El fenómeno del dopaje desde la perspectiva de las ciencias sociales. V.2

El volumen recoge una selección de las comunicaciones presentadas al 5º Congreso Internacional "Deporte, Dopaje y Sociedad", organizado conjuntamente por la Universidad Politécnica de Madrid y por la Agencia Española de Protección de la Salud en el Deporte (AEPSAD)

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.J.P.L.’s lab is sponsored by Grant PID2020-118527RB-I00 funded by MCIN/AEI/10.13039/ 501100011039; Grant PDC2021-121735-I00 funded by MCIN/AEI/10.13039/501100011039 and by the “European Union Next Generation EU/PRTR”, the Regional Government of Castile and León (CSI144P20). J.P.L. and P.L.S. are supported by the Carlos III Health Institute (PIE14/00066). AGN laboratory and human patients’ studies are supported by an ISCIII project grant (PI18/01242). The Human Genotyping unit is a member of CeGen, PRB3, and is supported by grant PT17/0019 of the PE I + D + i 2013–2016, funded by ISCIII and ERDF. SCLl is supported by MINECO/FEDER research grants (RTI2018-094130-B-100). CH was supported by the Department of Defense (DoD) BCRP, No. BC190820; and the National Cancer Institute (NCI) at the National Institutes of Health (NIH), No. R01CA184476. Lawrence Berkeley National Laboratory (LBNL) is a multi-program national laboratory operated by the University of California for the DOE under contract DE AC02-05CH11231. The Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019/0023 of the PE I + D +i, 2017–2020, funded by ISCIII and FEDER. RCC is funded by fellowships from the Spanish Regional Government of Castile and León. NGS is a recipient of an FPU fellowship (MINECO/FEDER). hiPSC-CM studies were funded in part by the “la Caixa” Banking Foundation under the project code HR18-00304 and a Severo Ochoa CNIC Intramural Project (Exp. 12-2016 IGP) to J.J.S

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

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

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

Células mesenquimales troncales en el tratamiento de la enfermedad injerto contra huésped y experiencia en Andalucía.

3) Resultados: En el meta-análisis objetivamos un aumento de la supervivencia general del 17 % y menor incidencia de la forma aguda grado IV y de la forma crónica en la profilaxis con células estromales mesenquimales en comparación con los controles. La supervivencia general de los pacientes se correlacionó positivamente con la dosis de células recibida. La respuesta total (respuesta completa + respuesta parcial) se logró en el 67 % de los pacientes con enfermedad aguda y solamente el 22% (IC 95 %, 0,16–0,29) desarrollaron una forma crónica. El 64% (IC 95%, 0,47–0,80) de los pacientes crónicos que recibieron una infusión de células estromales mesenquimales sobrevivió; la respuesta total fue del 66 % (IC 95 %, 0,55–0,76). En la serie de casos, la respuesta total se logró en el 58,7 % de los pacientes con enfermedad aguda y la supervivencia a dos años para los respondedores fue del 51,85 %. La respuesta total de los pacientes con enfermedad crónica fue del 65,50 % y la tasa de supervivencia a 2 años para los que respondieron fue del 70 %. 4) Conclusiones: Nuestro meta-análisis indica que las células estromales mesenquimales alogénicas son seguras y útiles en la profilaxis y el tratamiento de la enfermedad injerto contra huésped. Futuros ensayos deberían investigar el efecto de esta terapia celular como terapia adyuvante desde el inicio de la enfermedad. En la serie de casos, la edad en el momento del trasplante fue el único predictor correlacionado, inversamente, con la supervivencia. En cuanto a la seguridad, en la serie de casos se reportaron cuatro eventos adversos, todos recuperados sin secuelas. El análisis de esta serie de casos tratados vía uso compasivo muestra que es una opción terapéutica efectiva y segura para tratar la enfermedad injerto contra huésped refractaria, ya que una proporción significativa de pacientes respondió a la terapia. Los resultados del análisis de la serie de casos deben tomarse en consideración con cautela debido a la ausencia de grupo control. Sin embargo, puede proporcionar información valiosa respecto a la efectividad, al evaluar el efecto terapéutico en un escenario más realista, sin las limitaciones de los estrictos criterios de inclusión y exclusión de los ensayos clínicos. Respecto al diseño de futuros ensayos de terapia celular con células estromales mesenquimales, sería aconsejable, entre otras cosas, analizar la respuesta durante períodos de tiempo más largos e incluir un seguimiento a largo plazo.1) Antecedentes y objetivos: La enfermedad de injerto contra huésped es una patología grave que puede desencadenarse después de recibir un trasplante de progenitores hematopoyéticos alogénicos. La incidencia de la enfermedad aguda varía entre un 40% (en donantes haploidénticos) hasta un 80% y la forma crónica se presenta entre el 30 y el 50% de los pacientes que se someten a un alo-trasplante. Desde 1995 se han utilizado las células estromales mesenquimales para prevenir y tratar la enfermedad de injerto contra huésped refractaria al tratamiento con corticoides en multitud de estudios clínicos, con resultados poco concluyentes. Los objetivos de esta tesis fueron analizar la evidencia existente sobre la seguridad y eficacia de las células estromales mesenquimales en la enfermedad injerto contra huésped mediante la realización de un metaanálisis de los ensayos clínicos disponibles, evaluar su seguridad y efectividad mediante el análisis de una serie de casos en condiciones reales de uso clínico, en el marco de un programa de uso compasivo en Andalucía y, por último, determinar si existen aspectos de eficacia y seguridad que requieran de un mayor nivel de evidencia en el diseño de los ensayos clínicos con células estromales mesenquimales. 2) Métodos: Llevamos a cabo una revisión sistemática y meta-análisis de los ensayos clínicos publicados entre 2004 y 2019, con datos sobre la supervivencia y la respuesta obtenida después de la administración de células estromales mesenquimales alogénicas para la prevención (n = 654 pacientes) y el tratamiento de la enfermedad injerto contra huésped aguda (n = 943 pacientes) o crónica (n = 76 pacientes). Por otro lado, se analizó la supervivencia y respuesta al tratamiento con MSC de 62 pacientes tratados por la vía del uso compasivo en el programa de la comunidad autónoma de Andalucía

Study on the Usefulness of Machine Translation in the Migratory Context: Analysis of Translators’ Perceptions

The use of machine translation in the field of migrations seems to be very limited and, in view of the latest developments, it is only natural to explore its usefulness in the migratory context. In an attempt to introduce this technology into this particular area, this article reports on a qualitative study on translators’ perceptions towards machine translation and post-editing tasks. The findings of the study indicate that both are not widely developed within the migratory context and further work is required. Based on our findings, we believe that this study can contribute to opening the way for machine translation and post-editing tasks to be included into the field of migrations