Estudio prospectivo, de seguimiento en pacientes con enfermedad de Gaucher Tipo 1 que reciben tratamiento con CERDELGA®. Proyecto TRAZELGA

Poster [PC-303] Introducción: La enfermedad de Gaucher tipo 1 (EG1), secundaria al déficit en la enzima glucocerebrosidasa lisosomal, provoca el acúmulo de glucocerebrósido principalmente en macrófagos, causando deterioro de los órganos en los que se deposita. El nuevo inhibidor de substrato Eliglustat (ELG), aprobado por la EMEA en 2015 y disponible desde enero 2017, inhibe de forma selectiva y potente la enzima glucosilceramida sintasa, disminuyendo el acúmulo de substrato, está indicado en EG1 metabolizadores rápidos, intermedios o lentos para el citocromo CYP2D6. Los ensayos clínicos de fase 2 y 3 demostraron mejora y estabilización de los parámetros tanto en los pacientes naïve, como en los de tratamiento enzimático sustitutivo. En este trabajo se expone el estudio de trazabilidad del tratamiento con eliglustat en pacientes con GD1 en España (TRAZELGA). Material y Métodos: El estudio nacional, multicéntrico TRAZELGA, ha sido diseñado como herramienta para evaluar de forma uniforme la respuesta al tratamiento durante un año, analizando los cambios en parámetros clínicos y biomarcadores habituales, registro de medicamentos concomitantes y efectos adversos a ELG, estudio de calidad de vida e incorporando un estudio exploratorio de marcadores de activación del sistema inmune (perfil de citoquinas, ferritina, lipocalina, gammaglobulinas, marcadores de estrés oxidativo), así como cambios en la infiltración medular cuantificados por RM y DEXA. Previo al inicio de ELG se realizó una evaluación de función cardíaca, hepática y renal. Resultados: 35 pacientes han iniciado tratamiento oral con Eliglustat. En esta presentación aportamos resultados preliminares de 21 pacientes (mediana de edad: 43, 8 años(23-75), 47% varones), genotipo de EG N370S/N370S: (29, 4%), N370S/L444P (41, 2%), otros dobles heterocigotos con N370S (29, 4%), metabolismo del CYP2D6 (12% metabolizadores lentos, 64, 5% intermedios y 33, 5% rápidos, ningún paciente recibió el tratamiento en prímera línea y sus características basales (tabla1), son de pacientes estabilizados con TES (15 casos) o miglustat (6). Un paciente esplenectomizado. 3 pacientes esplenomegalia palpable al momento de inclusión. 6 pacientes con multimorbilidades y polimedicaciones y 5 pacientes aquejaban astenia como síntoma principal antes de su inclusión en este estudio. El seguimiento medio actual es de 6 meses. Conclusiones: Se espera incluir un total de 30 pacientes en el estudio y analizar la influencia de Eliglustat sobre los biomarcadores, marcadores de inflamación, densidad mineral ósea. Tener información sobre adherencia, efectos adversos en práctica clínica habitual y grado de satisfacción. Aunque escasos, hasta ahora no hay publicada información de la respuesta al tratamiento en pacientes provenientes de tratamiento con miglustat. En caso de aceptación se presentará un análisis exhaustivo, invitando a todos los interesados a unirse al proyecto

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies

The 2010 very high energy gamma-ray flare & 10 years of multi-wavelength observations of M 87

Abridged: The giant radio galaxy M 87 with its proximity, famous jet, and very massive black hole provides a unique opportunity to investigate the origin of very high energy (VHE; E>100 GeV) gamma-ray emission generated in relativistic outflows and the surroundings of super-massive black holes. M 87 has been established as a VHE gamma-ray emitter since 2006. The VHE gamma-ray emission displays strong variability on timescales as short as a day. In this paper, results from a joint VHE monitoring campaign on M 87 by the MAGIC and VERITAS instruments in 2010 are reported. During the campaign, a flare at VHE was detected triggering further observations at VHE (H.E.S.S.), X-rays (Chandra), and radio (43 GHz VLBA). The excellent sampling of the VHE gamma-ray light curve enables one to derive a precise temporal characterization of the flare: the single, isolated flare is well described by a two-sided exponential function with significantly different flux rise and decay times. While the overall variability pattern of the 2010 flare appears somewhat different from that of previous VHE flares in 2005 and 2008, they share very similar timescales (~day), peak fluxes (Phi(>0.35 TeV) ~= (1-3) x 10^-11 ph cm^-2 s^-1), and VHE spectra. 43 GHz VLBA radio observations of the inner jet regions indicate no enhanced flux in 2010 in contrast to observations in 2008, where an increase of the radio flux of the innermost core regions coincided with a VHE flare. On the other hand, Chandra X-ray observations taken ~3 days after the peak of the VHE gamma-ray emission reveal an enhanced flux from the core. The long-term (2001-2010) multi-wavelength light curve of M 87, spanning from radio to VHE and including data from HST, LT, VLA and EVN, is used to further investigate the origin of the VHE gamma-ray emission. No unique, common MWL signature of the three VHE flares has been identified.Comment: 19 pages, 5 figures; Corresponding authors: M. Raue, L. Stawarz, D. Mazin, P. Colin, C. M. Hui, M. Beilicke; Fig. 1 lightcurve data available online: http://www.desy.de/~mraue/m87

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

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Comparative study of methods for the determination of proteolytic activity in lactic acid bacteria and selection of an autochthonous starter to manufacture Manchego cheese

The acidifying and proteolytic activity of 18 isolates of Lactococcus and Lactobacillus isolated from artisanal and industrial Manchego cheeses were studied in order to know which of them presented the best activities to be employed in the manufacture of this cheese. Of the two methods used to evaluate the proteolytic activity, Folin-Ciocalteau and opthaldehyde (oPA) methods, the latter gave higher values and showed a higher discriminating capacity with important differences for the values obtained for Lc. lactis subsp. lactis isolates. Of all the isolates studied, the Lactococcus lactis subp. lactis (Lc 8) showed the highest acidifying (0.79 % lactic acid) and proteolytic (2.19 mmol Gly/L) activity and could be selected as a starter culture for Manchego cheese manufacture.Peer reviewe