Sofosbuvir más glecaprevir/pibrentasvir como terapia de rescate postrasplante hepático en pacientes con exposición previa a inhibidores de NS5A. Serie de casos / Sofosbuvir plus glecaprevir/pibrentasvir as salvage therapy after liver transplantation in NS5A inhibitor-experienced patients. A case series

Resumen Antecedentes: El tratamiento de la infección crónica por el virus de la hepatitis C (VHC) con antivirales de acción directa logra tasas de respuesta virológica sostenida superiores a 95 %. Sin embargo, el manejo del fracaso virológico sigue siendo un desafío clínico y la evidencia sobre el retratamiento es limitada, especialmente en poblaciones como los receptores de trasplante hepático (TH). Objetivo: Este estudio evaluó el régimen de sofosbuvir más glecaprevir/pibrentasvir (GLE/PIB) en receptores de TH en quienes falló el régimen basado en inhibidores de la proteína no estructural 5A (NS5A). Material y métodos: Estudio retrospectivo de 111 pacientes trasplantados entre enero de 2018 y diciembre de 2020; 18 pacientes presentaron infección recurrente por VHC posterior al TH, tres de ellos tuvieron antecedentes de al menos un régimen basado en inhibidores de NS5A. Se inició terapia de rescate con sofosbuvir más GLE/PIB durante 12 semanas posterior al TH; se registraron las características basales de los pacientes y sus desenlaces. Resultados: En los tres pacientes se logró obtener una carga viral indetectable de VHC a las 12 semanas de finalizar el tratamiento. No se observaron eventos adversos graves. Conclusión: En nuestra serie, sofosbuvir más GLE/PIB durante 12 semanas demostró ser una terapia de rescate efectiva y segura posterior al TH en pacientes previamente tratados con inhibidores de NS5A.

Abstract Background: Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals achieves a sustained virologic response rates higher than 95%. However, virologic failure remains a clinical challenge, and data on retreatment are limited, especially in special populations such as liver transplant (LT) recipients. Objective: This study evaluated the sofosbuvir plus glecaprevir-pibrentasvir (GLE/PIB) regimen in LT recipients who had failed to a nonstructural protein 5A (NS5A) inhibitor-based regimen. Material and methods: Retrospective study of 111 liver transplant recipients between January 2018 and December 2020; 18 patients presented with HCV recurrent infection after LT, out of whom three had a history of at least one NS5A inhibitor-based regimen. Salvage therapy with sofosbuvir plus GLE/PIB was started for 12 weeks; baseline characteristics and outcomes were recorded. Results: All three patients (100%) achieved an undetectable HCV viral load 12 weeks after treatment completion. No serious adverse events were observed. Conclusion: In our series, sofosbuvir plus GLE/PIB for 12 weeks is an effective and safe salvage therapy after LT in patients previously treated with NS5A inhibitors.

Servicio de atención psicológica a niños y adolescentes convalecientes a la COVID-19 en Villa Clara

Fundamento: los niños y los adolescentes constituyen una población sensible a los impactos psicológicos de la pandemia de COVID-19. Reconocerlo implica la necesidad de evaluación, seguimiento e intervención, especialmente cuando se trata de infantes que padecieron la enfermedad y requieren una atención pediátrica integral. Objetivo implementar un servicio de atención psicológica a niños y adolescentes convalecientes a la COVID-19. Métodos: se aplicó un diseño de investigación acción participativa desde un enfoque cualitativo constructivo-interpretativo. Está integrado por tres ejes de acciones: evaluación psicológica, intervención psicoterapéutica y apoyo social. Su diseño e implementación siguió etapas y se realizó de forma colaborativa. Los participantes implicados establecieron relaciones simétricas y siguieron un proceso cíclico de planificación-actuación-observación-reflexión; procedimiento base para atender y perfeccionar la práctica. Resultados: los resultados se obtuvieron con respecto a la evaluación y las acciones de intervención psicológica. Sobre la evaluación se destacan alteraciones clínico psicológicas con afectación de las funciones psíquicas y necesidades de preservación de la salud en los ámbitos personal y familiar. Respecto a la intervención psicológica, la totalidad de los beneficiarios recibió acciones de orientación psicológica y los diagnosticados con afección psiquiátrica recibieron acciones psicoterapéuticas. Todas las familias recibieron apoyo social. Conclusiones: se constató reducción o remisión de la intensidad de síntomas psicológicos, elaboración del duelo ante la pérdida, adecuación de afrontamientos o modificación de comportamientos, fortalecimiento de la capacidad de las redes sociales de apoyo, ampliación del conocimiento de la familia, y creación de canales de información entre la familia y la escuela.

Background: children and adolescents constitute a sensitive population to the psychological impacts of the COVID-19 pandemic. Recognizing it implies the need for evaluation, monitoring and intervention, especially when it comes to infants who have suffered from the disease and require comprehensive pediatric care. Objective: to implement a psychological care service for children and adolescents convalescent from COVID-19. Methods: a participatory action research design was applied from a constructive-interpretive qualitative approach. It is made up of three lines of action: psychological evaluation, psychotherapeutic intervention and social support. Its design and implementation followed stages and was carried out collaboratively. The participants involved established symmetrical relationships and followed a cyclical process of planning-acting-observing-reflecting; basic procedure to attend and improve the practice. Results: the results were obtained regarding the evaluation and the actions of psychological intervention. Regarding the evaluation, clinical-psychological alterations with affectation of the psychic functions and needs for the preservation of health in the personal and family spheres stand out. Regarding the psychological intervention, all the beneficiaries received psychological counseling actions and those diagnosed with a psychiatric condition received psychotherapeutic actions. All families received social support. Conclusions: The psychological symptoms intensity reduction or remission was verified, elaboration of grief in the loss, adaptation of coping or behavior modification, strengthening of the social support networks' capacity, expansion of family knowledge, and creation of information channels between the family and the school.

Consecuencias psicológicas y recursos psicosociales de afrontamiento en niños y adolescentes convalecientes a la COVID-19 / Psychological consequences and psychosocial coping resources in children and adolescents convalescing from COVID-19

RESUMEN Introducción: Los niños y los adolescentes constituyen una población vulnerable al impacto psicológico que desencadena la COVID-19. Objetivo: Develar consecuencias psicológicas y recursos psicosociales de afrontamiento en niños y adolescentes convalecientes a la COVID-19. Métodos: Se realizó una investigación con enfoque cualitativo constructivo interpretativo, en el período comprendido entre abril de 2020 y septiembre de 2021. Las técnicas empleadas para la obtención de la información fueron: el rombo afectivo, la composición temática, la entrevista semiestructurada, el examen psiquiátrico, la Prueba de Percepción del Funcionamiento Familiar FF-SIL y la historia social psiquiátrica. La muestra estuvo conformada por 25 niños y adolescentes, a partir de criterios de conveniencia y disponibilidad, y con previo consentimiento informado de sus padres. En el procesamiento de los datos obtenidos se empleó la herramienta ATLAS.ti 9, software que permitió el análisis de frecuencias y de coocurrencias de códigos. Resultados: Se señalan, entre otros aspectos, alteraciones clínico-psicológicas con afectación de las funciones afectivas, conativas y de relación, así como necesidades de preservación de la salud en los ámbitos personal y familiar. Conclusiones: Las niñas, los niños y los adolescentes convalecientes a la COVID-19, evidencian síntomas clínico-psicológicos como la ansiedad, el miedo, la tristeza y la irritabilidad, y enfermedades psiquiátricas que clasifican dentro de los trastornos de ansiedad y de adaptación; los recursos psicosociales de afrontamiento, se caracterizaron por la limitada movilización de alternativas resilientes, el predominio de estados emocionales de felicidad ante el alta clínica y la presencia de apoyo social de tipo emocional.

ABSTRACT Introduction: children and adolescents constitute a vulnerable population to the psychological impact triggered by COVID-19. Objective: to reveal the psychological consequences and psychosocial coping resources in children and adolescents convalescing from COVID-19. Methods: a qualitative, constructive and interpretive research was carried out between April 2020 and September 2021. The affective rhombus and thematic composition techniques, the semi-structured interview, the psychiatric examination, the Family Functioning Perception Questionnaire (FF-SIL) and the psychiatric social history were used to obtain the information. The sample consisted of 25 children and adolescents, based on criteria of convenience and availability, and with the prior informed consent of their parents. The ATLAS.ti 9 software was the tool used to process the obtained data, allowing us the analysis of frequencies and code co-occurrences. Results: we pointed out, among other aspects, clinical and psychological alterations with impairment of the affective, conative and relational dimensions, as well as health preserving needs in personal and family spheres. Conclusions: children and adolescents convalescing from COVID-19 show clinical and psychological symptoms such as anxiety, fear, sadness, irritability and psychiatric diseases which classify within anxiety and adaptation disorders; the psychosocial coping resources were characterized by the limited mobilization of resilient alternatives, the predominance of emotional states of happiness after being discharge, and the presence of emotional social support.

Non-invasive diagnosis and follow-up of chronic infection with Hepatitis C Virus.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Clinical care for patients with HCV-related liver disease has advanced considerably with developments in screening, diagnostic procedures to evaluate liver fibrosis and improvements in therapy with pangenotypic direct antivirals and prevention. These AFEF guidelines on the non-invasive diagnosis and follow up of chronic infection with HCV describe the optimal management of HCV positive patients with non-invasive methods in screening, in assessing viral disease and liver fibrosis and the follow-up of these patients according to the value of FibroScan®, Fibrotest® or Fibrometer®. Hepatocellular carcinoma screening must continue in patients with liver stiffness by FibroScan® ≥10 kPa or Fibrotest® >0.58 or Fibrometer® >0.78 prior to treatment initiation. After reaching sustained virologic response, patients with a measurement of liver stiffness by FibroScan®<10 kPa or Fibrotest®≤0.58 or Fibrometer®≤0.78 before treatment initiation and without liver comorbidity (alcohol consumption, metabolic syndrome, HBV co-infection etc.) no longer require specific monitoring. The role of liver biopsy is discussed in some rare situations.

Cirrhosis etiology trends in developing countries: Transition from infectious to metabolic conditions. Report from a multicentric cohort in central Mexico.

Background: Cirrhosis is a public health threat associated with high mortality. Alcoholic Liver Disease (ALD) is the leading cause in Latin America and Metabolic Associated Fatty Liver Disease (MAFLD) in western countries. In Mexico, ALD and chronic Hepatitis C Virus infection (HCV) were the most frequent aetiologies during the past decades. We aimed to describe the trends in the aetiologies of cirrhosis in a middle-income country. Methods: We performed a retrospective cohort study including patients diagnosed with cirrhosis between 2000 and 2019 from six different tertiary care hospitals in central Mexico. We collected information regarding cirrhosis etiology, year of diagnosis, hepatocellular carcinoma development, liver transplantation, and death. We illustrated the change in the tendencies of cirrhosis aetiologies by displaying the proportional incidence of each etiology over time stratified by age and gender, and we compared these proportions over time using chi square tests. Findings: Overall, 4,584 patients were included. In 2019, MAFLD was the most frequent cirrhosis etiology (30%), followed by ALD (24%) and HCV (23%). During the study period, MAFLD became the leading etiology, ALD remained second, and HCV passed from first to fourth. When analysed by gender, ALD was the leading etiology for men and MAFLD for women. The annual incidence of HCC was 3·84 cases/100 persons-year, the median survival after diagnosis was 12·1 years, and seven percent underwent LT. Interpretation: Increased alcohol consumption and the obesity epidemic have caused a transition in the aetiologies of cirrhosis in Mexico. Public health policies must be tailored accordingly to mitigate the burden of alcohol and metabolic conditions in developing countries. Funding: None.

Premisas conceptuales acerca de la categoría subjetividad que requiere el proceso formativo del médico general / Conceptual premises about the subjectivity category required by the training process of the general practitioner

RESUMEN El proceso formativo del médico general en la educación médica superior cubana no enfatiza en las premisas conceptuales como garantía de una adecuada comprensión cultural e histórica del sujeto y la subjetividad, que este profesional aporta en acción y relación dentro del tejido social. Se pretende sintetizar las premisas conceptuales implícitas en la categoría subjetividad, devenida objeto de estudio del proceso formativo del médico general; por ello, resultó indispensable la descripción de los principales aportes teóricos que posibilitaron, desde inicios de la década de los 80 del pasado siglo XX, el desarrollo dentro del contexto nacional de una teoría de la subjetividad. Se concluyó que las premisas conceptuales acerca de la categoría subjetividad que requiere el proceso formativo del médico general, aluden a determinadas zonas de sentido donde se vinculan las categorías subjetividad individual y social, sentidos subjetivos, mediaciones por la subjetividad, así como sujeto individual y social.

ABSTRACT The training process of the general practitioner in Cuban higher medical education does not emphasize the conceptual premises as a guarantee of an adequate cultural and historical understanding of the subject and subjectivity, which this professional contributes in action and relationship within the social fabric. The aim is to synthesize the implicit conceptual premises in the subjectivity category, which has become an object of study in the training process of the general practitioner; For this reason, it was essential to describe the main theoretical contributions that made possible, since the beginning of the 80s of the last century, the development within the national context of a theory of subjectivity. It was concluded that the conceptual premises about the subjectivity category required by the training process of the general practitioner, allude to certain areas of meaning where the categories individual and social subjectivity, subjective senses, mediations by subjectivity, as well as individual and social subject are linked.

Macrophage autophagy protects against hepatocellular carcinogenesis in mice.

Autophagy is a lysosomal degradation pathway of cellular components that regulates macrophage properties. Macrophages are critically involved in tumor growth, metastasis, angiogenesis and immune suppression. Here, we investigated whether macrophage autophagy may protect against hepatocellular carcinoma (HCC). Experiments were performed in mice with deletion of the autophagy gene Atg5 in the myeloid lineage (ATG5Mye-/- mice) and their wild-type (WT) littermates. As compared to WT, ATG5Mye-/- mice were more susceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, as shown by enhanced tumor number and volume. Moreover, DEN-treated ATG5Mye-/- mice exhibited compromised immune cell recruitment and activation in the liver, suggesting that macrophage autophagy invalidation altered the antitumoral immune response. RNA sequencing showed that autophagy-deficient macrophages sorted from DEN mice are characterized by an enhanced expression of immunosuppressive markers. In vitro studies demonstrated that hepatoma cells impair the autophagy flux of macrophages and stimulate their expression of programmed cell death-ligand 1 (PD-L1), a major regulator of the immune checkpoint. Moreover, pharmacological activation of autophagy reduces hepatoma cell-induced PD-L1 expression in cultured macrophages while inhibition of autophagy further increases PD-L1 expression suggesting that autophagy invalidation in macrophages induces an immunosuppressive phenotype. These results uncover macrophage autophagy as a novel protective pathway regulating liver carcinogenesis.

Configuración subjetiva del afrontamiento psicológico a la COVID-19 de adolescentes convalecientes del primer rebrote / Subjective configuration of psychological facing up to COVID-19 of convalescent adolescent´s for the first regrowth

Introducción: Para los adolescentes, enfermar de la COVID-19 constituye un acontecimiento estresante ante las demandas del ingreso hospitalario y la intervención médica. Objetivo: Reflejar la configuración subjetiva del afrontamiento psicológico a la COVID-19 de adolescentes convalecientes del primer rebrote de la enfermedad. Métodos: La investigación siguió un enfoque cualitativo constructivo interpretativo, a través de un estudio de casos múltiples. La muestra se seleccionó de forma intencional; se accedió a 13 adolescentes convalecientes de la COVID-19 en el período abril-octubre de 2020, que fueron incluidos para seguimiento por los servicios de Psicología y Psiquiatría infanto-juvenil, a partir de su permanencia en la provincia de Villa Clara. Se emplearon para la obtención de la información las técnicas composición y el rombo afectivo. El análisis de los contenidos se procesó con la herramienta ATLAS.ti. Resultados: El afrontamiento psicológico a la COVID-19 de adolescentes convalecientes del primer rebrote de la enfermedad, se caracterizó por malestares psicológicos como el miedo y la tristeza, la valoración positiva del trabajo del personal de la salud, la limitada movilización de recursos resilientes y la escasa percepción de apoyo social. Conclusiones: La rehabilitación en contextos de la vida cotidiana se afronta desde la preocupación por el proyecto de formación profesional, la necesidad de seguridad y protección encaminada a erradicar la pandemia, la preservación de la salud personal y familiar, y la compañía de los familiares que viven en el hogar(AU)

Introduction: For adolescent´s getting sick of COVID-19 constitute a stressful situation considering demands of being in hospital and due to the medical attention. Objective: Making known the subjective configuration of psychological facing up to COVID-19 of convalescent adolescent´s for the first regrowth of this illness trough a multi-case study. Methods: The research was carried out following an interpretative constructive qualitative approach trough a multi-case study. The sample was selected intentionally, having access to 13 convalescent adolescent´s suffering from COVID-19 over period of April-October, in 2020 that were included in order to be followed by infant and young psychiatric and psychology service from their stay on in our province of Villa Clara. Writing a composition and affective rhombus technique, were used to get some information. Content analysis was processed using the tool ATLAS.ti. Results: The psychological facing up to COVID-19 of convalescent adolescent´s for the first regrowth of this illness was characterized by psychological discomfort as fears and sadness, favorable assessment on the work of health staff, limited mobilization of tough resources and short of perception of social support. Conclusions: The rehabilitation on daily life context is faced from the concern for the Project of professional training, the protection and security needs putting into the end of pandemic, family and personal health preservation and the company of family that live at home(AU)

Concepción teórico-metodológica para la formación del modo de actuación atención médica integral desde la Psicología / Theoretical-methodological conception in view of the formation of a model of action in comprehensive medical care from psychology

Introducción: El reciente perfeccionamiento curricular de la carrera de Medicina en la educación superior cubana suscita la búsqueda de alternativas científicas que contribuyan a la sistematización del proceso formativo de la atención médica integral en los servicios de la asistencia sanitaria esencial. Objetivo: Exponer una concepción teórico-metodológica para la formación del modo de actuación atención médica integral desde la disciplina Psicología. Métodos: El proceso investigativo asumió un enfoque metodológico mixto o multimodal, que siguió un diseño mixto explicativo secuencial, en el que se integraron métodos teóricos, empíricos, así como de análisis de la información y procesamiento de los datos. Este se desarrolló en la carrera de Medicina de la Universidad de Ciencias Médicas de Villa Clara entre septiembre de 2016 y enero de 2019, y abarcó los momentos de la exploración, el diseño y la evaluación del resultado científico propuesto. Resultados: Se pudo definir la connotación científica de la concepción teórico-metodológica propuesta, en respuesta a la estructura formal para la formación del modo de actuación atención médica integral y a la forma lógica de su vinculación con la disciplina Psicología. Conclusiones: Se estableció que una concepción teórico-metodológica para la formación del modo de actuación atención médica integral desde la disciplina Psicología debe integrar en su estructura los fundamentos generales que sustentan la lógica interna de esta, y los componentes teórico-conceptual y metodológico-instrumental que definen su organización e implementación práctica(AU)

Introduction: The recent curricular improvement of the medical major in Cuban higher education brings about the search for scientific alternatives that contribute to systematization of the training process for comprehensive medical care in essential healthcare services. Objective: To present a theoretical-methodological conception for the formation of a mode of action in comprehensive medical care from the psychology discipline. Methods: The research process followed a mixed or multimodal methodological approach, under a mixed sequential explanatory design, in which theoretical and empirical methods were integrated, as well as information analysis and data processing. This was developed, between September 2016 and January 2019, in the medical major of Villa Clara University of Medical Sciences, and covered the moments of exploration, design and assessment of the proposed scientific result. Results: It was possible to define the scientific connotation of the proposed theoretical-methodological conception, in response to the formal structure for the formation of a mode of action in comprehensive medical care and the logical way of its link with the psychology discipline. Conclusions: It was established that a theoretical-methodological conception for the formation of a mode of action in comprehensive medical care from the psychology discipline must integrate, into its structure, the general foundations that support its internal logic, as well as the theoretical-conceptual and methodological-instrumental components that define its organization and practical implementation(AU)

Hepatocellular carcinoma: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, AFEF, SIAD, SFR/FRI).

INTRODUCTION: This document is a summary of the French Intergroup guidelines regarding the management of hepatocellular carcinoma (HCC) published in March 2019. METHOD: It is a collaborative work under the auspices of most of the French medical societies involved in the management of HCC. It is based on the previous guidelines published in 2017. Recommendations are graded in 3 categories according to the level of evidence of data found in the literature. RESULTS: The diagnosis and staging of HCC is essentially based on clinical, biological and imaging features. A pathological analysis obtained by a biopsy of tumoral and non-tumoral liver is recommended. HCCs can be divided into 2 groups, taking into account not only the tumor stage, but also liver function. HCCs accessible to curative treatments are tumors that are in Milan criteria or with an AFP score ≤ 2, mainly treated by surgical resection, local ablation or liver transplantation. Intermediate and advanced HCCs with no liver insufficiency, accessible only to palliative treatments, benefit from TACE, SIRT or systemic therapy according to the presence or absence of macrovascular invasion or extrahepatic spread. CONCLUSION: Such recommendations are in permanent optimization and each individual case must be discussed in a multidisciplinary expert board.

Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry.

BACKGROUND: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has been associated with a significant risk of thrombotic events in critically ill patients. AIM: To summarize the findings of a multinational observational cohort of patients with SARS-CoV-2 and cerebrovascular disease. METHODS: Retrospective observational cohort of consecutive adults evaluated in the emergency department and/or admitted with coronavirus disease 2019 (COVID-19) across 31 hospitals in four countries (1 February 2020-16 June 2020). The primary outcome was the incidence rate of cerebrovascular events, inclusive of acute ischemic stroke, intracranial hemorrhages (ICH), and cortical vein and/or sinus thrombosis (CVST). RESULTS: Of the 14,483 patients with laboratory-confirmed SARS-CoV-2, 172 were diagnosed with an acute cerebrovascular event (1.13% of cohort; 1130/100,000 patients, 95%CI 970-1320/100,000), 68/171 (40.5%) were female and 96/172 (55.8%) were between the ages 60 and 79 years. Of these, 156 had acute ischemic stroke (1.08%; 1080/100,000 95%CI 920-1260/100,000), 28 ICH (0.19%; 190/100,000 95%CI 130-280/100,000), and 3 with CVST (0.02%; 20/100,000, 95%CI 4-60/100,000). The in-hospital mortality rate for SARS-CoV-2-associated stroke was 38.1% and for ICH 58.3%. After adjusting for clustering by site and age, baseline stroke severity, and all predictors of in-hospital mortality found in univariate regression (p < 0.1: male sex, tobacco use, arrival by emergency medical services, lower platelet and lymphocyte counts, and intracranial occlusion), cryptogenic stroke mechanism (aOR 5.01, 95%CI 1.63-15.44, p < 0.01), older age (aOR 1.78, 95%CI 1.07-2.94, p = 0.03), and lower lymphocyte count on admission (aOR 0.58, 95%CI 0.34-0.98, p = 0.04) were the only independent predictors of mortality among patients with stroke and COVID-19. CONCLUSIONS: COVID-19 is associated with a small but significant risk of clinically relevant cerebrovascular events, particularly ischemic stroke. The mortality rate is high for COVID-19-associated cerebrovascular complications; therefore, aggressive monitoring and early intervention should be pursued to mitigate poor outcomes.

Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.

BACKGROUND: Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients. METHODS: In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death. FINDINGS: Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47-66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44-84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p<0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p<0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI -7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients. INTERPRETATION: Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic. FUNDING: European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.

MK-571, a Cysteinyl Leukotriene Receptor 1 Antagonist, Inhibits Hepatitis C Virus Replication.

The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct-acting antiviral (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with a 50% effective concentration (EC50 ± standard deviation) of 9 ± 0.3 µM and a maximum HCV RNA level reduction of approximatively 1 log10 MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonist SR2640 increased HCV-subgenomic replicon (SGR) RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle.

Small-Molecule Inhibitors of Cyclophilins Block Opening of the Mitochondrial Permeability Transition Pore and Protect Mice From Hepatic Ischemia/Reperfusion Injury.

BACKGROUND & AIMS: Hepatic ischemia/reperfusion injury is a complication of liver surgery that involves mitochondrial dysfunction resulting from mitochondrial permeability transition pore (mPTP) opening. Cyclophilin D (PPIF or CypD) is a peptidyl-prolyl cis-trans isomerase that regulates mPTP opening in the inner mitochondrial membrane. We investigated whether and how recently created small-molecule inhibitors of CypD prevent opening of the mPTP in hepatocytes and the resulting effects in cell models and livers of mice undergoing ischemia/reperfusion injury. METHODS: We measured the activity of 9 small-molecule inhibitors of cyclophilins in an assay of CypD activity. The effects of the small-molecule CypD inhibitors or vehicle on mPTP opening were assessed by measuring mitochondrial swelling and calcium retention in isolated liver mitochondria from C57BL/6J (wild-type) and Ppif-/- (CypD knockout) mice and in primary mouse and human hepatocytes by fluorescence microscopy. We induced ischemia/reperfusion injury in livers of mice given a small-molecule CypD inhibitor or vehicle before and during reperfusion and collected samples of blood and liver for histologic analysis. RESULTS: The compounds inhibited peptidyl-prolyl isomerase activity (half maximal inhibitory concentration values, 0.2-16.2 µmol/L) and, as a result, calcium-induced mitochondrial swelling, by preventing mPTP opening (half maximal inhibitory concentration values, 1.4-132 µmol/L) in a concentration-dependent manner. The most potent inhibitor (C31) bound CypD with high affinity and inhibited swelling in mitochondria from livers of wild-type and Ppif-/- mice (indicating an additional, CypD-independent effect on mPTP opening) and in primary human and mouse hepatocytes. Administration of C31 in mice with ischemia/reperfusion injury before and during reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage compared with vehicle. CONCLUSIONS: Recently created small-molecule inhibitors of CypD reduced calcium-induced swelling in mitochondria from mouse and human liver tissues. Administration of these compounds to mice during ischemia/reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage. These compounds might be developed to protect patients from ischemia/reperfusion injury after liver surgery or for other hepatic or nonhepatic disorders related to abnormal mPTP opening.

Importance of Evaluating Cardiovascular Risk and Hepatic Fibrosis in Patients With Newly Diagnosed Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a well-recognized health problem, with an estimated worldwide prevalence of 25%.1 It is associated with metabolic syndrome (MetSx) and complications such as cirrhosis and hepatocellular carcinoma. However, the main cause of death in patients with NAFLD is derived from cardiovascular disease, and outcome seems to be determined by the degree of hepatic fibrosis.2 The prevalence of NAFLD and associated cardiovascular risk factors in asymptomatic patients in Mexico are poorly documented, despite having one of the highest rates of obesity and metabolic syndrome worldwide.3.

El enfoque sicosocial expresivo de las relaciones interculturales contextualizadas en la enseñanza médica superior cubana / Expressive psychosocial approach to intercultural relationships put in context in Cuban higher medical education

RESUMEN Aunque la educación superior cubana constituye un espacio privilegiado para la atención a la diversidad cultural, se identifica la carencia de una concepción de la interculturalidad desde el sujeto que vive la experiencia y cuya cultura de origen se instaura como dimensión mediatizadora de la relación con respecto a otros; carencia no abordada en profundidad a través del prisma de la sicología social. En este orden se realizó una revisión bibliográfica con el objetivo de profundizar en el enfoque sicosocial expresivo de las relaciones interculturales contextualizadas en la enseñanza médica superior cubana; la misma, contribuyó a la comprensión de la expresión subjetiva conformada alrededor de la realidad objeto de estudio. Los resultados permitieron construir un cuerpo teórico descriptivo-explicativo de las emergencias subjetivas que adquieren su especificidad en las relaciones interculturales desde un compromiso práctico y axiológico. A modo de conclusiones se estableció que en la búsqueda de un campo académico unificado y coherente con la complejidad de la realidad objeto de estudio, la sicología social deviene tributaria de un enfoque centrado en el estudio de las formas de subjetividad social que median en las relaciones interculturales desde el contexto de la enseñanza médica superior cubana.

ABSTRACT Even though Cuban higher education is a privileged space for the attention of cultural diversity, the lack of an intercultural conception from the person who lives the experience and whose home culture is established as an interfering dimension in his relationship with others is identified; a problem which is not dealt with in depth through the perspective of social psychology. Therefore, a bibliographic review was made in order to go into depth in the expressive psychosocial approach to intercultural relationships put in context in Cuban higher medical education. It contributed to the understanding of the subjective expression which makes the reality of the object of study. The results allowed to make a descriptive-explanatory theoretical body of the subjective emergencies which become specific in intercultural relationships from a practical and axiological commitment. As a conclusion, it was established the search of an academic field which can be unifying and coherent with the complexity of the reality object of study. Social psychology becomes tributary of an approach that is centered in the study of social subjectivity forms that mediate in intercultural relationships from the context of Cuban higher medical education.

Corrientes psicológicas determinantes de la concepción del aprendizaje en la enseñanza médica superior / Psychological currents determinants for the perspective on learning in medical higher education

La concepción contemporánea del aprendizaje en la enseñanza médica superior cubana conduce a la apropiación de los contenidos y las formas de pensar, sentir y actuar, construidas en la experiencia socio-histórica con el fin de adaptarse a la realidad y transformarla. Ello acarrea cambios relativamente duraderos y generalizables, determinados a partir de los encuadres teórico-metodológicos provenientes de múltiples corrientes psicológicas que garantizan la orientación de los contenidos, procesos y condiciones, para el logro de los resultados esperados por la influencia educacional en las prácticas curriculares cotidianas. De ahí que en el presente artículo se propone argumentar el contenido de las corrientes psicológicas que determinan la concepción contemporánea del aprendizaje en la enseñanza médica superior cubana.

The contemporary perspective on learning in Cuban medical higher education leads to the apprehension of contents and forms of thinking, feeling and behaving, constructed upon the socio-historical experience with the aim at adapting to the reality and transform it. All this involves relatively long-standing and generalized changes, determined from the theoretical-methodological framings derived from multiple psychological currents which guarantee the orientation of the contents, processes and conditions, for the fulfillment of the expected results under the educational influence in daily curricular practices. Therefore, this articles aims at explaining the content of the psychological currents determining the contemporary conception of learning in the Cuban higher medical education.