Influence on effectiveness of early treatment with anti-TNF therapy in rheumatoid arthritis

Purpose. To evaluate the association between starting early treatment with anti-TNF and effectiveness as well as the possibility of applying therapeutic spacing in daily practice in patients with rheumatoid arthritis (RA). Methods. Observational, retrospective study conducted in two universitary hospitals in Spain. RA patients who received the first anti-TNF (adalimumab: ADA, etanercept: ETN or infliximab: IFX) during the study period (October 2006-2010) were included. Demographic data, time since diagnosis, disease activity (DAS28-ESR) and anti-TNF dosage were analyzed. Therapeutic objective was defined as DAS28<2.6. Also the response related to criteria of the European League Against Rheumatism (EULAR) was evaluated. Therapeutic spacing was defined as the use of a lower dose or a higher interval according to label doses. The main endpoint was to assess the association between the effectiveness and the moment when the anti-TNF therapy begins. The secondary target was to evaluate the association between RA activity at the beginning of treatment with anti-TNF and dose used. Results. 82 patients were included. The prescription profile was: ADA (48.8%), ETN (31.7%) and IFX (19.5%). 71.4% of patients treated with anti-TNF during the first year since diagnosis, 57.1% of those who started after 1-5 years and 30.6% of patients who started after 5 years were in remission when the study ended. De-escalation strategy was performed in 25.6% of patients: ETN (38.5%), ADA (20.0%) and IFX (18.8%). The patients treated with a higher dose according to label doses were: IFX (81%), ADA, (12.5%) and ETN (7.7%). Conclusions. Results suggest that early treatment with anti-TNF can achieve a higher percentage of remissions. Therapeutic spacing is established as a strategy that improves the efficiency in those patients in remission, being the ETN the anti-TNF most susceptible for spacing, although a relation between the early beginning with anti-TNF and the used dose was not found.Instituto de Investigaciones Bioquímicas de La Plat

Influence on effectiveness of early treatment with anti-TNF therapy in rheumatoid arthritis

Purpose. To evaluate the association between starting early treatment with anti-TNF and effectiveness as well as the possibility of applying therapeutic spacing in daily practice in patients with rheumatoid arthritis (RA). Methods. Observational, retrospective study conducted in two universitary hospitals in Spain. RA patients who received the first anti-TNF (adalimumab: ADA, etanercept: ETN or infliximab: IFX) during the study period (October 2006-2010) were included. Demographic data, time since diagnosis, disease activity (DAS28-ESR) and anti-TNF dosage were analyzed. Therapeutic objective was defined as DAS28<2.6. Also the response related to criteria of the European League Against Rheumatism (EULAR) was evaluated. Therapeutic spacing was defined as the use of a lower dose or a higher interval according to label doses. The main endpoint was to assess the association between the effectiveness and the moment when the anti-TNF therapy begins. The secondary target was to evaluate the association between RA activity at the beginning of treatment with anti-TNF and dose used. Results. 82 patients were included. The prescription profile was: ADA (48.8%), ETN (31.7%) and IFX (19.5%). 71.4% of patients treated with anti-TNF during the first year since diagnosis, 57.1% of those who started after 1-5 years and 30.6% of patients who started after 5 years were in remission when the study ended. De-escalation strategy was performed in 25.6% of patients: ETN (38.5%), ADA (20.0%) and IFX (18.8%). The patients treated with a higher dose according to label doses were: IFX (81%), ADA, (12.5%) and ETN (7.7%). Conclusions. Results suggest that early treatment with anti-TNF can achieve a higher percentage of remissions. Therapeutic spacing is established as a strategy that improves the efficiency in those patients in remission, being the ETN the anti-TNF most susceptible for spacing, although a relation between the early beginning with anti-TNF and the used dose was not found.Instituto de Investigaciones Bioquímicas de La Plat

Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis

In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis.Research at C.C.’s lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias, CSIC P.I.E., Junta de Castilla y León, and from an institutional grant from the Fundación Ramón Areces. Research in ISG group is partially supported by FEDER and by MICINN (SAF2012-32810), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program), by Junta de Castilla y León (BIO/SA06/13) and by “Proyecto en red de investigación en células madre tumorales” supported by Obra Social Kutxa y Consejería de Sanidad de la Junta de Castilla y Leon. C.V.D.’s research is supported by Junta de Castilla y León (proyecto de investigación en biomedicina SAN/39/2010). J.A.M.C.’s research is supported by the Instituto de Salud Carlos III (ISCIII), grants FIS-PI12/00202 and RTICC-RD12/0036/0063. All Spanish funding is co-sponsored by the European Union FEDER program. I.S.G. is an API lab of the EuroSyStem project and a partner of DECIDE European network. F.A.-J. and E.C.S. were supported by Spanish Ministry of Science and Innovation fellowships. E.C.-S. was a “Residencia de Estudiantes” Fellow. A.T.N. was the recipient of a “Beca de Postgrado de la Fundación Ramón Areces/UAM.”Peer Reviewe

Los resultados de aprendizaje en la mejora de la formación de los alumnos. Profundización a partir de la concreción y formulación inicial para el Máster en Educación Especial de la Facultad de Educación

El proyecto, a partir de la formación del profesorado, durante el curso anterior, en la formulación y concreción de resultados de aprendizaje, tiene el objetivo de analizar las posibles lagunas de resultados de aprendizaje del Máster en Educación Especial de la UCM en relación con las competencias del título, así como estudiar la valoración por parte de los alumnos del Máster del fomento de los resultados de aprendizaje propuestos para cada asignatura, así como profundizar en las posibles mejoras en la metodología que podrían favorecer una mejora de la formación en términos de los citados resultados de aprendizaje

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

GrassPlot - a database of multi-scale plant diversity in Palaearctic grasslands

GrassPlot is a collaborative vegetation-plot database organised by the Eurasian Dry Grassland Group (EDGG) and listed in the Global Index of Vegetation-Plot Databases (GIVD ID EU-00-003). GrassPlot collects plot records (releves) from grasslands and other open habitats of the Palaearctic biogeographic realm. It focuses on precisely delimited plots of eight standard grain sizes (0.0001; 0.001;... 1,000 m(2)) and on nested-plot series with at least four different grain sizes. The usage of GrassPlot is regulated through Bylaws that intend to balance the interests of data contributors and data users. The current version (v. 1.00) contains data for approximately 170,000 plots of different sizes and 2,800 nested-plot series. The key components are richness data and metadata. However, most included datasets also encompass compositional data. About 14,000 plots have near-complete records of terricolous bryophytes and lichens in addition to vascular plants. At present, GrassPlot contains data from 36 countries throughout the Palaearctic, spread across elevational gradients and major grassland types. GrassPlot with its multi-scale and multi-taxon focus complements the larger international vegetationplot databases, such as the European Vegetation Archive (EVA) and the global database " sPlot". Its main aim is to facilitate studies on the scale-and taxon-dependency of biodiversity patterns and drivers along macroecological gradients. GrassPlot is a dynamic database and will expand through new data collection coordinated by the elected Governing Board. We invite researchers with suitable data to join GrassPlot. Researchers with project ideas addressable with GrassPlot data are welcome to submit proposals to the Governing Board

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020

[EN] Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3,4,5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes.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