Nuevos fármacos antiepilépticos en Pediatría

Se estima que unos 70 millones de personas padecen epilepsia a nivel mundial de los cuales más de la mitad son niños, en los que la prevalencia estimada se sitúa en torno al 0,5-0,8%. Aunque existen diversas terapias, el tratamiento de la epilepsia se basa mayoritariamente en fármacos, que en función de su año de comercialización se clasifican como de primera, segunda o tercera generación. En el presente artículo se revisan las principales características de los fármacos antiepilépticos de última generación (lacosamida, acetato de eslicarbazepina, brivaracetam, perampanel, retigabina, everolimus y cannabidiol) que, con excepción de la retigabina (ya no está comercializada), se consideran seguros y efectivos en población pediátrica. El everolimus y el cannabidiol tienen indicaciones muy concretas (esclerosis tuberosa, síndrome de Dravet y síndrome de Lennox Gastaut) mientras que el resto están indicados en el manejo de crisis de origen focal en niños a partir de 4 años. Estas nuevas moléculas han sido desarrolladas para aportar un perfil farmacocinético y de tolerancia superior a los fármacos previamente disponibles y es previsible que a medida que aumente su uso, se vaya perfilando y ampliando su verdadero potencial. Además, por primera vez en epileptología pediátrica, se ha utilizado la extrapolación de datos de efectividad en adultos (junto con estudios de seguridad y farmacocinética específicos en población pediátrica), para acelerar la aprobación de uso en población infantil.It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5 to 0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of antiepileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol). These, with the exception of retigabine (is not yet on the market), are considered safe and effective in the paediatric population. Everolimus and cannabidiol have very specific indications (tuberous sclerosis, Dravet syndrome, and Lennox Gastaut syndrome), while the rest are indicated in the management of seizures of focal origin in children from 4 years-old. These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology,the extrapolation ofthe efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología

Novel competitive enzyme-linked immunosorbent assay for the detection of the high-risk Human Papillomavirus 18 E6 oncoprotein

Cervical cancer represents a global concern with 604,000 new cases and 342,000 deaths reported annually, with the vast majority diagnosed in low income countries. Despite high-risk Human Papillomavirus (HR HPV)-induced cervical cancer has become highly preventable through prophylactic vaccines, screening programs are critical in the control of cervical carcinogenesis in populations with limited access to vaccination and in older generations of women who have already been exposed to HR HPV infection. The surge of HPV molecular tests has provided a more sensitive and accurate diagnostic alternative to cytology screening. Given that HPV DNA testing presents a low positive predicted value, leading to unnecessary treatment, the E6 oncoprotein from HR HPV types arises as a promising diagnostic marker for its overexpression in transformed HPV-positive cancer cells. For these reasons, this study aimed at obtaining monoclonal antibodies (mAbs) against the E6 oncoprotein of one of the most prevalent HR HPV types worldwide, HPV18, in order to develop a highly specific and sensitive indirect competitive ELISA (icELISA). The production of hybridomas secreting HPV18 E6 mAbs was carried out through a combined tolerization and immunization strategy, in order to avoid cross-reactivity with the E6 protein from low-risk HPV types 6 and 11. We selected the 7D2 hybridoma clone, which recognized HPV18 E6 and showed some cross-reactivity against the HR HPV45 E6 oncoprotein. The 7D2 mAb enabled the development of a sensitive, reliable and reproducible icELISA to detect and quantify small amounts of HPV18 E6 biomarker for cervical cancer progression. The present study establishes a valid 7D2-based icELISA that constitutes a promising bioanalytical method for the early detection and quantification of HPV18 E6 oncoprotein in cervical swab samples and cancer prevention.Fil: Contreras, Natalia Estefania. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Roldán, Julieta S.. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Castillo, Daniela Susana. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentin

Desarrollo morfológico del neopalio durante la etapa prenatal en alpaca (Vicugna pacos)

The aim of this study was to describe the macroscopic anatomy of the neopallium in alpaca foetuses. Fifteen foetuses with gestational ages ranging from days 101 to 323 were used. The brains were infiltrated with 10% formaldehyde by injections at the frontoparietal and nasofrontal junction of the skull. Then, 30 days later the brains were dissected and the neopallium was exposed. Photographs in situ and ex situ of the dorsal, lateral, rostral, caudal, and ventral view were taken. By using the pictures, the brain sulcus and gyri were identified. In chronological order, the sulcus that were described were: Lateral Fissure, Suprasylvian Sulcus, Endosagittal Sulcus, Coronal Sulcus, Splenial Sulcus, Genual Sulcus, Calcarine Sulcus, Presylvian Sulcus, Central Sulcus, Sagittal Sulcus, Ectosagittal Sulcus, Diagonal Sulcus and Ectosilvian Sulcus. The gyrus were: Cingulate Gyrus, Rostral Silvian Gyrus, Caudal Silvian Gyrus, Sagittal Gyrus, Postcentral Gyrus, Precentral Gyrus, Middle Ectosylvian Gyrus, Caudal Ectosylvian Gyrus and Middle Ectosagittal Gyrus. An asymmetry between hemispheres of the same individual was evidenced, both due to the length and shape of some sulcus and gyrus, as well as their location.El objetivo del presente estudio fue describir la anatomía macroscópica del neopalio en fetos de alpaca. Se utilizaron 15 fetos con edades gestacionales comprendidas entre los días 101 a 323. Se infiltró formaldehído al 10% a los cerebros mediante inyecciones en la unión frontoparietal y nasofrontal del cráneo. Se esperaron 30 días para posteriormente diseccionarlos y hacer la exposición del neopalio, tomándose fotografías in situ y ex situ de la vista dorsal, lateral, rostral, caudal y ventral. Con estas fotografías se identificaron los surcos y giros cerebrales. En orden cronológico, los surcos que se describieron fueron: Fisura Lateral, Surco Suprasilviano, Surco Endosagital, Surco Coronal, Surco Esplenial, Surco Genual, Surco Calcarino, Surco Presilviano, Surco Central, Surco Sagital, Surco Ectosagital, Surco Diagonal y Surco Ectosilviano. Asimismo, los giros: Giro Cingulado, Giro Silviano Rostral, Giro Silviano Caudal, Giro Sagital, Giro Poscentral, Giro Precentral, Giro Ectosilviano Medio, Giro Ectosilviano Caudal y Giro Ectosagital Medio. Se evidenció una asimetría entre hemisferios del mismo individuo, tanto por el largo y forma de algunos surcos y giros, como por su ubicación

A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fuorescence-guided surgery in newly diagnosed glioblastoma patients

Background: Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypoth‐ esized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients’ survival. Methods: We conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were fnally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan–Meier method. Immune response were assessed in blood samples obtained before each vaccines. Results: Thirty-two consecutive patients were screened, one of which was a screening failure due to insufcient resection. Median age was 61 years (range 42–70). Karnofsky performance score (KPS) was 90–100 in 29%, 80 in 35.5% and 60–70 in 35.5% of cases. MGMT (O6 -methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse efects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7–16) and median OS was 23.4 months (95% CI 16–33.1). Increase in post-vaccination tumor specifc immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correla‐ tion between immune response and survival was found. Conclusions: Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival beneft of this therapeutic approach

Marine and Coastal Cultural Ecosystem Services: knowledge gaps and research priorities

Cultural ecosystem services (CES) reflect peoples’ physical and cognitive interactions with nature and are increasingly recognised for providing non-material benefits to human societies. Whereas coasts, seas, and oceans sustain a great proportion of the human population, CES provided by these ecosystems have remained largely unexplored. Therefore, our aims were (1) to analyse the state of research on marine and coastal CES, (2) to identify knowledge gaps, and (3) to pinpoint research priorities and the way forward. To accomplish these objectives, we did a systematic review of the scientific literature and synthesised a subset of 72 peer-reviewed publications. Results show that research on marine and coastal CES is scarce compared to other ecosystem service categories. It is primarily focused on local and regional sociocultural or economic assessments of coastal ecosystems from Western Europe and North America. Such research bias narrows the understanding of social-ecological interactions to a western cultural setting, undermining the role of other worldviews in the understanding of a wide range of interactions between cultural practices and ecosystems worldwide. Additionally, we have identified clusters of co-occurring drivers of change affecting marine and coastal habitats and their CES. Our systematic review highlights knowledge gaps in: (1) the lack of integrated valuation assessments; (2) linking the contribution of CES benefits to human wellbeing; (3) assessing more subjective and intangible CES classes; (4) identifying the role of open-ocean and deep-sea areas in providing CES; and (5) understanding the role of non-natural capital in the co-production of marine and coastal CES. Research priorities should be aimed at filling these knowledge gaps. Overcoming such challenges can result in increased appreciation of marine and coastal CES, and more balanced decision-supporting mechanisms that will ultimately contribute to more sustainable interactions between humans and marine ecosystems.Fil: Garcia Rodrigues, João. Universidad de Santiago de Compostela; EspañaFil: Conides, Alexis J.. Institute for Marine Biological Resources and Inland Waters; GreciaFil: Rivero Rodriguez, Susana. Centro Tecnológico del Mar; EspañaFil: Raicevich, Saša. National Research Council ; Italia. Italian National Institute for Environmental Protection and Research; ItaliaFil: Pita, Pablo. Universidad de Santiago de Compostela; España. International Campus of Excellence; EspañaFil: Kleisner, Kristin M.. Northeast Fisheries Science Center, National Oceanic and Atmospheric Administration; Estados UnidosFil: Pita, Cristina. University of Aveiro; PortugalFil: Lopes, Priscila F. M.. Federal University of Rio Grande do Norte; BrasilFil: Alonso Roldán, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; ArgentinaFil: Ramos, Sandra S.. University of Porto; Portugal. University of Hull; Reino UnidoFil: Klaoudatos, Dimitris. Hellenic Centre for Marine Research, Institute for Marine Biological Resources and Inland Waters; GreciaFil: Outeiro, Luís. Universidade de Santiago de Compostela; EspañaFil: Armstrong, Claire. University of Tromsø; NoruegaFil: Teneva, Lida. Center for Oceans, Conservation International; Estados UnidosFil: Stefanski, Stephanie. Duke University; Estados UnidosFil: Böhnke-Henrichs, Anne. Wageningen University; Países Bajos. Foundation for Sustainable Development; Países BajosFil: Kruse, Marion. Kiel University; AlemaniaFil: Lillebø, Ana I.. University of Aveiro; PortugalFil: Bennett, Elena M.. McGill University; CanadáFil: Belgrano, Andrea. Swedish University of Agricultural Sciences; Suecia. Swedish Institute for the Marine Environment (SIME); SueciaFil: Murillas, Arantza. Marine Research Division; EspañaFil: Sousa Pinto, Isabel. University of Porto; PortugalFil: Burkhard, Benjamin. Leibniz Universität Hannover; Alemania. Leibniz Centre for Agricultural Landscape Research ZALF; AlemaniaFil: Villasante, Sebastián. Universidade de Santiago de Compostela; España. International Campus of Excellence; Españ

Evolution over Time of Ventilatory Management and Outcome of Patients with Neurologic Disease∗

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease