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Abstract Background Moderate/severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state. This is a study protocol of an open-label, multi-center, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the safety, tolerability, alloreactivity, and efficacy of the administration of allogeneic memory T cells and natural killer (NK) cells in COVID-19 patients with lymphopenia and/or pneumonia. The aim of the study is to determine the safety and the efficacy of the recommended phase 2 dose (RP2D) of this treatment for patients with moderate/severe COVID-19. Methods In the phase I trial, 18 patients with COVID-19-related pneumonia and/or lymphopenia with no oxygen requirement or with an oxygen need of ≤ 2.5 liters per minute (lpm) in nasal cannula will be assigned to two arms, based on the biology of the donor and the patient. Treatment of arm A consists of the administration of escalating doses of memory T cells, plus standard of care (SoC). Treatment of arm B consists of the administration of escalating doses of NK cells, plus SoC. In the phase II trial, a total of 182 patients with COVID-19-related pneumonia and/or lymphopenia requiring or not oxygen supplementation but without mechanical ventilation will be allocated to arm A or B, considering HLA typing. Within each arm, they will be randomized in a 1:1 ratio. In arm A, patients will receive SoC or RP2D for memory T cells plus the SoC. In arm B, patients will receive SoC or RP2D for NK cells plus the SoC. Discussion We hypothesized that SARS-CoV-2-specific memory T-lymphocytes obtained from convalescent donors recovered from COVID-19 can be used as a passive cell immunotherapy to treat pneumonia and lymphopenia in moderate/severe patients. The lymphopenia induced by COVID-19 constitutes a therapeutic window that may facilitate donor engraftment and viral protection until recovery. Trial registration ClinicalTrials.gov NCT04578210 . First Posted : October 8, 2020

Abstract Background Quantitative, reverse transcription PCR (qRT-PCR) is currently the gold-standard for SARS-CoV-2 detection and it is also used for detection of other virus. Manual data analysis of a small number of qRT-PCR plates per day is a relatively simple task, but automated, integrative strategies are needed if a laboratory is dealing with hundreds of plates per day, as is being the case in the COVID-19 pandemic. Results Here we present shinyCurves, an online shiny-based, free software to analyze qRT-PCR amplification data from multi-plate and multi-platform formats. Our shiny application does not require any programming experience and is able to call samples Positive, Negative or Undetermined for viral infection according to a number of user-defined settings, apart from providing a complete set of melting and amplification curve plots for the visual inspection of results. Conclusions shinyCurves is a flexible, integrative and user-friendly software that speeds-up the analysis of massive qRT-PCR data from different sources, with the possibility of automatically producing and evaluating melting and amplification curve plots.

Abstract We argue that the Standard Model quiver can be embedded into compact Calabi-Yau geometries through orientifolded D3-branes at del Pezzo singularities dP n with n ≥ 5 in a framework including moduli stabilisation. To illustrate our approach, we explicitly construct a local dP5 model via a combination of Higgsing and orientifolding. This procedure reduces the original dP5 quiver gauge theory to the Left-Right symmetric model with three families of quarks and leptons as well as a Higgs sector to further break the symmetries to the Standard Model gauge group. We embed this local model in a globally consistent Calabi-Yau flux compactification with tadpole and Freed-Witten anomaly cancellations. The model features closed string moduli stabilisation with a de Sitter minimum from T-branes, supersymmetry broken by the Kähler moduli, and the MSSM as the low energy spectrum. We further discuss phenomenological and cosmological implications of this construction.

Objectives: To describe non-relapse-related emergency consultations of patients with multiple sclerosis (MS): causes, difficulties in the diagnosis, clinical characteristics, and treatments administered. Methods: We performed a retrospective study of patients who attended a multiple sclerosis day hospital due to suspected relapse and received an alternative diagnosis, over a 2-year period. Demographic data, clinical characteristics, final diagnosis, and treatments administered were evaluated. Patients who were initially diagnosed with pseudo-relapse and ultimately diagnosed with true relapse were evaluated specifically. As an exploratory analysis, patients who consulted with non-inflammatory causes were compared with a randomly selected cohort of patients with true relapses who attended the centre in the same period. Results: The study included 50 patients (33 were women; mean age 41.4 ± 11.7 years). Four patients (8%) were initially diagnosed with pseudo-relapse and later diagnosed as having a true relapse. Fever and vertigo were the main confounding factors. The non-inflammatory causes of emergency consultation were: neurological, 43.5% (20 patients); infectious, 15.2% (7); psychiatric, 10.9% (5); vertigo, 8.6% (4); trauma, 10.9% (5); and miscellaneous, 10.9% (5). Conclusions: MS-related symptoms constituted the most frequent cause of non-inflammatory emergency consultations. Close follow-up of relapse and pseudo-relapse is necessary to detect incorrect initial diagnoses, avoid unnecessary treatments, and relieve patients’ symptoms. Resumen: Objetivos: Describir consultas urgentes de pacientes con esclerosis múltiple (EM) distintas a brotes: causas, dificultades diagnósticas, características clínicas y tratamientos empleados. Material y métodos: Estudio retrospectivo de los pacientes que acudieron a un Hospital de Día de EM en 2 años por sospecha de brote y que recibieron un diagnóstico alternativo. Se evaluaron variables demográficas, características clínicas de los pacientes, diagnósticos finales y tratamientos. Los pacientes con diagnóstico final de brote e inicialmente diagnosticados de pseudobrote se evaluaron específicamente. Con una finalidad exploratoria se compararon las características de los pacientes que consultaban por causas no inflamatorias con una cohort de pacientes aleatoriamente seleccionados que habían sufrido un brote en el mismo periodo de tiempo. Resultados: Se incluyeron un total de 50 pacientes inicialmente diagnosticados de pseudobrotes (33 mujeres, con edad media 41,4 ± 11,7 años). Cuatro pacientes (8% del total) fueron inicialmente diagnosticados de pseudobrote aunque posteriormente fueron diagnosticados de un verdadero brote. La fiebre y el vértigo fueron los principales factores de confusión. Las causas no inflamatorias de consulta urgente fueron: neurológicas: 43,5% (20); infecciosas: 15,2% (7); psiquiátricas: 10,9% (5); vértigo: 8,6% (4); traumatológicas: 10,9% (5), y otras: 10,9% (5). Conclusiones: La mayor parte de las consultas urgentes no inflamatorias fueron causadas por síntomas relacionados con la EM. El seguimiento estrecho de brotes y pseudobrotes es necesario para detectar diagnósticos incorrectos, evitar tratamientos innecesarios y aliviar los síntomas de los pacientes.

Liver transplantation is a lifesaving treatment that improves survival and quality of life. The procedure requires adequate transplant candidate selection carried out by a multidisciplinary team. Psychosocial evaluation is a necessary part of recipient selection and its primary aims are to identify problems and psychosocial needs of the patient and his/her family, to improve transplantation outcomes. Different psychosocial conditions are considered risk factors for morbidity and mortality after transplantation. The presence of those factors per se is not an absolute contraindication, thus adequate evaluation promotes equal access to healthcare, improves results, and optimizes resources. The present review provides an overview of and guidelines for the most important psychosocial issues during the pretransplantation phase. Resumen: El trasplante hepático es un tratamiento que salva vidas, mejora la supervivencia y la calidad de vida. El procedimiento requiere de una adecuada selección de los receptores, llevada a cabo por un equipo multidisciplinario. La evaluación psicosocial es necesaria para la selección de los receptores y tiene como objetivos principales la identificación de problemas y necesidades psicosociales del paciente y su familia para mejorar los resultados del trasplante. Diferentes condiciones psicosociales son consideradas factores de riesgo para morbilidad y mortalidad posterior al trasplante. La presencia de estos factores por si solos no es considerada contraindicación absoluta, por lo que una adecuada evaluación, promueve la equidad en el acceso a la salud, mejora los resultados y optimiza los recursos. Esta revisión proporciona una visión general y una guía de los aspectos psicosociales más importantes durante la fase pre-trasplante.

Reliable quantitative vegetation reconstructions for Europe during the Holocene are crucial to improving our understanding of landscape dynamics, making it possible to assess the past effects of environmental variables and land-use change on ecosystems and biodiversity, and mitigating their effects in the future. We present here the most spatially extensive and temporally continuous pollen-based reconstructions of plant cover in Europe (at a spatial resolution of 1° × 1°) over the Holocene (last 11.7 ka BP) using the ‘Regional Estimates of VEgetation Abundance from Large Sites’ (REVEALS) model. This study has three main aims. First, to present the most accurate and reliable generation of REVEALS reconstructions across Europe so far. This has been achieved by including a larger number of pollen records compared to former analyses, in particular from the Mediterranean area. Second, to discuss methodological issues in the quantification of past land cover by using alternative datasets of relative pollen productivities (RPPs), one of the key input parameters of REVEALS, to test model sensitivity. Finally, to validate our reconstructions with the global forest change dataset. The results suggest that the RPPs.st1 (31 taxa) dataset is best suited to producing regional vegetation cover estimates for Europe. These reconstructions offer a long-term perspective providing unique possibilities to explore spatial-temporal changes in past land cover and biodiversity.

Abstract Despite the improved accuracy of next-generation sequencing (NGS), it is widely accepted that variants need to be validated using Sanger sequencing before reporting. Validation of all NGS variants considerably increases the turnaround time and costs of clinical diagnosis. We comprehensively assessed this need in 1109 variants from 825 clinical exomes, the largest sample set to date assessed using Illumina chemistry reported. With a concordance of 100%, we conclude that Sanger sequencing can be very useful as an internal quality control, but not so much as a verification method for high-quality single-nucleotide and small insertion/deletions variants. Laboratories might validate and establish their own thresholds before discontinuing Sanger confirmation studies. We also expand and validate 23 copy number variations detected by exome sequencing in 20 samples, observing a concordance of 95.65% (22/23).

Resumen: El diagnóstico y tratamiento del melanoma en atención especializada es un campo en el que se han producido numerosos cambios. El objetivo de esta guía es ofrecer a los dermatólogos españoles una referencia para resolver las dudas clínicas más frecuentes basándose en la evidencia actual. Para la realización de esta guía se escogió a miembros del Grupo Español de Dermato-Oncología y Cirugía con experiencia en el tratamiento de estos tumores y con interés en participar en la elaboración de la guía. Se hizo una adaptación de las guías de práctica clínica existentes mediante el método ADAPTE: inicialmente se resumió el proceso de atención y se elaboraron las preguntas clínicas relevantes. Se seleccionaron las guías mejor puntuadas mediante el instrumento AGREE II, realizando la búsqueda de las respuestas en dichas guías y elaborando las recomendaciones. Finalmente se sometió la guía a revisión externa. La guía se estructuró a partir de 21 preguntas clínicas que fueron seleccionadas por su relevancia, dado que se centran en aspectos que pueden plantear decisiones difíciles en el manejo del melanoma, y se han respondido empleando la evidencia obtenida de las mejores guías existentes. Entre las limitaciones de esta guía merece reseñarse que la evidencia es escasa para responder a algunas preguntas. En algunos aspectos el cambio es rápido y exige una actualización frecuente de la guía. Esta guía responde a preguntas habituales sobre el manejo del melanoma en la práctica clínica diaria, sirviendo a los dermatólogos como referencia en la toma de decisiones, siempre teniendo presente los recursos y preferencias del paciente. Abstract: Specialist approaches to the diagnosis and treatment of melanoma have undergone many changes. This guideline aims to provide Spanish dermatologists with evidence-based information for resolving the most common doubts that arise in clinical practice. Members of the Spanish Oncologic Dermatology and Surgery Group (GEDOC) with experience treating melanoma were invited to participate in drafting the guideline. The group developed a new guideline on the basis of existing ones, using the ADAPTE collaboration process, first summarizing the care process and posing relevant clinical questions, then selecting guidelines with the best scores according to the AGREE II (Appraisal of Guidelines for Research and Evaluation) tool. Finally, the group searched the selected guidelines for answers to the clinical questions, drafted recommendations, and sent them for external review. The guideline is structured around 21 clinical questions chosen for their relevance to issues that make clinical decisions about the management of melanoma difficult. Evidence from existing guidelines was used to answer the questions. A limitation of this guide derives from the scarce evidence available for answering some questions. Moreover, some areas are changing rapidly, so recommendations must be updated often. The present guideline offers answers to clinical questions about the routine management of melanoma in clinical practice and provides dermatologists with a reference to guide decisions, taking into consideration the resources available and patient preferences.

Resumen: Introducción: La epilepsia es una enfermedad prevalente en países en vías de desarrollo debido al mayor número de causas que pueden producirla, al menos duplicándose tanto incidencia como prevalencia en comparación con nuestro medio. Además, existe una gran estigmatización y los medios para su manejo son limitados. Material y métodos: Estudio observacional descriptivo mediante la realización de un cuestionario a profesionales sanitarios de 3 hospitales de Camerún, interrogando sobre factores relacionados con el manejo de la epilepsia, en diciembre de 2016. Se presentan los datos como media o porcentaje. Resultados: Participaron 38 profesionales sanitarios, de los cuales el 42,1% eran mujeres, con una edad media de 40,1 años (rango 22-62). Respecto a la causa de la enfermedad un 68,4% la considera psiquiátrica, 34,2% degenerativa, 28,9% hereditaria y 21,1% secundaria a una infección. En cuanto al manejo un 23,7% consideraba suficiente la anamnesis para llegar al diagnóstico. Solo un 60,5% consideraba la historia importante en el diagnóstico, 52,6% consideraba necesario un EEG, un 28,9% creía importantes las pruebas de laboratorio y un 13,2% la neuroimagen. Durante el embarazo solo un 36,8% considera importante asociar ácido fólico, solo el 65,8% cree que hay que mantener el tratamiento y solo un 39,5% creía recomendable la lactancia. Acerca del conocimiento de antiepilépticos, el número medio de fármacos conocido era de 2, siendo el más conocido el fenobarbital (81,6%) seguido de carbamacepina (55,3%) y ácido valproico (28,9%). Conclusiones: La educación y la mejor información sobre la enfermedad, su diagnóstico y las opciones de manejo son necesarias en los profesionales sanitarios para optimizar el manejo y con ello la calidad de vida de los pacientes. Abstract: Introduction: Epilepsy is especially prevalent in developing countries: incidence and prevalence rates are at least twice as high as in our setting. Epilepsy is also highly stigmatised, and few resources are available for its management. Material and methods: We performed a descriptive observational study in December 2016, distributing a questionnaire on epilepsy management to healthcare professionals from 3 different hospitals in Cameroon. Data are presented as means or percentages. Results: Thirty-eight healthcare providers participated in the survey; 42.1% were female and mean age was 40.1 years (range, 22-62). Regarding the causes of epilepsy, 68.4% considered it a psychiatric condition, 34.2% a degenerative disease, 28.9% a hereditary condition, and 21.1% secondary to infection. In terms of management, 23.7% considered that thorough clinical history is sufficient to establish a diagnosis. Only 60.5% considered the clinical interview to be important for diagnosis, 52.6% considered EEG to be necessary, and 28.9% considered laboratory analyses to be important. Only 13.2% mentioned neuroimaging. In the treatment of pregnant women, 36.8% recommended folic acid supplementation, 65.8% believed antiepileptic treatment should be maintained, and only 39.5% recommended breastfeeding. Concerning treatment, the participants knew a mean of 2 antiepileptic drugs: phenobarbital was the best known (81.6%), followed by carbamazepine (55.3%) and valproic acid (28.9%). Conclusions: There is a need among healthcare professionals for education and information on the disease, its diagnosis, and management options, in order to optimise management and consequently improve patients’ quality of life.

Introduction: Epilepsy is especially prevalent in developing countries: incidence and prevalence rates are at least twice as high as in our setting. Epilepsy is also highly stigmatised, and few resources are available for its management. Material and methods: We performed a descriptive observational study in December 2016, distributing a questionnaire on epilepsy management to healthcare professionals from 3 different hospitals in Cameroon. Data are presented as means or percentages. Results: Thirty-eight healthcare providers participated in the survey; 42.1% were female and mean age was 40.1 years (range, 22-62). Regarding the causes of epilepsy, 68.4% considered it a psychiatric condition, 34.2% a degenerative disease, 28.9% a hereditary condition, and 21.1% secondary to infection. In terms of management, 23.7% considered that thorough clinical history is sufficient to establish a diagnosis. Only 60.5% considered the clinical interview to be important for diagnosis, 52.6% considered EEG to be necessary, and 28.9% considered laboratory analyses to be important. Only 13.2% mentioned neuroimaging. In the treatment of pregnant women, 36.8% recommended folic acid supplementation, 65.8% believed antiepileptic treatment should be maintained, and only 39.5% recommended breastfeeding. Concerning treatment, the participants knew a mean of 2 antiepileptic drugs: phenobarbital was the best known (81.6%), followed by carbamazepine (55.3%) and valproic acid (28.9%). Conclusions: There is a need among healthcare professionals for education and information on the disease, its diagnosis, and management options, in order to optimise management and consequently improve patients’ quality of life. Resumen: Introducción: La epilepsia es una enfermedad prevalente en países en vías de desarrollo debido al mayor número de causas que pueden producirla, al menos duplicándose tanto incidencia como prevalencia en comparación con nuestro medio. Además, existe una gran estigmatización y los medios para su manejo son limitados. Material y métodos: Estudio observacional descriptivo mediante la realización de un cuestionario a profesionales sanitarios de 3 hospitales de Camerún, interrogando sobre factores relacionados con el manejo de la epilepsia, en diciembre de 2016. Se presentan los datos como media o porcentaje. Resultados: Participaron 38 profesionales sanitarios, de los cuales 42,1% eran mujeres, con una edad media de 40,1 años (rango 22-62). Respecto a la causa de la enfermedad, un 68,4% la considera psiquiátrica, 34,2% degenerativa, 28,9% hereditaria y 21,1% secundaria a una infección. En cuanto al manejo, un 23,7% consideraba suficiente la anamnesis para llegar al diagnóstico. Sólo un 60,5% consideraba la historia importante en el diagnóstico, 52,6% consideraba necesario un EEG, un 28,9% creía importantes las pruebas de laboratorio y un 13,2% la neuroimagen. Durante el embarazo, sólo un 36,8% considera importante asociar ácido fólico, sólo el 65,8% cree que hay que mantener el tratamiento y sólo un 39,5% creía recomendable la lactancia. Acerca del conocimiento de antiepilépticos, el número medio de fármacos conocido era de 2, siendo el más conocido el fenobarbital (81,6%) seguido de carbamacepina (55,3%) y ácido valproico (28,9%). Conclusiones: La educación y la mejor información sobre la enfermedad, su diagnóstico y las opciones de manejo son necesarias en los profesionales sanitarios para optimizar el manejo y con ello la calidad de vida de los pacientes.

Introduction Multifamily interventions have shown to reduce the risk of relapse of psychotic symptoms in first episodes of psychosis (FEPs) but are not frequently implemented in specific treatment programs. We have develop a pilot study for the implementation of the interfamily therapy in FEPs within a Mental Health Centre in the Community of Madrid. Objectives The aims were to examine: relapses (measured as re-hospitalization), duration of re-hospitalizations and voluntary versus involuntary re-hospitalizations during participation in MFG compared with the previous year. Methods 21 subjects participated in a MFG during 12 months, 11 participants with a diagnosis of psychosis and 10 family members. Interfamily therapy works as a new model of interactive psychoeducation among families where they share their own experiences and look for comprehension and solutions all together. Results Our clinical experience in an interfamily therapy intervention over 12 months has led us to identify a high degree of participation and acceptance by users and their families, and we have observed a lower relapse rate, with fewer of psychiatric admissions and of shorter duration among patients during the year of participation in the MFG compared to the year before treatment. Conclusions MFG has been well accepted by both patients and their families, with a high degree of participation.The results observed in our experience of MFG treatment are consistent with the findings of previous studies that support the reduction of the relapse rate, the number of hospitalizations and their duration when family interventions are incorporated into treatment in recent-onset psychosis, especially in a multi-family group format. Disclosure No significant relationships.

Objective: Patients with nonmelanoma skin cancer (NMSC)—ie, basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)—have an increased risk of developing a second skin cancer. The aim of this study was to describe the frequency, incidence per 1000 person-years, and predictors of a second skin cancer in a cohort of patients with NMSC treated with Mohs micrographic surgery (MMS). Material and methods: Prospective study of a national cohort of patients with NMSC who underwent MMS at 22 Spanish hospitals between July 2013 and February 2020; case data were recorded in the REGESMOHS registry. The study variables included demographic characteristics, frequency and incidence per 1000 person-years of second skin cancers diagnosed during the study period, and risk factors identified using mixed-effects logistic regression. Results: We analyzed data for 4768 patients who underwent MMS; 4397 (92%) had BCC and 371 (8%) had SCC. Mean follow-up was 2.4 years. Overall, 1201 patients (25%) developed a second skin cancer during follow-up; 1013 of the tumors were BCCs (21%), 154 were SCCs (3%), and 20 were melanomas (0.4%). The incidence was 107 per 1000 person-years (95% CI, 101–113) for any cancer, 90 per 1000 person-years (95% CI, 85–96) for BCC, 14 (95% CI, 12–16) per 1000 person-years for SCC, and 2 (95% CI, 1–3) per 1000 person-years for melanoma. More men than women developed a subsequent skin cancer (738 [61%] vs 463 [39%]). The main risk factors were a history of multiple tumors before diagnosis (relative risk [RR], 4.6; 95% CI, 2.9–7.1), immunosuppression (RR, 2.1; 95% CI, 1.4–3.1), and male sex (RR, 1.6; 95% CI, 1.4–1.9). Conclusion: Patients have an increased risk of developing a second tumor after MMS treatment of NMSC. Risk factors are a history of multiple tumors at diagnosis, immunosuppression, and male sex. Resumen: Objetivo: Los pacientes diagnosticados de cáncer queratinocítico (carcinoma basocelular y carcinoma epidermoide cutáneo) o cáncer cutáneo no melanoma (CCNM) tienen un riesgo aumentado de desarrollar una segunda neoplasia cutánea. Nuestro objetivo es describir la frecuencia, la tasa de incidencia y los factores de riesgo predisponentes para desarrollar una segunda neoplasia cutánea en una cohorte de pacientes tratados mediante cirugía micrográfica de Mohs (CMM). Material y métodos: Estudio prospectivo de una cohorte nacional de pacientes incluidos para realización de CMM para tratar CCNM en 22 centros españoles (julio 2013-febrero 2020) REGESMOHS. Las variables analizadas incluyen las características demográficas, la frecuencia de aparición de segundas neoplasias cutáneas, sus tasas de incidencia y los factores de riesgo, y se estimaron utilizando un modelo de regresión logístico multivariante de efectos mixtos. Resultados: Fueron intervenidos 4.768 pacientes: 4.397 (92%) carcinomas basocelulares y 371 (8%) carcinomas epidermoides. El tiempo medio de seguimiento fue de 2,4 años. Se diagnosticó un nuevo tumor durante el seguimiento en 1.201 pacientes (25%); 1.013 (21%) fueron carcinomas basocelulares, 154 (3%) carcinomas epidermoides cutáneos, 20 melanomas (0,4%) La tasa de incidencia fue de 107 (101-113) por 1.000 personas/año para cualquier tumor; 90 (85-96) para el carcinoma basocelular, 14 (12-16) para el carcinoma epidermoide cutáneo y 2 (1-3) para el melanoma. El riesgo de nueva neoplasia fue mayor en varones que en mujeres 738 (61%) vs. 463 (39%). Los factores de riesgo más significativos fueron la historia de múltiples tumores previos al diagnóstico (RR: 4,6; IC 95%: 2,9-7,1); la inmunosupresión (RR: 2,1; IC 95%: 1,4-3,1) y paciente varón (RR: 1,6; IC 95%: 1,4-1,9). Conclusión: Los pacientes diagnosticados de cáncer queratinocítico intervenido mediante cirugía de Mohs tienen un riesgo aumentado de aparición de segundas neoplasias, sobre todo en aquellos pacientes con historia de tumores múltiples al diagnóstico, inmunodeprimidos y varones.

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.

Childhood-onset psoriasis generally follows an indolent course but patients with moderate or severe disease may require systemic treatment. The aim of this study was to determine the relative proportion of children and young people aged up to 21 years with moderate to severe psoriasis in the BIOBADADERM registry and to analyze the characteristics of these patients, treatments used, and adverse events. Of the 3946 patients in the registry, 24 were aged 21 years or younger. The mean age of this group when they started treatment upon registration on Biobadaderm was 16.1 years and the mean Psoriasis Area and Severity Index was 9.4. In 67% the first treatment recorded was with a conventional systemic drug. Treatment was discontinued in 14 patients (58%) due to adverse events or a loss or lack of effectiveness. In conclusion, the BIOBADADERM registry shows that young people account for a small proportion of psoriasis patients receiving systemic treatment, and they are more likely to be treated using conventional systemic drugs. Resumen: El comienzo de la psoriasis en la edad pediátrica, aunque generalmente leve, puede requerir tratamiento sistémico en las formas moderadas o graves de la enfermedad. El objetivo de este trabajo es analizar la frecuencia relativa, las características de los pacientes, el tratamiento empleado y los eventos adversos observados a partir del registro BIOBADADERM en niños y jóvenes con psoriasis moderada-grave. Del total de 3.946 pacientes del registro, se incluyen 24 pacientes menores de 21 años, con una edad media al inicio del tratamiento en BIOBADADERM de 16,1 años y un PASI medio de 9,4. El 67% de los pacientes estaban en tratamiento sistémico clásico al inicio del registro. Catorce pacientes (58%) suspendieron el tratamiento por pérdida o falta de eficacia o por eventos adversos. En conclusión, los datos del registro BIOBADADERM muestran que los menores representan un grupo muy pequeño dentro de los pacientes con psoriasis que reciben tratamiento sistémico y son manejados más frecuentemente con tratamientos clásicos.

Resumen: La enfermedad por coronavirus 2019 (COVID-19) es una enfermedad respiratoria seria causada por el virus SARS-CoV-2. Existe controversia respecto a si los inmunosupresores representan un factor de riesgo para desarrollar una enfermedad más grave.Aquí reportamos el desenlace clínico de tres miembros de una familia que se infectaron de COVID-19, con la presencia y ausencia de diferentes factores de riesgo que han sido descritos en casos de enfermedad grave. Paradójicamente, el receptor de trasplante hepático presentó un desenlace similar comparado con los otros dos miembros de la familia. Mostró un periodo de hospitalización mas corto, con desenlace clínico similar y con menor requerimiento de oxigeno.Esta observación clínica muestra un posible efecto benéfico del tacrolimus en pacientes que presentaron la COVID-19. El tacrolimus presenta una actividad inhibitoria en los coronavirus humanos a través de: 1) Un efecto antiviral al unirse con las proteínas FKBP, con la inhibición subsiguiente de su actividad de peptidil-prolil isomerasa, cuyas actividades enzimáticas promueven la replicación del coronavirus; 2) La regulación de la respuesta inmunitaria a través de la interacción con la calcineurina, que evita la translocación nuclear de su sustrato, el factor nuclear de las células T, lo que inhibe la activación de células T.Esta observación clínica muestra que el receptor de trasplante hepático con la COVID-19 no presenta un peor desenlace comparado con pacientes que tienen otros factores de riesgo para la COVID-19 y pone en evidencia los dos mecanismos relacionados con el tacrolimus. Abstract: Coronavirus disease 2019 (COVID-19) is a serious respiratory illness caused by SARS-CoV-2. There is controversy about whether their immunosuppressive status is a risk factor or a protective factor for developing severe disease.We report herein the clinical outcome of three family members that had COVID-19 infection, presenting with and without different risk factors that have been described in more severe disease. Paradoxically, the patient with more risks of developing a severe disease, a 64-year-old woman, 2-years liver transplant recipient under treatment with tacrolimus, presented a similar outcome compared to the two other members of the family. She showed shorter hospitalization time, similar clinical outcome with fewer oxygen needs.The present clinical observation raises the question about the possible beneficial effect of tacrolimus in patients with COVID-19. Indeed, tacrolimus (FK-506) have an inhibitory effect on human coronaviruses by: 1) an antiviral effect by binding to the FK-506-binding proteins (FKBP) with a subsequent inhibition of their peptidyl-prolyl cis/trans isomerase (PPIase) activity, which seems to be important for the coronavirus life cycle; and 2) regulating the immune response by the inhibition of the activity of the nuclear factor of activated T-cells (NFAT) required for immunosuppression.The present observation states that liver recipients’ patients with COVID-19 may not have worse outcomes when compared with other patients that have COVID-19 risk factors and puts in evidence the two mechanisms related to tacrolimus.

The Eurasian (née European) Modern Pollen Database (EMPD) was established in 2013 to provide a public database of high-quality modern pollen surface samples to help support studies of past climate, land cover, and land use using fossil pollen. The EMPD is part of, and complementary to, the European Pollen Database (EPD) which contains data on fossil pollen found in Late Quaternary sedimentary archives throughout the Eurasian region. The EPD is in turn part of the rapidly growing Neotoma database, which is now the primary home for global palaeoecological data. This paper describes version 2 of the EMPD in which the number of samples held in the database has been increased by 60 % from 4826 to 8134. Much of the improvement in data coverage has come from northern Asia, and the database has consequently been renamed the Eurasian Modern Pollen Database to reflect this geographical enlargement. The EMPD can be viewed online using a dedicated map-based viewer at https://empd2.github.io and downloaded in a variety of file formats at https://doi.pangaea.de/10.1594/PANGAEA.909130 (Chevalier et al., 2019).

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. COVID-19 affected close to 2 million persons worldwide in fewer than 4 months, after the report of the first cases in China in December 2019. The relation of the disease caused by SARS-Cov-2 to immunosuppressive treatment used in different gastrointestinal disorders is uncertain, resulting in debate with regard to suspending immunosuppressive therapy to improve infection outcome. Said suspension implies the inherent risk for graft rejection or autoimmune disease exacerbation that can potentially worsen the course of the infection. Based on the presently available evidence, a treatment stance has been established for patients with gastrointestinal diseases that require immunosuppressive therapy. Resumen: La enfermedad por coronavirus 2019 (COVID-19) es causada por el virus de Síndrome Respiratorio Agudo Grave - Coronavirus 2 (SARS-CoV-2). COVID 19 afectó cerca de 2 millones de personas en todo el mundo en menos de 4 meses posterior al reporte de los primeros casos en China en diciembre 2019. La relación que guarda la enfermedad por SARS-Cov-2 con el tratamiento inmunosupresor utilizado en diversos trastornos gastrointestinales es incierta, esto genera el debate sobre suspender el tratamiento inmunosupresor para mejorar el pronóstico de la infección, lo cual incluye el riesgo inherente de rechazo de injerto o agudización de enfermedades autoinmunes que potencialmente pudieran agravar el curso de la infección. En base a la evidencia disponible se logra establecer una postura de tratamiento en pacientes con enfermedades gastrointestinales que requieren terapia inmunosupresora.

Resumen: La enfermedad por coronavirus 2019 (COVID-19) es causada por el virus del síndrome respiratorio agudo grave-coronavirus 2 (SARS-CoV-2). La COVID-19 ha afectado a unos 6 millones de personas en todo el mundo en menos de 4 meses posterior al reporte de los primeros casos en China en diciembre de 2019. La relación que guarda la enfermedad por SARS-CoV-2 con el tratamiento inmunosupresor utilizado en diversos trastornos gastrointestinales es incierta, y esto genera el debate sobre suspender el tratamiento inmunosupresor para mejorar el pronóstico de la infección, lo cual incluye el riesgo inherente de rechazo de injerto o agudización de enfermedades autoinmunes que potencialmente pudieran agravar el curso de la infección. En base a la evidencia disponible se logra establecer una postura de tratamiento en pacientes con enfermedades gastrointestinales que requieren terapia inmunosupresora. Abstract: The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. COVID-19 affected more than 6 million persons worldwide in fewer than 4 months, after the report of the first cases in China in December 2019. The relation of the disease caused by SARS-Cov-2 to immunosuppressive treatment used in different gastrointestinal disorders is uncertain, resulting in debate with regard to suspending immunosuppressive therapy to improve infection outcome. Said suspension implies the inherent risk for graft rejection or autoimmune disease exacerbation that can potentially worsen the course of the infection. Based on the presently available evidence, a treatment stance has been established for patients with gastrointestinal diseases that require immunosuppressive therapy.

Background and objective: Predominantly sexually transmitted infections (STIs) and infestations and other anogenital dermatoses are covered in the training of specialists in dermatology and venereology in Spain. This study aimed to analyze the proportion of the dermatology caseload these diseases account for within the public and private dermatological activity of the Spanish health system. Material and methods: Observational cross-sectional study of time periods describing the diagnoses made in outpatient dermatology clinics, obtained through the anonymous DIADERM survey of a representative random sample of dermatologists. Based on diagnostic codes of the International Classification of Diseases, Tenth Revision, 36 related diagnoses were selected, and classified into 12 groups. Results: Only 3.16% of diagnoses corresponded to STIs and other anogenital dermatoses. The most common diagnostic group was anogenital human papillomavirus infection, followed by molluscum contagiosum, and inflammatory anogenital dermatoses. Lesions with these diagnoses were usually the main reasons for first visits in the National Health Service. In private practice, the diagnoses usually came after referrals from other physicians. Conclusions: STIs and other anogenital dermatoses account for a very small proportion of the dermatology caseload in Spain, although the inclusion of molluscum contagiosum diagnoses overestimates these conditions. The fact that no STI centers or monographic STI consultations were included in the random sample of dermatology partly explains the under-representation of these areas of the specialty. A determined effort to support and promote monographic STI centres and clinics should be made. Resumen: Introducción: Las infecciones e infestaciones de transmisión predominantemente sexual y otras dermatosis anogenitales forman parte de la formación específica de los médicos especialistas en Dermatología y Venereología en España. El presente estudio pretende analizar la carga que suponen dichas patologías en la actividad dermatológica pública y privada del sistema de salud español. Material y método: Estudio observacional de corte transversal de dos períodos de tiempo describiendo los diagnósticos realizados en consultas externas dermatológicas, obtenidos a través de la encuesta anónima DIADERM, realizada a una muestra aleatoria y representativa de dermatólogos. A partir de la codificación de diagnósticos CIE-10, se seleccionó toda la patología relacionada (36 diagnósticos codificados en los dos períodos), que se clasificó en 12 grupos. Resultados: Tan solo el 3,16% de los diagnósticos globales fueron de infecciones e infestaciones de transmisión predominantemente sexual y otras dermatosis anogenitales. Los 3 grupos diagnósticos más frecuentes fueron las lesiones por virus del papiloma humano anogenital, seguido de los molluscum contagiosum y las dermatosis anogenitales inflamatorias. Con significación estadística, y comparando con el global de diagnósticos, los seleccionados constituyeron más habitualmente el motivo de consulta primario y, en el ámbito privado, fue más frecuente que viniesen derivados de otros especialistas. Conclusión: Las infecciones e infestaciones de transmisión predominantemente sexual y otras dermatosis anogenitales tienen un peso muy limitado en la asistencia dermatológica en España, a pesar de que la inclusión del diagnóstico de molluscum contagiosum sobreestima estos diagnósticos. La ausencia de inclusión de centros y consultas monográficas de ITS en la muestra aleatoria contribuye a la infrarrepresentación de estas parcelas de la especialidad. Es importante hacer un esfuerzo decidido por potenciarlas con consultas y centros monográficos.

Different global events such as industrial development and the population increment have triggered the presence and persistence of several organic and inorganic contaminants, representing a risk for the environment and human health. Consequently, the search and application of novel technologies for alleviating the challenge of environmental pollution are urgent. Nanotechnology is an emerging science that could be employed in different fields. In particular, Nanoremediation is a promising strategy defined as the engineered materials employed to clean up the environment, is an effective, rapid, and efficient technology to deal with persistent compounds such as pesticides, chlorinated solvents, halogenated chemicals, or heavy metals. Furthermore, nanoremediation is a sustainable alternative to eliminate emerging pollutants such as pharmaceutics or personal care products. Due to the variety of nanomaterials and their versatility, they could be employed in water, soil, or air media. This review provides an overview of the application of nanomaterials for media remediation. It analyzes the state of the art of different nanomaterials such as metal, carbon, polymer, and silica employed for water, soil, and air remediation.

That the preservation of twentieth concrete heritage is an area scantly explored can be attributed to a lack of appreciation for such a young material. In most cases conservation is broached from a technical perspective with little regard for heritage value. Ongoing assessment of the condition of structures is the primary strategy to minimise such misguided action. This study involved characterising the condition of the concrete in a number of singular elements forming part of the Eduardo Torroja Institute for Construction Science headquarters at Madrid, Spain, a modernist compound listed by the city of Madrid as a protected asset. The in situ findings using non-destructive and laboratory techniques revealed the core concrete to be in good condition. The surface material, however, exhibits signs of durability issues calling for conservation treatments and techniques compatible with the preservation of the integrity and authenticity of this young heritage material.

Background: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy. Methods: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA− memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA− memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants’ clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA− memory T cells is feasible and safe. Funding: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.

Abstract The Compact Linear Collider (CLIC) is a proposed future high-luminosity linear electron-positron collider operating at three energy stages, with nominal centre-of-mass energies s $$ \sqrt{s} $$ = 380 GeV, 1.5 TeV, and 3 TeV. Its aim is to explore the energy frontier, providing sensitivity to physics beyond the Standard Model (BSM) and precision measurements of Standard Model processes with an emphasis on Higgs boson and top-quark physics. The opportunities for top-quark physics at CLIC are discussed in this paper. The initial stage of operation focuses on top-quark pair production measurements, as well as the search for rare flavour-changing neutral current (FCNC) top-quark decays. It also includes a top-quark pair production threshold scan around 350 GeV which provides a precise measurement of the top-quark mass in a well-defined theoretical framework. At the higher-energy stages, studies are made of top-quark pairs produced in association with other particles. A study of t̄tH production including the extraction of the top Yukawa coupling is presented as well as a study of vector boson fusion (VBF) production, which gives direct access to high-energy electroweak interactions. Operation above 1 TeV leads to more highly collimated jet environments where dedicated methods are used to analyse the jet constituents. These techniques enable studies of the top-quark pair production, and hence the sensitivity to BSM physics, to be extended to higher energies. This paper also includes phenomenological interpretations that may be performed using the results from the extensive top-quark physics programme at CLIC.

Resumen: Introducción: Las enfermedades hepáticas son una causa importante de muerte en las personas adultas mayores, y el trasplante de hígado suele ser la única opción curativa. Sin embargo, es incierto si los buenos resultados obtenidos en esta población trasplantada en países desarrollados pueden ser replicados en los países de economías emergentes. Objetivo: Determinar si hay una diferencia en la sobrevida de adultos mayores (≥ 60 años) y adultos jóvenes sometidos a trasplante hepático en un hospital universitario de tercer nivel en la Ciudad de México. Material y métodos: Estudio longitudinal de 244 personas con 2 años de seguimiento y que se dividieron por edad al momento del trasplante: adultos mayores y jóvenes. La sobrevida se definió como el número de días ocurridos entre trasplante y muerte. Esta se analizó mediante curvas de Kaplan-Meier. Resultados: El promedio de edad en los adultos mayores (n = 52) fue de 63.0 (RIC = 60-69) y 23 participantes fueron mujeres (44.2%). En los adultos jóvenes (n = 196) el promedio de edad fue de 47.0 (RIC = 16-59) y 104 fueron mujeres (52%). La principal indicación para trasplante fue infección por el virus de la hepatitis C. Durante el seguimiento, 15 personas murieron (12 adultos jóvenes y 3 adultos mayores). No hubo diferencia estadísticamente significativa entre los grupos con respecto a la frecuencia de complicaciones postoperatorias, número de reingresos hospitalarios o sobrevida postrasplante. Conclusiones: No hay diferencia en la sobrevida entre los adultos mayores y jóvenes que reciben un trasplante hepático. Los adultos mayores en los países de economías emergentes no deberían ser excluidos del proceso de selección para recibir este órgano solo por el criterio de edad. Abstract: Introduction: Liver disease is currently one of the leading causes of death in older adults and the only option deemed curative is liver transplantation. However, it is uncertain whether the successful results obtained in older adults that receive a liver transplant in developed countries can be replicated in developing countries. Aim: To determine if there are differences in the survival time between older (≥ 60 years) and younger adults that underwent liver transplantation at a university-affiliated tertiary care center in Mexico City. Materials and methods: A 2-year longitudinal study was conducted. It included 244 participants that were divided into 2 groups according to age at the time of transplantation: older adults (≥ 60 years) and younger adults (18-59 years). Survival time was defined as the number of days that elapsed between transplantation and death. Survival was expressed as Kaplan-Meier curves. Results: Median age in the older adults (n = 52) was 63.0 (IQR = 60-69) and 23 participants were females (44.2%). In the younger adults (n = 196) median age was 47.0 (IQR = 16-59) and 104 were females (52%). The leading indication for transplant was hepatitis C virus. After the follow-up, fifteen participants died (12 younger adults and 3 older adults). No significant differences were observed between older and younger participants in postoperative complications, the number of re-admissions, or mean post-transplantation survival time. Conclusions: There were no statistically significant differences in relation to survival times between older and younger adults that received a liver transplant. Older patients in developing countries should not be excluded from the selection process due only to age. Palabras clave: Envejecimiento, Evaluación funcional, Edad fisiológica, Desenlaces, Keywords: Aging, Functional assessment, Physiological age, Transplant outcomes

Introduction: Liver disease is currently one of the leading causes of death in older adults and the only option deemed curative is liver transplantation. However, it is uncertain whether the successful results obtained in older adults that receive a liver transplant in developed countries can be replicated in developing countries. Aim: To determine if there are differences in the survival time between older (≥60 years) and younger adults that underwent liver transplantation at a university-affiliated tertiary care center in Mexico City. Materials and methods: A 2-year longitudinal study was conducted. It included 244 participants that were divided into 2 groups according to age at the time of transplantation: older adults (≥60 years) and younger adults (18–59 years). Survival time was defined as the number of days that elapsed between transplantation and death. Survival was expressed as Kaplan-Meier curves. Results: Median age in the older adults (n = 52) was 63.0 (IQR = 60–69) and 23 participants were females (44.2%). In the younger adults (n = 196) median age was 47.0 (IQR = 16–59) and 104 were females (52%). The leading indication for transplant was hepatitis C virus. After the follow-up, fifteen participants died (twelve younger adults and three older adults). No significant differences were observed between older and younger participants in postoperative complications, the number of re-admissions, or mean post-transplantation survival time. Conclusions: There were no statistically significant differences in relation to survival times between older and younger adults that received a liver transplant. Older patients in developing countries should not be excluded from the selection process due only to age. Resumen: Introducción: Las enfermedades hepáticas son una causa importante de muerte en las personas adultas mayores y el trasplante de hígado suele ser la única opción curativa. Sin embargo, es incierto si los buenos resultados obtenidos en esta población trasplantada en países desarrollados pueden ser replicados en los países de economías emergentes. Objetivo: Determinar si hay una diferencia en la sobrevida de adultos mayores (≥60 años) y adultos jóvenes sometidos a trasplante hepático en un hospital universitario de tercer nivel en la Ciudad de México. Material y métodos: Estudio longitudinal de 244 personas con dos años de seguimiento, los cuales fueron divididos por edad al momento del trasplante: adultos mayores y jóvenes. La sobrevida se definió como el número de días ocurridos entre trasplante y muerte. Esta se analizó mediante curvas de Kaplan-Meier. Resultados: El promedio de edad en los adultos mayores (n = 52) fue 63.0 (RIC = 60–69) y 23 participantes fueron mujeres (44.2%). En los adultos jóvenes (n = 196), el promedio de edad fue 47.0 (RIC = 16–59) y 104 fueron mujeres (52%). La principal indicación para trasplante fue infección por virus C. Durante el seguimiento, 15 personas murieron (doce adultos jóvenes y tres adultos mayores). No hubo diferencia estadísticamente significativa entre los grupos con respecto a la frecuencia de complicaciones posoperatorias, número de reingresos hospitalarios o sobrevida postrasplante. Conclusiones: No hay diferencia en la sobrevida entre los adultos mayores y jóvenes que reciben un trasplante hepático. Los adultos mayores en los países de economías emergentes no deberían ser excluidos del proceso de selección para recibir este órgano sólo por el criterio de edad. Keywords: Aging, Functional assessment, Physiologic age, Transplant outcomes, Palabras clave: Envejecimiento, Evaluación funcional, Edad fisiológica, Desenlaces

Exosome-derived miR-21 was independently associated with CD4 T cell decline in HIV-1-infected elite controllers (OR 0.369, 95% CI 0.137–0.994, p = 0.049). Also, a negative correlation between miR-21 expression and MCP-1 level was found (r = −0.649, p = 0.020), while no correlation between soluble biomarkers or cellular immune activation was found. Keywords: Exosomes, miRNAs, HIV-1, Elite controllers, Immune activation, Soluble biomarkers

The University is currently a complex and a key system for the development of the scientific knowledge and the training of future professional workers. It is happening a global digital inclusion, specifically in the university context. This digital transformation is defined in different types of resources. The use of digital platforms is one of the clearest mainstreaming. The digital innovation at universities points out a challenge to their community. The challenge at the institutions consists of transforming the face-to-face training model into a flexible model, even a mixed model combining face-to-face with online training. In fact, it is necessary to talk about a change of paradigm when we conceptualise the university training towards new approaches in order to search for a sustainable teaching. This contribution aims to show the newest aspects from the educational research about the changes in the Spanish university teaching. From the different reviewed reports, it is added some data about the implementation of virtual or digital platforms into the Spanish university system. This review affirms the generalised use of this type of resource. There are other analysed aspects about the impact of this technological tool to the teaching. Some proposals are added to consider in future lines of research, such us the emerging technologies which start to be used in educational contexts. We talk about learning analytics, makerspaces, active learning or adaptative learning. In short, it is affirmed the technological transformation towards the improvement of a more scalable and sustainable system.

Introduction: The contrast sensitivity test determines the quality of visual function in patients with multiple sclerosis (MS). The purpose of this study is to analyse changes in visual function in patients with relapsing-remitting MS with and without a history of optic neuritis (ON). Methods: We conducted a longitudinal study including 61 patients classified into 3 groups as follows: (a) disease-free patients (control group); (b) patients with MS and no history of ON; and (c) patients with MS and a history of unilateral ON. All patients underwent baseline and 6-year follow-up ophthalmologic examinations, which included visual acuity and monocular and binocular Pelli-Robson contrast sensitivity tests. Results: Monocular contrast sensitivity was significantly lower in MS patients with and without a history of ON than in controls both at baseline (P = .00 and P = .01, respectively) and at 6 years (P = .01 and P = .02). Patients with MS and no history of ON remained stable throughout follow-up whereas those with a history of ON displayed a significant loss of contrast sensitivity (P = .01). Visual acuity and binocular contrast sensitivity at baseline and at 6 years was significantly lower in the group of patients with a history of ON than in the control group (P = .003 and P = .002 vs P = .006 and P = .005) and the group with no history of ON (P = .04 and P = .038 vs P = .008 and P = .01). However, no significant differences were found in follow-up results (P = .1 and P = .5). Conclusions: Monocular Pelli-Robson contrast sensitivity test may be used to detect changes in visual function in patients with ON. Resumen: Introducción: El examen de la sensibilidad al contraste permite determinar la calidad de la función visual en pacientes con esclerosis múltiple (EM). El objetivo de este estudio es analizar las modificaciones evolutivas de la función visual en pacientes con EM remitente-recurrente. Métodos: Estudio longitudinal de 61 pacientes clasificados en 3 grupos: a) pacientes libres de enfermedad (grupo control); b) pacientes con EM y sin antecedentes de neuritis óptica (NO), y c) pacientes con EM y antecedentes de NO unilateral. A todos los pacientes se les realizó una exploración oftalmológica que incluía agudeza visual y test de sensibilidad al contraste tipo Pelli-Robson mono y binocularmente, tanto al inicio como a los 6 años de seguimiento. Resultados: La sensibilidad al contraste monocular en pacientes con EM con y sin antecedentes de NO fue significativamente inferior al grupo control tanto al inicio (p = 0,00 y p = 0,01) como a los 6 años (p = 0,01 y p = 0,02), manteniéndose estable a lo largo del seguimiento excepto en el grupo de pacientes con NO en el cual existe una pérdida significativa de sensibilidad al contraste (p = 0,01). La agudeza visual y la sensibilidad al contraste binocular al inicio y a los 6 años de seguimiento fueron significativamente inferiores en el grupo de pacientes con antecedentes de NO que en el grupo control (p = 0,003 y p = 0,002; p = 0,006 y p = 0,005) y con EM sin NO (p = 0,04 y p = 0,038; p = 0,008 y p = 0,01); sin embargo, no encontramos diferencias significativas en el seguimiento (p = 0,1 y p = 0,5). Conclusiones: El test de Pelli-Robson monocular podría servir como marcador evolutivo del deterioro de la función visual en ojos con NO. Keywords: Visual acuity, Multiple sclerosis, Visual function, Optic neuritis, Pelli-Robson, Contrast sensitivity, Palabras clave: Agudeza visual, Esclerosis múltiple, Función visual, Neuritis óptica, Pelli-Robson, Sensibilidad al contraste

Resumen: Introducción: El examen de la sensibilidad al contraste permite determinar la calidad de la función visual en pacientes con esclerosis múltiple (EM). El objetivo de este estudio es analizar las modificaciones evolutivas de la función visual en pacientes con EM remitente-recurrente. Métodos: Estudio longitudinal de 61 pacientes clasificados en 3 grupos: a) pacientes libres de enfermedad (grupo control); b) pacientes con EM y sin antecedentes de neuritis óptica (NO), y c) pacientes con EM y antecedentes de NO unilateral. A todos los pacientes se les realizó una exploración oftalmológica que incluía agudeza visual y test de sensibilidad al contraste tipo Pelli-Robson mono y binocularmente, tanto al inicio como a los 6 años de seguimiento. Resultados: La sensibilidad al contraste monocular en pacientes con EM con y sin antecedentes de NO fue significativamente inferior al grupo control tanto al inicio (p = 0,00 y p = 0,01) como a los 6 años (p = 0,01 y p = 0,02), manteniéndose estable a lo largo del seguimiento excepto en el grupo de pacientes con NO en el cual existe una pérdida significativa de sensibilidad al contraste (p = 0,01). La agudeza visual y la sensibilidad al contraste binocular al inicio y a los 6 años de seguimiento fueron significativamente inferiores en el grupo de pacientes con antecedentes de NO que en el grupo control (p = 0,003 y p = 0,002; p = 0,006 y p = 0,005) y con EM sin NO (p = 0,04 y p = 0,038; p = 0,008 y p = 0,01); sin embargo, no encontramos diferencias significativas en el seguimiento (p = 0,1 y p = 0,5). Conclusiones: El test de Pelli-Robson monocular podría servir como marcador evolutivo del deterioro de la función visual en ojos con NO. Abstract: Introduction: The contrast sensitivity test determines the quality of visual function in patients with multiple sclerosis (MS). The purpose of this study is to analyse changes in visual function in patients with relapsing-remitting MS with and without a history of optic neuritis (ON). Methods: We conducted a longitudinal study including 61 patients classified into 3 groups as follows: a) disease-free patients (control group); b) patients with MS and no history of ON; and c) patients with MS and a history of unilateral ON. All patients underwent baseline and 6-year follow-up ophthalmologic examinations, which included visual acuity and monocular and binocular Pelli-Robson contrast sensitivity tests. Results: Monocular contrast sensitivity was significantly lower in MS patients with and without a history of ON than in controls both at baseline (P=.00 and P=.01, respectively) and at 6 years (P=.01 and P=.02). Patients with MS and no history of ON remained stable throughout follow-up whereas those with a history of ON displayed a significant loss of contrast sensitivity (P=.01). Visual acuity and binocular contrast sensitivity at baseline and at 6 years was significantly lower in the group of patients with a history of ON than in the control group (P=.003 and P=.002 vs P=.006 and P=.005) and the group with no history of ON (P=.04 and P=.038 vs P=.008 and P=.01). However, no significant differences were found in follow-up results (P=.1 and P=.5). Conclusions: Monocular Pelli-Robson contrast sensitivity test may be used to detect changes in visual function in patients with ON. Palabras clave: Agudeza visual, Esclerosis múltiple, Función visual, Neuritis óptica, Pelli-Robson, Sensibilidad al contraste, Keywords: Visual acuity, Multiple sclerosis, Visual function, Optic neuritis, Pelli-Robson, Contrast sensitivity

Resumen: La enfermedad por hígado graso no alcohólico (EHGNA) afecta prácticamente a un tercio de la población mundial. México es uno de los países cuya población reúne varios factores de riesgo para esta enfermedad y su prevalencia podría superar el 50%; es por eso que el panorama a mediano plazo es muy pesimista si no se toman acciones inmediatas para contrarrestar lo que ya se considera un problema de salud nacional.De ahí el interés de la Asociación Mexicana de Gastroenterología y de la Asociación Mexicana de Hepatología para realizar el Consenso mexicano de EHGNA, en el cual se hizo una revisión actualizada y a fondo de temas como epidemiología, fisiopatología, formas clínicas, diagnóstico y tratamiento, con el objetivo de ofrecer al médico mexicano una herramienta útil para la prevención y el manejo de esta enfermedad. Abstract: Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak.This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease. Palabras clave: Enfermedad por hígado graso no alcohólico, Consenso mexicano, Keywords: Nonalcoholic fatty liver disease, Mexican consensus

Resumen: La enfermedad renal crónica (ERC) es una de las principales comorbilidades que afectan a los pacientes receptores de trasplante hepático. Muchos de ellos son trasplantados con cierto grado de disfunción renal aguda o crónica, sin embargo, también pueden desarrollar ERC de novo una vez trasplantados. Se ha observado un incremento importante de la incidencia de ERC en la «era MELD», en parte se ha atribuido este fenómeno al peso que tiene la función renal para la asignación de órganos. Por otro lado, el uso generalizado de inhibidores de calcineurina también ha contribuido a este fenómeno. Es de suma importancia familiarizarnos con los métodos actuales para evaluar la función renal antes y después de un trasplante hepático. Los 2 principales biomarcadores disponibles hoy en día para este fin son la creatinina sérica y la cistatina C. Existen varias ecuaciones derivadas de estos biomarcadores que han sido probadas en este contexto, obteniéndose resultados mixtos debido a su variabilidad biológica y a la falta de estandarización en su determinación. El estándar de oro continúa siendo la medición directa de la tasa de filtrado glomerular por diversos métodos, sin embargo, esto solo se realiza con fines de investigación. También es importante conocer la clasificación actual de la lesión renal aguda y de la ERC con el fin de poder realizar un diagnóstico temprano. Esta revisión se centra en el reconocimiento, diagnóstico y clasificación de la ERC y la lesión renal aguda en pacientes receptores de trasplante hepático. Abstract: Chronic kidney disease is one of the main comorbidities affecting liver transplant recipients. Most of those patients have some degree of acute or chronic kidney dysfunction at the time of transplantation, moreover they can also develop de novo chronic kidney disease once transplanted. An important increase in the incidence of chronic kidney disease in the «MELD era» has been observed. This phenomenon has partially been attributed to the weight that kidney function carries for organ allocation. In addition, the generalized use of calcineurin inhibitors has also been a contributing factor. It is of the utmost importance for us to be familiar with the current methods for evaluating kidney function before and after a liver transplantation. The two main biomarkers available today for that purpose are serum creatinine and cystatin C. Several equations have been derived from those biomarkers and have been tested in that context with mixed results, due to their biologic variability and the lack of standardization in their measurement. The gold standard continues to be the direct determination of the glomerular filtration rate through different methods; however, that is only done for research purposes. It is also essential to know the current classification of acute kidney injury and chronic kidney disease in order to make early diagnosis. The present review focuses on the recognition, diagnosis, and classification of chronic kidney disease and acute kidney injury in liver transplantation recipients. Palabras clave: Trasplante hepático, Enfermedad renal crónica, Tasa de filtrado glomerular, Lesión renal aguda, Keywords: Liver transplantation, Chronic kidney disease, Glomerular filtration rate, Acute kidney injury

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak.This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease. Resumen: La enfermedad por hígado graso no alcohólico (EHGNA) afecta prácticamente a un tercio de la población mundial. México es uno de los países cuya población reúne varios factores de riesgo para esta enfermedad y su prevalencia podría superar el 50%; es por eso que el panorama a mediano plazo es muy pesimista si no se toman acciones inmediatas para contrarrestar lo que ya se considera un problema de salud nacional.De ahí el interés de la Asociación Mexicana de Gastroenterología y de la Asociación Mexicana de Hepatología para realizar el Consenso mexicano de EHGNA, en el cual se hizo una revisión actualizada y a fondo de temas como epidemiología, fisiopatología, formas clínicas, diagnóstico y tratamiento, con el objetivo de ofrecer al médico mexicano una herramienta útil para la prevención y el manejo de esta enfermedad. Keywords: Nonalcoholic fatty liver disease, Mexican consensus, Palabras clave: Enfermedad por hígado graso no alcohólico, Consenso mexicano

Chronic kidney disease is one of the main comorbidities affecting liver transplant recipients. Most of those patients have some degree of acute or chronic kidney dysfunction at the time of transplantation, moreover they can also develop de novo chronic kidney disease once transplanted. An important increase in the incidence of chronic kidney disease in the «MELD era» has been observed. This phenomenon has partially been attributed to the weight that kidney function carries for organ allocation. In addition, the generalized use of calcineurin inhibitors has also been a contributing factor. It is of the utmost importance for us to be familiar with the current methods for evaluating kidney function before and after a liver transplantation. The two main biomarkers available today for that purpose are serum creatinine and cystatin C. Several equations have been derived from those biomarkers and have been tested in that context with mixed results, due to their biologic variability and the lack of standardization in their measurement. The gold standard continues to be the direct determination of the glomerular filtration rate through different methods, however that is only done for research purposes. It is also essential to know the current classification of acute kidney injury and chronic kidney disease in order to make early diagnosis. The present review focuses on the recognition, diagnosis, and classification of chronic kidney disease and acute kidney injury in liver transplantation recipients. Resumen: La enfermedad renal crónica (ERC) es una de las principales comorbilidades que afectan a los pacientes receptores de trasplante hepático. Muchos de ellos son trasplantados con cierto grado de disfunción renal aguda o crónica, sin embargo, también pueden desarrollar ERC de novo una vez trasplantados. Se ha observado un incremento importante de la incidencia de ERC en la «era MELD», en parte se ha atribuido este fenómeno al peso que tiene la función renal para la asignación de órganos. Por otro lado, el uso generalizado de inhibidores de calcineurina también ha contribuido a este fenómeno. Es de suma importancia familiarizarnos con los métodos actuales para evaluar la función renal antes y después de un trasplante hepático. Los 2 principales biomarcadores disponibles hoy en día para este fin son la creatinina sérica y la cistatina C. Existen varias ecuaciones derivadas de estos biomarcadores que han sido probadas en este contexto, obteniéndose resultados mixtos debido a su variabilidad biológica y a la falta de estandarización en su determinación. El estándar de oro continúa siendo la medición directa de la tasa de filtrado glomerular por diversos métodos, sin embargo, esto solo se realiza con fines de investigación. También es importante conocer la clasificación actual de la lesión renal aguda y de la ERC con el fin de poder realizar un diagnóstico temprano. Esta revisión se centra en el reconocimiento, diagnóstico y clasificación de la ERC y la lesión renal aguda en pacientes receptores de trasplante hepático. Keywords: Liver transplantation, Chronic kidney disease, Glomerular filtration rate, Acute kidney injury, Palabras clave: Trasplante hepático, Enfermedad renal crónica, Tasa de filtrado glomerular, Lesión renal aguda

Quantum multifractality is a fundamental property of systems such as noninteracting disordered systems at an Anderson transition and many-body systems in Hilbert space. Here we discuss the origin of the presence or absence of a fundamental symmetry related to this property. The anomalous multifractal dimension Δ_{q} is used to characterize the structure of quantum states in such systems. Although the multifractal symmetry relation Δ_{q}=Δ_{1−q} is universally fulfilled in many known systems, recently some important examples have emerged where it does not hold. We show that this is the result of two different mechanisms. The first one was already known and is related to Gaussian fluctuations well described by random matrix theory. The second one, not previously explored, is related to the presence of an algebraically localized envelope. While the effect of Gaussian fluctuations can be removed by coarse graining, the second mechanism is robust to such a procedure. We illustrate the violation of the symmetry due to algebraic localization on two systems of very different nature, a 1D Floquet critical system and a model corresponding to Anderson localization on random graphs.

Oxide dispersion strengthened steels are candidate materials for nuclear reactor applications due to a powerful combination of properties, such as reduced activation, high-temperature strength and increased creep resistance. The dispersion of nanometric oxide particles in the steel matrix may also enhance radiation resistance by acting as trapping sites for irradiation induced defects. In this work, an Fe–14Cr–2 W–0.3-Ti–0.3Y2O3 (wt%) steel and a model Fe-14Cr (wt%) alloy were sequentially irradiated with He+ and Fe+ ions up to 15 dpa and 8000 appm to simulate fusion radiation damage. Their microstructural stability was investigated by positron annihilation spectroscopy and transmission electron microscopy. Transmission electron microscopy studies show that under these irradiation conditions there are no significant changes in the mean size, qualitative chemical composition and number density of nanoparticles, although the irradiation appears to induce a slight coarsening of the smaller nanoparticles. Both materials exhibit very small (

Early life adversities during childhood (such as maltreatment, abuse, neglect, or parental deprivation) may increase the vulnerability to cognitive disturbances and emotional disorders in both, adolescence and adulthood. Maternal separation (MS) is a widely used model to study stress-related changes in brain and behavior in rodents. In this study, we investigated the effect of MS (postnatal day 2–14, 3 ​h/day) in both, female and male adolescent mice. Specifically, we evaluated (i) the spatial working memory, anxiety and depressive-like behavior, (ii) the hippocampal synaptic gene expression, and (iii) the hippocampal neuroinflammatory response.Our results show that MS significantly increased depressive-like behavior in adolescent female mice and altered the spatial memory in adolescent male mice. In addition, MS led to decreased expression of genes related to synaptic function (5ht6r, Synaptophysin, and Cox-2) and induced an exacerbated microglial activation in dentate gyrus (DG), CA1, and CA3. However, while the levels of hippocampal inflammatory cytokines were not modified by MS, they did follow a sex-specific expression in adolescent mice.Taken together, our results suggest that MS induces long-term changes in hippocampal microglia and synaptic gene expression, alters the spatial memory, and induces depressive-like behavior in the adolescent mice, in a sex-specific manner.

Climate change has challenged growers and researchers alike to better understand how warm temperatures may impact winegrape plant development across varieties. Yet multi-variety studies present challenges. Here we review studies of controlled warming on winegrape varieties alongside a new study of the budburst and flowering phenology of 50 varieties of Vitis vinifera subsp. vinifera in the lab, with a small set of plants exposed to higher temperatures (20, 26, 30, 34, and 37°C mean temperatures in growth chambers) during flowering. We found few studies have examined more than one variety, which may be due to the challenge of growing diverse varieties together. Indeed, we found high variability in flowering success across varieties in the lab (28 out of 50 varieties had no flowering), which made it impossible to study variety-specific response to temperature. Across varieties, however, we found results in line with a literature review (which we also present): higher temperatures did not have a significant effect on the rate at which vines progressed through the flowering stage, but higher temperatures did correlate with flower abortion. These results suggest a potential decrease in winegrape yields in a warmer climate due to flower abortion, but also highlight the challenges of understanding heat responses across many varieties.