Estudio exploratorio sobre las experiencias y conocimientos acerca del uso del misoprostol en un grupo de profesionales de salud españoles/as y latinoamericanos/as que prestan servicios en la Comunidad de Madrid.

Este informe forma parte del proyecto “Necesidades, Experiencias y conocimientos en salud sexual reproductiva entre los profesionales de salud y las mujeres inmigrantes en San Juan (Puerto Rico), Madrid (España) y Nueva York (EE.UU.): Anticoncepción y Embarazo No Deseado” auspiciado por Saludpromujer, Departamento de Obstetricia y Ginecología de la Escuela de Medicina, Universidad de Puerto Rico. En esta parte de la investigación hemos explorado el acceso a los servicios de salud sexual y reproductiva (SSR) de las mujeres inmigrantes en Madrid a partir de las experiencias y conocimientos de un grupo de profesionales de la salud acerca del uso del misoprostol como alternativa para interrumpir embarazos no deseados en población inmigrante y española. Este acercamiento nos ha permitido profundizar en las necesidades en salud sexual y reproductiva del colectivo de mujeres inmigrantes en Madrid y las estrategias para satisfacerlas.http://saludpromujer.md.rcm.upr.edu/index.php?option=com_content&view=section&id=26&Itemid=26

Lectura crítica de artículos científicos que la industria farmacéutica ofrece a los médicos de familia

ObjetivoConocer la validez, la importancia y la aplicabilidad de los datos proporcionados por las publicaciones biomédicas que ofrece la industria farmacéutica en su actividad promocional mediante la visita médica a un centro de salud.DiseñoEstudio transversalEmplazamientoCentro de salud rural con una población asignada de 19.474 habitantes.Participantes y métodoDurante un período de 5 meses consecutivos (desde el 1 de septiembre de 2005 al 31 de enero de 2006), un médico recogió todas las publicaciones a texto completo relativas al tratamiento, que de forma espontánea le entregaron los visitadores de la industria farmacéutica: guías de práctica clínica, revisiones descriptivas, revisiones sistemáticas, metaanálisis o ensayos clínicos. Se excluyeron estudios solicitados a iniciativa del facultativo, trabajos relativos a otros ámbitos del conocimiento no relacionados con el tratamiento (como estudios epidemiológicos o de diagnóstico), resúmenes de publicaciones, folletos publicitarios, monografías de productos, cursos de formación continuada, publicaciones de casos clínicos y resúmenes de congresos o reuniones científicas.La valoración crítica de los trabajos se hizo por pares y de forma independiente, al menos por un tutor y un residente de medicina familiar y comunitaria formados en habilidades de lectura crítica. En caso de discrepancia se procedía a un intercambio de valoraciones para llegar a un acuerdo. Los criterios aplicados para la lectura crítica de revisiones de tratamientos y de ensayos clínicos han sido los propuestos por el centro para la medicina basada en la evidencia, resumidos en el programa informático CATmaker1 y, para las guías de práctica clínica, una adaptación del instrumento Agree2. Si un estudio no se consideraba válido, no se valoraba su importancia o aplicabilidad. Si un estudio se consideraba válido pero sus resultados eran poco importantes, no se valoraba su aplicabilidad. Si un estudio era considerado válido, importante y aplicable, se calificaba como aceptable. Si un estudio no era considerado válido, o con resultados poco importantes para la práctica clínica, o no era aplicable, se calificaba como no aceptable. Para cuantificar resultados se ha realizado un análisis descriptivo mediante el cálculo de proporciones.Mediciones principalesNúmero y tipo de trabajos incluidos. Tasa de estudios considerados aceptables. Motivos por los que algunos fueron considerados no aceptables.ResultadosSe incluyeron 26 trabajos (10 guías de práctica clínica, 7 revisiones de tratamientos y 9 ensayos clínicos), de los cuales fueron aceptables 4 (un 15,38% del total). De los estudios no aceptables 19 fueron considerados no válidos (73,07%) y 3, no importantes (11,53%). No hubo ninguno que fuera considerado no aceptable sólo por no ser aplicable. De las guías, 2 de las 8 fueron aceptables. El resto fueron consideradas no válidas, y la causa más frecuente fue no aludir a métodos sistemáticos para buscar y seleccionar las evidencias. De las revisiones, ninguna de las 7 fue considerada aceptable: en 6 por falta de validez, cuyo motivo fue siempre la ausencia en la sección de métodos de una búsqueda e inclusión de todos los ensayos clínicos relevantes, y en una por imposibilidad de valorar la importancia de los datos ofrecidos. En el caso de los ensayos clínicos, 2 de los 9 fueron aceptables: 5 fueron inaceptables por falta de validez (3 de ellos no eran aleatorios, uno no tuvo un seguimiento suficientemente completo y otro no cumplió los criterios necesarios para validar subgrupos de un ensayo clínico), y 2 porque sus resultados no fueron considerados importantes (en un caso por usar variables no centradas en el paciente y en otro por haber alternativas terapéuticas disponibles más eficaces).Discusión y conclusionesAlgunos de los estudios previos sobre la información proporcionada por la industria farmacéutica se han centrado en evaluar la correlación entre los mensajes ofrecidos en la visita médica y la literatura biomédica que los avala, concluyéndose que hay una inexactitud entre ellos3,4. El presente trabajo se ha centrado en evaluar la validez de estudios de tratamiento a texto completo cuando éstos se entregan de forma espontánea a los médicos. La mayoría de las veces, la información proporcionada ha sido considerada inadecuada. La lectura crítica de su validez, importancia y aplicabilidad es un esfuerzo considerable, que tiene sentido como tarea investigadora o como experiencia docente en la que se ejerciten las habilidades de lectura crítica de los residentes, para quien lo desee enfocar de este modo. Los datos obtenidos indican que esta fuente de información, es decir, «estudios de tratamiento a texto completo ofrecidos espontáneamente por la industria farmacéutica», es un formato inaceptable de acceso a información biomédica o como método de formación continuada. No obstante, se requieren otros estudios que superen las limitaciones del presente trabajo y valoren si se confirman los resultados obtenidos

Stability study over time of clinical solutions of ziv-aflibercept prepared in infusion bags using a proper combination of physicochemical and functional strategies

The study was entirely funded by Project FIS: PI-17/00547(Instituto Carlos III, Ministerio de Economia y Competitividad, Spain), which means that it was also partially supported by European Regional Development Funds (ERDF).A range of biopharmaceutical products are used to target Vascular Endothelial Growth Factor (VEGF), including Eylea (R) (aflibercept, AFL) and Zaltrap (R) (ziv-aflibercept, ziv-AFL). The first is indicated for ophthalmological diseases such as neovascular (wet) age-related macular degeneration, while the second is used in the treatment of metastatic colorectal cancer. The stability of AFL in prefilled syringes has been widely studied; however, no research has yet been done on the stability of ziv-AFL in polyolefin infusion bags. Therefore, the purpose of the present research is to evaluate the stability of ziv-AFL (Zaltrap (R)) clinical solutions prepared under aseptic conditions in polyolefin infusion bags at two different concentrations, i.e. 4.0 and 0.6 mg/mL, and stored refrigerated in darkness at 2-8 degrees C for 14 days. With that aim, the ziv-AFL clinical solutions were assessed by analysing changes in its physicochemical and functional properties. The distribution of the particulates was studied over a range of 0.001-10 mu m by Dynamic Light Scattering (DLS); oligomers were analysed by Size-Exclusion High-Performance Chromatography with Diode Array Detection (SE/HLPC-DAD); the secondary structure of the protein was studied by far UV Circular Dichroism (CD) and the tertiary structure by Intrinsic Tryptophan Fluorescence (IT-F) and Intrinsic Protein Fluorescence (IP-F); charge variants were assessed by Strong Cation Exchange Ultra High-Performance Chromatography with UV detection (SCX/UHPLC-UV); functionality was evaluated by ELISA by measuring the biological activity as manifested in the extension of the immunological reaction of the ziv-AFL with its antigen (VEGF). Neither aggregation nor oligomerization were detected by the techniques mentioned above. Secondary and tertiary structures remained unchanged over the 14-day period, as did charge variants. The functionality observed initially was maintained along time. Therefore, it could be proposed that the ziv-AFL clinical solutions studied showed great physicochemical and functional stability over a period of two weeks, regardless of the concentration, i.e. 4 or 0.6 mg/mL.Project FIS (Instituto Carlos III, Ministerio de Economia y Competitividad, Spain) PI-17/00547European Commissio

Comprehensive biophysical and functional study of ziv-aflibercept: characterization and forced degradation

This study was entirely funded by Project FIS: PI-17/00547 (Instituto Carlos III, Ministerio de Economia y Competitividad, Spain), which means that it was also partially supported by European Regional Development Funds (ERDF).Aflibercept (AFL) is an Fc fusion protein used in the treatment of colorectal cancers and different ophthalmological diseases. There are two medicines in which AFL is the active substance: Zaltrap and Eylea, referred as ziv-AFL and AFL respectively. No proper accelerated degradation studies were published on either AFL or ziv-AFL. These studies are essential during research, development and manufacturing stages. Here, we characterized ziv-AFL and submitted it to different stress conditions: light, 60 °C, freeze-thaw cycles, changes in pH, high hypertonic solution and strong denaturing conditions. We used an array of techniques to detect aggregation (SE-HPLC/DAD and DLS), changes in secondary structure (Far-UV circular dichroism), changes in conformation or tertiary structure (Intrinsic tryptophan fluorescence) and alterations in functionality (ELISA). Results indicate that aggregation is common degradation pathway. Two different types of aggregates were detected: dimers and high molecular weight aggregates attributed to β-amyloid-like structures. Secondary structure was maintained in most of the stress tests, while conformation was altered by almost all the tests except for the freeze-thaw cycles. Functionality, evaluated by its immunochemical reaction with VEGF, was found to be stable but with decrease when exposed to light and with likely partial inactivation of the drug when pH was altered.European Union (EU) FIS: PI-17/0054

Engineering the HOMO–LUMO gap of indeno[1,2- b]fluorene

A direct, efficient and versatile strategy for the modulation of optoelectronic and magnetic properties of indeno[1,2-b]fluorene has been developed. 4-Substituted-2,6-dimethylphenyl acetylene groups placed in the apical carbon of the five-membered rings lead to redshifted absorption maxima (lmax ranging from 600–700 nm) and considerable narrowing of the HOMO–LUMO energy gap (down to 1.5 eV). Experimental and theoretical data show an increase in the diradical character (y) and a decrease of the singlet-triplet energy gap. Moreover, we have investigated the single-molecule conductance of the antiaromatic indeno[1,2-b]fluorene for the first time by including thiomethyl (-SMe) anchor groups on the phenylacetylene moiety. Conductance values one order of magnitude higher than those of a reference linear 3-ring para-phenylene ethylene have been found, despite the longer length of the S-to- S molecular junction. First principles transport calculations support this high conductance value.MCIN/AEIERDF A way of making Europe PGC2018-101873-A-I00 FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento A-FQM-221-UGR18Instituto de Salud Carlos IIISpanish GovernmentEuropean Commission PID2019-106732GB-I00 PID2019-105458RB-I00 PRE2018-083406'Severo Ochoa' Programme for Centers of Excellence in RD SEV-2016-0686'Maria de Maeztu' Programme for Units of Excellence in RD CEX2018- 000805-MMinisterio de Universidades FPU19/03751 MCIN/AEI PTA2017-13681-IComunidad de Madrid 2019-T1/IND-16384European Social Fund (ESF

HLA-B*08 identified as the most associated MHC locus for anti-carbamylated protein antibody-positive/anti-CCP-negative rheumatoid arthritis

Objective: Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA. Methods: Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP-), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 × 10-5 . Results: The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 × 10-7 ; I2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. Conclusion: These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies. © 2020, American College of Rheumatology

Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when = 50 years and symptomatic for <= 7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with <= 5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution

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

E-cadherin germline missense mutations and cell phenotype: evidence for the independence of cell invasion on the motile capabilities of the cells

10 páginas, 9 figuras, 1 tabla.-- et al.In Hereditary Diffuse Gastric Cancer syndrome, E-cadherin germline mutations of the missense type harbour significant functional consequences. In this study, we have characterised the effect of T340A, A617T, A634V and V832M E-cadherin germline missense mutations on cell morphology, motility and proliferation. Wild-type E-cadherin and A617T expressing cells have an epithelial-like morphology, with polarised cells migrating unidirectionally. T340A and A634V expressing cells, fibroblast-like, have a high motile phenotype. We show that this phenotype is dependent on an increased level of active RhoA. V832M expressing cells grow in piled-up structure of round cells, as an effect of the disturbance of the binding between alpha-catenin and beta-catenin. The destabilisation of the adhesion complex is shown to hamper the motile capabilities of these cells. We did not observe any effect of the E-cadherin mutations on cell proliferation. We show the existence of a genotype-phenotype correlation between different E-cadherin mutations and cell behaviour. However, we demonstrate that the ability of cells expressing the different E-cadherin mutations to invade is independent on their motile capabilities, providing evidence that motility is neither necessary nor sufficient for cells to invade. Our data give new insights into the understanding of the mechanisms linking invasion and E-cadherin mutations in diffuse gastric cancer.This study was funded by grants from the Fundação para a Ciência e a Tecnologia, Portugal (BD 15980, Project: POCTI/35374/CBO/2000 and POCTI/CBO/40820/2001), FORTIS Verzekerngen and the Fund for Scientific Research, Flanders (FWO), Brussels, Belgium.Peer reviewe