularly for liver fibrosis, despite the robust preclinical drug development. We aimed to assess the histological response after the experimental treatment versus placebo by carrying out a meta-analysis of NAFLD clinical trials. Methods After a systematic review of NAFLD clinical trials to May 2021, applying strict selection criteria, the following primary outcomes were observed: (a) NASH resolution, with no worsening of fibrosis when available; (b) fibrosis improvement ≥ 1 stage, with no worsening of NAS when available; (c) worsening of NAS; (d) worsening of liver fibrosis ≥ 1 stage, including the progression to cirrhosis on histopathology. Other histological, clinical, and biochemical outcomes were considered secondary endpoints. Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression. Results Twenty-seven randomized clinical trials were included. The pooled efficacy for NASH resolution receiving experimental therapy was 19% (95%CI 15–23; I2 96.2%) compared with placebo 10% (95%CI 7–12; I2 85.8%) (OR 1.66 (95%CI 1.24–2.21); I2 57.8%), while it was 26% (95%CI 22–29); I2 90%)) versus 18% (95%CI 15–21; I2 59%)) for fibrosis improvement (OR 1.34 (95%CI 1.13–1.58); I2 25.4%). For these outcomes, the therapy showed higher efficacy in trials longer than 48 weeks, with

En esta tesis se analiza el régimen de responsabilidad que deben observar los prestadores de servicios de intermediación en la Directiva de Comercio Electrónico y que actualmente se aplica en España por la LSSICE, así como el sistema que se concretará y profundizará con la Ley de Servicios Digitales. Todo ello para responder a la pregunta general que guía el desarrollo de esta tesis: ¿Cumple el régimen de responsabilidad aplicable a los prestadores de servicios de intermediación contenido en la normativa con los postulados constitucionales en los que se basa la libertad de expresión? Para ello, se analiza especialmente en el marco supranacional y constitucional y bajo los parámetros de la jurisprudencia. Para desarrollar esta cuestión general, es necesario establecer, en primer lugar, el alcance, los elementos básicos y las garantías del derecho a la libertad de expresión en Internet. Para ello es necesario conocer a fondo los planteamientos constitucionales y la naturaleza de la libertad de expresión. Además, es imprescindible estudiar y analizar la doctrina jurisprudencial sobre los límites de la libertad de expresión. A partir de esta teoría, será posible abordar los principales retos que el avance de Internet ha planteado para esta libertad fundamental, como por ejemplo, la restricción de la libertad de expresión entre particulares. En segundo lugar, es necesario identificar las condiciones que establece el régimen de responsabilidad de los prestadores de servicios intermediarios de la Directiva de Comercio Electrónico, la LSSICE y la Ley de Servicios Digitales. En cuanto al alojamiento de contenidos de los usuarios en las plataformas (redes sociales, blogs, YouTube, foros, etc.) y su incidencia en la gestión de las plataformas a la luz de la libertad de expresión. Además, se estudiaan las obligaciones específicamente asignadas a los prestadores de servicios de intermediación, con especial atención a las garantías previstas en la LSSICE, actualmente en proceso de aprobación. Todos los aspectos anteriores tendrán como principal punto de referencia los postulados constitucionales correspondientes a la libertad de expresión. Finalmente, en tercer lugar, es necesario acercarse a las plataformas digitales para establecer cómo los prestadores de servicios de intermediación gestionan sus plataformas digitales (Facebook, Twitter y YouTube) y cuáles son los mecanismos de restricción entre particulares (moderación, mecanismos de control automatizado de contenidos, entre otros) que se implementan en ellas. Para ello, es fundamental revisar las normas internas implementadas por los proveedores de servicios de intermediación, para analizar los controles realizados y su impacto en la libertad de expresión considerando las garantías constitucionales de la libertad de expresión. This thesis analyses the liability regime to be observed by intermediary service providers in the E-Commerce Directive and which is currently applied in Spain by the LSSICE, as well as the system that will be specified and deepened by the DSA. All of this to answer the general question that guides the development of this thesis: Does the liability regime applicable to intermediary service providers contained in the regulations comply with the constitutional postulates on which freedom of expression is based? For this purpose, it is analysed especially in the supranational and constitutional framework and under the parameters of jurisprudence. To develop this general question, it is first necessary to establish the scope, basic elements and guarantees of the right to freedom of expression on the Internet. This requires a full understanding of constitutional approaches and the nature of freedom of expression. Furthermore, it is essential to study and analyse the jurisprudential doctrine on the limits to freedom of expression. Based on this theory, it will be possible to address the major challenges that the advance of the Internet has posed for this fundamental freedom, such as, for example, the restriction of freedom of expression between private individuals. Secondly, it is necessary to identify the conditions established by the liability regime for intermediary service providers under the E-Commerce Directive, the DSA and the LSSICE. Regarding the hosting of user content on platforms (social networks, blogs, YouTube, forums, etc.) and their impact on the management of the platforms in the light of freedom of expression. In addition, the obligations specifically assigned to intermediary service Providers will be studied, with special attention to the guarantees provided for in the DSA, currently in the process of being approved. All the above aspects will have as their main reference point the constitutional postulates corresponding to freedom of expression, as mentioned in the previous paragraph. Finally, thirdly, it is necessary to approach digital platforms to establish how intermediary service providers manage their digital platforms (Facebook, Twitter, and YouTube) and what are the mechanisms of restriction between individuals (moderation, automated content control mechanisms, among others) that are implemented in them. To this end, it is essential to review the internal rules implemented by intermediary service providers, to analyse the controls carried out and their impact on freedom of expression considering constitutional guarantees of freedom of expression.