Cell Senescence-Related Pathways Are Enriched in Breast Cancer Patients With Late Toxicity After Radiotherapy and Low Radiation-Induced Lymphocyte Apoptosis

Background: Radiation-induced late effects are a common cause of morbidity among cancer survivors. The biomarker with the best evidence as a predictive test of late reactions is the radiation-induced lymphocyte apoptosis (RILA) assay. We aimed to investigate the molecular basis underlying the distinctive RILA levels by using gene expression analysis in patients with and without late effects and in whom we had also first identified differences in RILA levels. Patients and Methods: Peripheral blood mononuclear cells of 10 patients with late severe skin complications and 10 patients without symptoms, selected from those receiving radiotherapy from 1993 to 2007, were mock-irradiated or irradiated with 8 Gy. The 48-h response was analyzed in parallel by RILA assay and gene expression profiling with Affymetrix microarrays. Irradiated and non-irradiated gene expression profiles were compared between both groups. Gene set enrichment analysis was performed to identify differentially expressed biological processes. Results: Although differentially expressed mRNAs did not reach a significant adjusted p-value between patients suffering and not suffering clinical toxicity, the enriched pathways indicated significant differences between the two groups, either in irradiated or non-irradiated cells. In basal conditions, the main differentially expressed pathways between the toxicity and non-toxicity groups were the transport of small molecules, interferon signaling, and transcription. After 8 Gy, the differences lay in pathways highly related to cell senescence like cell cycle/NF-κB, G-protein-coupled receptors, and interferon signaling. Conclusion: Patients at risk of developing late toxicity have a distinctive pathway signature driven by deregulation of immune and cell cycle pathways related to senescence, which in turn may underlie their low RILA phenotype

Long-term anticoagulation in secondary ischemic stroke prevention: The prospective multicenter RESTAIC registry

Background and Objective: Oral anticoagulation (OAC) for secondary stroke prevention is recommended in atrial fibrillation (AF) and other sources of cardioembolic stroke. Our objectives were to explore the differences in ischemic and hemorrhagic events when using OAC for secondary stroke prevention according to the type of anticoagulant treatment and to analyze the number and reasons for OAC switches during long-term follow-up. Methods: Ischemic stroke (IS) patients who were discharged on OAC for secondary stroke prevention from January 2014 to October 2017 were recruited in a prospective, multicenter, hospital-based registry. Follow-up at 3 months was scheduled at the outpatient clinic with subsequent annual phone interviews for 3 years. Patients were classified into three study groups according to OAC at discharge: Vitamin K antagonist (VKA), Factor Xa inhibitor (FXa), or direct thrombin inhibitor (DTI). We compared stroke recurrences, intracranial hemorrhage, major bleeding, and all-cause mortality during the follow-up. We recorded any switches in OAC and the main reasons for the change. Results: A total of 241 patients were included. An anticoagulant was indicated in the presence of a source of cardioembolic stroke in 240 patients (99.6%) and lupus plus antiphospholipid syndrome in one patient. Up to 86 patients (35.6%) were on OAC before the index stroke; in 71 (82.5%) of them, this was VKA. At hospital discharge, 105 were treated with FXa (43.8%), 96 with VKA (39.6%), and 40 with DTI (16.6%). The cumulative incidences at 3 years were 17% for stroke recurrence, 1.6% for intracranial hemorrhage, 4.9% for major hemorrhage, and 22.8% for all-cause mortality, with no differences among the OAC groups in any outcomes. During the follow-up, 40 OAC switches were recorded (63% of them to FXa), mostly due to stroke recurrence. Conclusion: Long-term OAC in secondary stroke prevention is associated with a lower frequency of bleeding complications than stroke recurrences. No differences between anticoagulant drugs were found in any of the analyzed outcomes. The main cause for OAC switch during follow-up was stroke recurrence.This study was supported by grants from the Foundation for Biomedical Research of La Paz University Hospital (PI 1131

Plan de formación docente de jóvenes investigadores pre- y postdoctorales del Departamento de Farmacología y Toxicología.

Los objetivos que se han alcanzado son los siguientes: 1. Teniendo en cuenta los resultados obtenidos durante el curso 2018-19 (además de los resultados obtenidos en el curso 2017-18) los participantes han alcanzado una formación por encima de lo esperado en Farmacología habiendo asistido a una media de 57% del curso en su primer año de participación (cuando lo estipulado en el Plan de Formacion Docente es del 30%). Además, han superado un 42,3% de la materia entre su primer y segundo año con una calificación media de 8,3. 2. Los jóvenes investigadores han realizado una media de 10 horas de prácticas docentes contabilizando aquellas dedicadas a la asistencia a prácticas como oyentes, el ensayo de las prácticas con tutores y la impartición misma de las sesiones de prácticas. El número de horas está muy limitado por el bajo número de horas prácticas en las asignaturas de Farmacología del Dpto. y el elevado número de jóvenes investigadores incorporados al Dpto. 3. Con todo lo anterior, los jóvenes investigadores han alcanzado la formación en competencias docentes y las horas realizadas han sido acreditadas a las respectivas autoridades de sus becas/contratos. Su participación en la docencia práctica les permitirá en el futuro solicitar un certificado de actividades docentes emitido por las autoridades académicas de la Facultad de Medicina que avalaran su experiencia docente en solicitudes de acreditación a las diferentes figuras de profesor ante la ANECA. Además, el Dpto. de Farmacología y Toxicología ha emitido informes detallados de Aptitud Docente en Farmacología reflejando su participación en el Plan de Formación Docente del Dpto. que podrán ser consideradas en solicitudes a puestos docentes en el futuro

Influence of elevated-CRP level-related polymorphisms in non-rheumatic Caucasians on the risk of subclinical atherosclerosis and cardiovascular disease in rheumatoid arthritis

Association between elevated C-reactive protein (CRP) serum levels and subclinical atherosclerosis and cardiovascular (CV) events was described in rheumatoid arthritis (RA). CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 exert an influence on elevated CRP serum levels in non-rheumatic Caucasians. Consequently, we evaluated the potential role of these genes in the development of CV events and subclinical atherosclerosis in RA patients. Three tag CRP polymorphisms and HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were genotyped in 2,313 Spanish patients by TaqMan. Subclinical atherosclerosis was determined in 1,298 of them by carotid ultrasonography (by assessment of carotid intima-media thickness-cIMT-and presence/absence of carotid plaques). CRP serum levels at diagnosis and at the time of carotid ultrasonography were measured in 1,662 and 1,193 patients, respectively, by immunoturbidimetry. Interestingly, a relationship between CRP and CRP serum levels at diagnosis and at the time of the carotid ultrasonography was disclosed. However, no statistically significant differences were found when CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were evaluated according to the presence/absence of CV events, carotid plaques and cIMT after adjustment. Our results do not confirm an association between these genes and CV disease in RA

Monitorización y seguimiento del esfuerzo realizado por los estudiantes y de su asistencia a actividades presenciales

Este artículo documenta el planteamiento, la metodología y los primeros resultados de un plan de monitorización detallada del esfuerzo y de asistencia a actividades presenciales por parte de los estudiantes de las titulaciones ofertadas por la Escuela Técnica Superior de Ingenieros Navales de la Universidad Politécnica de Madrid durante el segundo cuatrimestre del curso 2011-2012. Se ha establecido un sistema mecánico de recogida de datos de esfuerzo por parte de los estudiantes utilizando una hoja tipo test especialmente configurada al efecto. Se pasa una hoja en todas y cada una de las actividades presenciales realizadas y en la hoja se solicita información sobre el trabajo "fuera de clase". Se documenta en este artículo cómo se ha estructurado esa hoja, qué tipo de datos se recogen, cómo se tratan mediante una base de datos creada al efecto, qué tipo de análisis se puede realizar y qué resultados preliminares obtenemos de dichos análisis

Patient preferences and treatment safety for uncomplicated vulvovaginal candidiasis in primary health care

<p>Abstract</p> <p>Background</p> <p>Vaginitis is a common complaint in primary care. In uncomplicated candidal vaginitis, there are no differences in effectiveness between oral or vaginal treatment. Some studies describe that the preferred treatment is the oral one, but a Cochrane's review points out inconsistencies associated with the report of the preferred way that limit the use of such data. Risk factors associated with recurrent vulvovaginal candidiasis still remain controversial.</p> <p>Methods/Design</p> <p>This work describes a protocol of a multicentric prospective observational study with one year follow up, to describe the women's reasons and preferences to choose the way of administration (oral vs topical) in the treatment of not complicated candidal vaginitis. The number of women required is 765, they are chosen by consecutive sampling. All of whom are aged 16 and over with vaginal discharge and/or vaginal pruritus, diagnosed with not complicated vulvovaginitis in Primary Care in Madrid.</p> <p>The main outcome variable is the preferences of the patients in treatment choice; secondary outcome variables are time to symptoms relief and adverse reactions and the frequency of recurrent vulvovaginitis and the risk factors. In the statistical analysis, for the main objective will be descriptive for each of the variables, bivariant analysis and multivariate analysis (logistic regression).. The dependent variable being the type of treatment chosen (oral or topical) and the independent, the variables that after bivariant analysis, have been associated to the treatment preference.</p> <p>Discussion</p> <p>Clinical decisions, recommendations, and practice guidelines must not only attend to the best available evidence, but also to the values and preferences of the informed patient.</p

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

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

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