IIS-PRINCESA - Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (Madrid)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16980

El Instituto de Investigación del Hospital de La Princesa fue constituido el 15 de diciembre del 2009 en virtud de un convenio firmado entre centros sanitarios de la Consejería de Sanidad de la Comunidad de Madrid y otras instituciones de investigación básica. Está formado por el Hospital Universitario de La Princesa (como núcleo básico del Instituto), Hospital Universitario de Santa Cristina, Hospital Infantil del Niño Jesús, Área de Influencia de Atención Primaria del Hospital U. de La Princesa y la Universidad Autónoma de Madrid. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2010, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

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Electrical impedance tomography for PEEP titration in ARDS patients: a systematic review and meta-analysis
(Springer, 2025-02-26) Sanchez-Piedra, Carlos; Rodriguez Ortiz de Salazar, Begoña; Roca, Oriol; Prado-Galbarro, Francisco-Javier; Perestelo-Perez, Lilisbeth; Sanchez-Gomez, Luis Maria
To assess the efficacy of electrical impedance tomography (EIT)-guided positive end-expiratory pressure (PEEP) titration in improving outcomes for patients with acute respiratory distress syndrome (ARDS). A systematic review and meta-analysis was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomized controlled trials and observational studies with a control group comparing EIT-guided PEEP titration to other strategies were included. Endpoints analysed included mortality, days of mechanical ventilation (MV), intensive care unit (ICU) length of stay (LOS), weaning success rate, barotrauma, driving pressure (∆P), mechanical power (MP), Sequential Organ Failure Assessment (SOFA) score and adverse events. Pooled results were presented as Risk Ratio (RR) for dichotomous outcomes and standardized difference in means (SMD) for continuous outcomes. A total of 4 studies were identified (3 randomized controlled trials and one observational study). All studies were single-center studies (N total = 271 patients). The main limitations were related to potential bias in selecting reported outcomes. EIT-guided PEEP titration was associated with a significant reduction in mortality among critically ill patients with ARDS (RR = 0.64, 95% CI: 0.45-0.91). No significant differences were found in other outcomes. Our findings suggest that EIT may be a valuable tool for PEEP titration in critically ill patients with ARDS. By optimizing lung mechanics, EIT-guided PEEP titration may potentially reduce mortality rates. While larger, multicenter studies are needed to definitively establish the clinical role of EIT in ARDS management, our results provide promising evidence for its potential clinical impact.
Phase IV adaptive randomised clinical trials evaluating efficacy and cost-efficacy of pre-emptive pharmacogenetic genotyping strategies in the Spanish National Health System: iPHARMGx Master Protocol and PREVESTATGx nested clinical trial
(BMJ Publishing Group, 2024-11-07) Stewart, Stefan; Seco-Meseguer, Enrique; Diago-Sempere, Elena; Marín-Candón, Alicia; Carmona, Montserrat; Estébanez, Miriam; López-Fernández, Luis A; Imaz-Iglesia, Iñaki; Del Mar García Saiz, María; Laserna-Mendieta, Emilio J; Peiró, Ana M; Farré, Magí; Rodriguez-Jimenez, Consuelo; Saiz-Rodriguez, Miriam; Sanabria-Cabrera, Judith; Rosas-Alonso, Rocío; Abad-Santos, Francisco; Pedrosa-Pérez, Lucía; Carcas, Antonio J; García García, Irene; Borobia, Alberto M; iPHARMGx study group; Instituto de Salud Carlos III; Unión Europea. Comisión Europea. NextGenerationEU
Introduction: Genetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside of tertiary hospitals is limited due to a lack of pharmacoeconomic evidence to support widespread implementation by healthcare policy-makers. The Spanish Consortium for the Implementation of Pharmacogenetics (iPHARMGx Consortium) addresses this by developing a clinical trial master protocol that will govern multiple nested adaptive clinical trials that compare genotype-guided treatments to standard care in specific drug-gene-population triads, asses their cost-efficacy and identify novel biomarkers through advanced sequencing techniques. The first of these studies aims to assess whether a pre-emptive statin therapy genotyping scheme reduces the incidence of statin-associated muscle symptoms (SAMS) in a population at risk of cardiovascular disease susceptible of receiving high-intensity or moderate-intensity doses of statins: The PREVESTATGx trial. Methods and analysis: the PREVESTATGX trial is a multicentre, adaptive randomised controlled pragmatic phase IV clinical trial nested to the iPHARMGx master protocol with two parallel arms, aiming for superiority. Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial and genotyping has been performed, subjects will be randomly allocated to experimental group (pharmacogenetic genotype-guided statin prescription) or standard-of-care statin prescription (as deemed by attending physician). The main objective is to assess the efficacy of a statin pre-emptive genotyping strategy in reducing the incidence of SAMS. A total of 225 subjects will be recruited among the 10 participating centres if no futility/efficacy boundary is reached in the prespecified interim analyses. Recruitment will be carried out during a 12-month period and subjects will be followed for a 9-month period. Ethics and dissemination: The PREVESTATGx trial received ethical approval on 24 April 2024. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. Trial results will be submitted for publication in an open-access peer-reviewed medical speciality-specific publication. Trial registration number: EU CT number: 2023-509418-12-00/Clinical trial Identifier (ClinicalTrials.gov): NCT06262685. Protocol version 1.2 12 April 2024 (includes non-substantial modification number 14 June 2024). Trial registration of this study can be located at both the EU Clinical Trials Register available from https:// euclinicaltrials.eu/search-for-clinical-trials/?lang=en and https://clinicaltrials.gov. Registration on both websites was done before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according to the WHO.
Exploring the sequence diversity and surface expression of Factor H-Binding Protein among invasive serogroup B meningococcal strains from selected European countries
(Taylor & Francis, 2024-12-31) Clark, Stephen A; Willerton, Laura; Claus, Heike; Carannante, Anna; Stefanelli, Paola; Abad, Raquel; Vazquez-Moreno, Julio Alberto; Borrow, Ray; Pfizer
Factor H-Binding Protein (fHbp) is a key component of meningococcal vaccines such as MenB-fHbp, licensed in the EU, UK, and other countries. Sufficient expression of fHbp on the bacterial surface is necessary for vaccine-induced antibodies to bind and exert bactericidal activity. The flow cytometric MEASURE assay quantifies fHbp expression in vitro, and previous studies have shown that strains with a Mean Fluorescence Intensity (MFI) >1000 are likely to be killed by MenB-fHbp-induced antibodies. This study assessed fHbp peptide distribution and expression among 451 invasive group B strains collected in 2016 across England, Wales, and Northern Ireland (EW&NI), Germany, Italy, and Spain. We found that 92% of the strains expressed fHbp above the MFI 1000 threshold. The strain distribution across EW&NI, Germany, and Italy was similar, with coverage ranging from 92.1% to 94.6%, dominated by a small number of clonal complexes and fHbp peptides. Although, the Spanish subset had a higher proportion of lower-expressing strains, particularly clonal complex 213, resulting in a lower predicted coverage for Spain (84%). These results, along with other published MEASURE data, can provide a basis for genotypic MenB-fHbp coverage predictions, however, inclusion of the upstream intergenic sequence of the fHbp gene in the prediction improved its accuracy by distinguishing between low- and high-expressing strains. Future MEASURE analyses of strains with less common fHbp variants would serve to further refine vaccine coverage predictions.
Diagnostic potential of combining plasma biomarkers of tissue damage and inflammation in pediatric TB
(Elsevier, 2024-12) López-Suárez, Andrea; Santos-Sebastián, Mar; Hernanz-Lobo, Alicia; Rincón-López, Elena; Aguilera-Alonso, David; Saavedra-Lozano, Jesús; Ruiz Serrano, María Jesús; Hernández-Bartolomé, Ángel; Medrano, Luz Maria; Jiménez Fuentes, José Luis; Navarro, María Luisa; Tebruegge, Marc; Santiago-García, Begoña; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); European Society for Paediatric Infectious Diseases
Introduction: Immune-based diagnostic tests for tuberculosis (TB) have suboptimal sensitivity in children and cannot differentiate between latent infection (LTBI) and active disease. This study evaluated the diagnostic potential of a broad range of biomarkers of tissue damage and inflammation in unstimulated plasma in children. Methods: We analyzed 17 biomarkers in 15 non-M. tuberculosis (MTB)-infected controls and 33 children with TB infection (LTBI, n = 8; probable TB, n = 19; confirmed TB, n = 6). Biomarker concentrations were measured using a Luminex magnetic bead-based platform and multiplex sandwich immunoassays. Concentrations, correlations and diagnostic accuracy assessments were conducted among patient groups. Results: Confirmed TB cases had significantly higher concentrations of IFN-γ and IL-2 and higher IFN-γ/MCP-1 and IL-2/MCP-1 ratios compared to LTBI and non-MTB-infected children. Among children with confirmed TB, there was a strong correlation between IFN-γ and IL-10 (r = 0.95; p < 0.001) and a significant correlation between IL-2 and IL-1ra (r = 0.92), IL-21 (r = 0.91), MCP-3 (r = 0.84), and MMP-1 (r = 0.85). The IFN-γ/MCP-1 ratio was the most accurate biomarker combination for differentiating between MTB-infected and non-MTB-infected children (AUC, 0.82; sensitivity, 87.9%; specificity, 66.6%; p < 0.001) and between active TB and non-MTB-infected children (AUC 0.82; sensitivity 88.0%; specificity 60.0%; p < 0.001). None of the biomarkers investigated were able to discriminate between LTBI and active TB. Conclusion: Our data suggest that combining the analyses of multiple biomarkers in plasma has the potential to enhance diagnosis of TB in children and, thus, warrants additional investigation. In particular, the diagnostic potential of IFN-γ/MCP-1 ratios should be further explored in larger pediatric cohorts.
Clinical audit of COPD in outpatient respiratory clinics in Spain: the EPOCONSUL study.
(2017-01-25) Calle Rubio, Myriam; Alcázar Navarrete, Bernardino; Soriano, Joan B; Soler-Cataluña, Juan J; Rodríguez González-Moro, José Miguel; Fuentes Ferrer, Manuel E; Lopez-Campos, Jose Luis
Background: Chronic obstructive pulmonary disease (COPD) outpatients account for a large burden of usual care by respirologists. EPOCONSUL is the first national clinical audit conducted in Spain on the medical care for COPD patients delivered in outpatient respiratory clinics. We aimed to evaluate the clinical interventions and the degree of adherence to recommendations in outpatients of current COPD clinical practice guidelines. Methodology: This is an observational study with prospective recruitment (May 2014-May 2015) of patients with a COPD diagnosis as seen in outpatient respiratory clinics. The information collected was historical in nature as for the clinical data of the last and previous consultations, and the information concerning hospital resources was concurrent. Results: A total of 17,893 clinical records of COPD patients in outpatient respiratory clinics from 59 Spanish hospitals were evaluated. Of the 5,726 patients selected, 4,508 (78.7%) were eligible. Overall, 12.1% of COPD patients did not fulfill a diagnostic spirometry criteria. Considerable variability existed in the available resources and work organization of the hospitals, although the majority were university hospitals with respiratory inpatient units. There was insufficient implementation of clinical guidelines in preventive and educational matters. In contrast, quantitative evaluation of dyspnea grade (81.9%) and exacerbation history (70.9%) were more frequently performed. Only 12.4% had COPD severity calculated according to the Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity (BODE) index. Phenotype characteristics according to Spanish National Guideline for COPD were determined in 46.3% of the audited patients, and the risk evaluation according to Global initiative for chronic Obstructive Lung Disease was estimated only in 21.9%. Conclusion: The EPOCONSUL study reports the current situation of medical care for COPD patients in outpatient clinics in Spain, revealing its variability, strengths, and weaknesses. This information has to be accounted for by health managers to define corrective strategies and maximize good clinical practice.
Variability in adherence to clinical practice guidelines and recommendations in COPD outpatients: a multi-level, cross-sectional analysis of the EPOCONSUL study.
(2017-12-02) Calle Rubio, Myriam; Lopez-Campos, Jose Luis; Soler-Cataluña, Juan J; Alcázar Navarrete, Bernardino; Soriano, Joan B; Rodríguez González-Moro, José Miguel; Fuentes Ferrer, Manuel E; Rodríguez Hermosa, Juan Luis; EPOCONSUL Study
Background: Clinical audits have reported considerable variability in COPD medical care and frequent inconsistencies with recommendations. The objectives of this study were to identify factors associated with a better adherence to clinical practice guidelines and to explore determinants of this variability at the the hospital level. Methods: EPOCONSUL is a Spanish nationwide clinical audit that evaluates the outpatient management of COPD. Multilevel logistic regression with two levels was performed to assess the relationships between individual and disease-related factors, as well as hospital characteristics. Results: A total of 4508 clinical records of COPD patients from 59 Spanish hospitals were evaluated. High variability was observed among hospitals in terms of medical care. Some of the patient's characteristics (airflow obstruction, degree of dyspnea, exacerbation risk, presence of comorbidities), the hospital factors (size and respiratory nurses available) and treatment at a specialized COPD outpatient clinic were identified as factors associated with a better adherence to recommendations, although this only explains a small proportion of the total variance. Conclusion: To be treated at a specialized COPD outpatient clinic and some intrinsic patient characteristics were factors associated with a better adherence to guideline recommendations, although these variables were only explaining part of the high variability observed among hospitals in terms of COPD medical care.
Diagnosis and treatment of disorders of intracranial pressure: consensus statement of the Spanish Society of Neurology's Headache Study Group
(Elsevier, 2024-02-29) García-Ull, J; González-García, N; Torres-Ferrus, Marta; García-Azorín, D; Molina-Martinez, Francisco José; Beltrán-Blasco, I; Santos-Lasaosa, Sonia; Latorre, G; Gago-Veiga, A B; Láinez, J M; Porta-Etessam, J; Nieves-Castellanos, C; Mínguez-Olaondo, A; López-Bravo, A; Quintas, S; Morollón, N; Díaz-Insa, S; Belvís, R; Irimia, P
[EN] Primary intracranial pressure disorders include idiopathic intracranial hypertension and spontaneous intracranial hypotension. These two entities have presented a remarkable advance in diagnostic and therapeutic techniques in recent years. Therefore, the Spanish Society of Neurology's Headache Study Group (GECSEN) considered it necessary to prepare this consensus document with the inclusion of diagnostic and therapeutic algorithms to facilitate and improve their management in clinical practice. This document was created by a committee of experts of the GECSEN based on a systematic review of the literature, incorporating the experience of the participants, and establishing practical recommendations with levels of evidence and grades of recommendation. [ES] Los trastornos primarios de la presión intracraneal incluyen la hipertensión intracraneal idiopática y la hipotensión intracraneal espontánea. El diagnóstico y tratamiento de ambas entidades ha presentado un avance destacable en los últimos años; por lo que desde el Grupo de Estudio de Cefaleas de la Sociedad Española de Neurología (GECSEN) consideramos necesaria la elaboración de este documento de consenso con la inclusión de algoritmos diagnósticos y terapéuticos para mejorar su manejo en la práctica diaria. Este documento ha sido redactado por un comité de expertos del GECSEN tras realizar una revisión sistemática de la bibliografía, incorporando la experiencia de los participantes y estableciendo unas recomendaciones prácticas con niveles de evidencia y grados de recomendación.
Hospital Epidemics Tracker (HEpiTracker): Description and Pilot Study of a Mobile App to Track COVID-19 in Hospital Workers
(JMIR Publications, 2020-07) Soriano, Joan B; Fernandez, Esteve; de Astorza, Alvaro; Perez de Llano, Luis Alejandro; Fernandez-Villar, Alberto; Carnicer-Pont, Dolors; Alcazar-Navarrete, Bernardino; Garcia, Arturo; Morales, Aurelio; Lobo, Maria; Maroto, Marcos; Ferreras, Eloy; Soriano, Cecilia; Del Rio-Bermudez, Carlos; Vega-Piris, Lorena; Basagana, Xavier; Muncunill Farreny, Josep; García-Cosío, Borja; Lumbreras, Sara; Catalina, Carlos; Alzaga, Jose María; Gomez Quilon, David; Alberto Valdivia, Carlos; de lara, Celia; Ancochea, Julio
Background: Hospital workers have been the most frequently and severely affected professional group during the COVID-19 pandemic, and have a big impact on transmission. In this context, innovative tools are required to measure the symptoms compatible with COVID-19, the spread of infection, and testing capabilities within hospitals in real time. Objective: We aimed to develop and test an effective and user-friendly tool to identify and track symptoms compatible with COVID-19 in hospital workers. Methods: We developed and pilot tested Hospital Epidemics Tracker (HEpiTracker), a newly designed app to track the spread of COVID-19 among hospital workers. Hospital staff in 9 hospital centers across 5 Spanish regions (Andalusia, Balearics, Catalonia, Galicia, and Madrid) were invited to download the app on their phones and to register their daily body temperature, COVID-19-compatible symptoms, and general health score, as well as any polymerase chain reaction and serological test results. Results: A total of 477 hospital staff participated in the study between April 8 and June 2, 2020. Of note, both health-related (n=329) and non-health-related (n=148) professionals participated in the study; over two-thirds of participants (68.8%) were health workers (43.4% physicians and 25.4% nurses), while the proportion of non-health-related workers by center ranged from 40% to 85%. Most participants were female (n=323, 67.5%), with a mean age of 45.4 years (SD 10.6). Regarding smoking habits, 13.0% and 34.2% of participants were current or former smokers, respectively. The daily reporting of symptoms was highly variable across participating hospitals; although we observed a decline in adherence after an initial participation peak in some hospitals, other sites were characterized by low participation rates throughout the study period. Conclusions: HEpiTracker is an already available tool to monitor COVID-19 and other infectious diseases in hospital workers. This tool has already been tested in real conditions. HEpiTracker is available in Spanish, Portuguese, and English. It has the potential to become a customized asset to be used in future COVID-19 pandemic waves and other environments.
Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2015 and GOLD 2019 staging: a pooled analysis of individual patient data
(European Respiratory Society (ERS), 2020-10-01) Garcia Castillo, Elena; Alonso Perez, Tamara; Ancochea, Julio; Pastor Sanz, Maria Teresa; Almagro, Pere; Martinez-Camblor, Pablo; Miravitlles, Marc; Rodriguez-Carballeira, Monica; Navarro, Annie; Lamprecht, Bernd; Ramirez-Garcia Luna, Ana S; Kaiser, Bernhard; Alfageme, Inmaculada; Casanova, Ciro; Esteban, Cristobal; Soler-Cataluna, Juan J; de-Torres, Juan P; Celli, Bartolome R; Marin, Jose M; ter Riet, Gerben; Sobradillo, Patricia; Lange, Peter; Garcia-Aymerich, Judith; Anto, Josep M; Turner, Alice M; Han, MeiLan K; Langhammer, Arnulf; Vikjord, Sigrid Anna Aalberg; Sternberg, Alice; Leivseth, Linda; Bakke, Per; Johannessen, Ane; Oga, Toru; García-Cosío, Borja; Echazarreta, Andres; Roche, Nicolas; Burgel, Pierre-Regis; Sin, Don D; Puhan, Milo A; Lopez-Campos, Jose Luis; Carrasco, Laura; Soriano, Joan B; 3CIA Collaboration
In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A-4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean +/- SD age was 63.9 +/- 9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66-0.68) for GOLD 2015 and 0.65 (95% CI 0.63-0.66) for GOLD 2019. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system.
A Proposed Approach to Chronic Airway Disease (CAD) Using Therapeutic Goals and Treatable Traits: A Look to the Future
(Dove Medical Press, 2020) Perez de Llano, Luis Alejandro; Miravitlles, Marc; Golpe, Rafael; Alvarez-Gutierrez, Francisco Javier; Cisneros, Carolina; Almonacid, Carlos; Martinez-Moragon, Eva; Gonzalez-Barcala, Francisco-Javier; Ramos-Barbon, David; Plaza, Vicente; Lopez-Campos, Jose Luis; de-Torres, Juan Pablo; Casanova, Ciro; Garcia Rivero, Juan Luis; Rodriguez Hermosa, Juan; Calle Rubio, Myriam; Soler-Cataluna, Juan José; García-Cosío, Borja
Chronic airflow obstruction affects a wide range of airway diseases, the most frequent of which are asthma, COPD, and bronchiectasis; they are clearly identifiable in their extremes, but quite frequently overlap in some of their pathophysiological and clinical characteristics. This has generated the description of new mixed or overlapping disease phenotypes with no clear biological grounds. In this special article, a group of experts provides their perspective and proposes approaching the treatment of chronic airway disease (CAD) through the identification of a series of therapeutic goals (TG) linked to treatable traits (TT) - understood as clinical, physiological, or biological characteristics that are quantifiable using biomarkers. This therapeutic approach needs validating in a clinical trial with the strategy of identification of TG and treatment according to TT for each patient independently of their prior diagnosis.
EpidemIBD: rationale and design of a large-scale epidemiological study of inflammatory bowel disease in Spain
(SAGE Publishing, 2019-05) Chaparro, Maria; Barreiro-de Acosta, Manuel; Benitez, Jose Manuel; Cabriada, Jose Luis; Casanova, Maria Jose; Ceballos, Daniel; Esteve, Maria; Fernandez, Hipolito; Ginard Vicens, Daniel; Gomollon, Fernando; Lorente, Rufo; Nos, Pilar; Riestra, Sabino; Rivero, Montserrat; Robledo, Pilar; Rodriguez, Cristina; Sicilia, Beatriz; Torrella, Emilio; Garre, Ana; Garcia-Esquinas, Esther; Rodríguez-Artalejo, Fernando; Gisbert, Javier P; EpidemIBD study group of GETECCU
Background: Inflammatory bowel disease (IBD) is associated with a considerable burden to the patient and society. However, current data on IBD incidence and burden are limited because of the paucity of nationwide epidemiological studies, heterogeneous designs, and a low number of participating centers and sample size. The EpidemIBD study is a large-scale investigation to provide an accurate assessment of the incidence of IBD in Spain, as well as treatment patterns and outcomes. Methods: This multicenter, population-based incidence cohort study included patients aged >18 years with IBD (Crohn's disease, ulcerative colitis, or unclassified IBD) diagnosed during 2017 in 108 hospitals in Spain, covering 50% of the Spanish population. Each participating patient will attend 10 clinic visits during 5 years of follow up. Demographic data, IBD characteristics and family history, complications, treatments, surgeries, and hospital admissions will be recorded. Results: The EpidemIBD study is the first large-scale nationwide study to investigate the incidence of IBD in Spain. Enrollment is now completed and 3627 patients are currently being followed up. Conclusions: The study has been designed to overcome many of the limitations of previous European studies into IBD incidence by prospectively recruiting a large number of patients from all regions of Spain. In addition to epidemiological information about the burden of IBD, the 5-year follow-up period will also provide information on treatment patterns, and the natural history and financial burden of IBD.
Behcet's disease and genetic interactions between HLA-B*51 and variants in genes of autoinflammatory syndromes
(Nature Publishing Group, 2019-02-26) Burillo-Sanz, Sergio; Montes-Cano, Marco-Antonio; Garcia-Lozano, Jose-Raul; Olivas-Martinez, Israel; Ortego-Centeno, Norberto; Garcia-Hernandez, Francisco-Jose; Espinosa, Gerard; Grana-Gil, Genaro; Sanchez-Burson, Juan; Rosa Julia, Maria; Solans, Roser; Blanco, Ricardo; Barnosi-Marin, Ana-Celia; Gomez de la Torre, Ricardo; Fanlo Mateo, Patricia; Rodriguez-Carballeira, Monica; Rodriguez-Rodriguez, Luis; Camps, Teresa; Castaneda, Santos; Alegre-Sancho, Juan-Jose; Martin, Javier; Gonzalez-Escribano, Maria-Francisca
Behcet's disease (BD) is an immune-mediated systemic disorder with a well-established genetic base. In a previous study, using a next generation sequencing approach, we found many rare variants and some functional polymorphisms in genes related to autoinflammatory syndromes (AID): CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A in our BD cohort. Our strategy did not allow us to establish either number of patients with variants, proportion of individuals accumulating them or relationship with other genetic factors. With the goal to answer these questions, the individual samples were sequenced. Additionally, three functional polymorphisms: NLRP3 p.Gln703Lys, NOD2 p.Arg702Trp and p. Val955Ile were genotyped using TaqMan assays. A total of 98 patients (27.6%) carried at least one rare variant and 13 of them (3.7%) accumulated two or three. Functional regression model analysis suggests epistatic interaction between B51 and MEFV (P=0.003). A suggestive protective association of the minor allele of NOD2 p.Arg702Trp (P=0.01) was found in both, B51 positive and negative individuals. Therefore, a high percentage of patients with BD have rare variants in AID genes. Our results suggest that the association of MEFV with BD could be modulated by the HLA molecules; whereas the protective effect of NOD2 p.Arg702Trp would be independent of HLA.
Association of Functional Polymorphisms of KIR3DL1/DS1 With Behcet's Disease
(Frontiers Media, 2019-11-29) Castano-Nunez, Angel; Montes-Cano, Marco-Antonio; Garcia-Lozano, Jose-Raul; Ortego-Centeno, Norberto; Garcia-Hernandez, Francisco-Jose; Espinosa, Gerard; Grana-Gil, Genaro; Sanchez-Burson, Juan; Julia Benique, Maria Rosa; Solans, Roser; Blanco, Ricardo; Barnosi-Marin, Ana-Celia; Gomez de la Torre, Ricardo; Fanlo Mateo, Patricia; Rodriguez-Carballeira, Monica; Rodriguez-Rodriguez, Luis; Camps, Teresa; Castaneda, Santos; Alegre-Sancho, Juan-Jose; Martin, Javier; Gonzalez-Escribano, Maria-Francisca
Behcet's disease (BD) is an immune-mediated vasculitis related to imbalances between the innate and adaptive immune response. Infectious agents or environmental factors may trigger the disease in genetically predisposed individuals. HLA-B51 is the genetic factor stronger associated with the disease, although the bases of this association remain elusive. NK cells have also been implicated in the etiopathogenesis of BD. A family of NK receptors, Killer-cell Immunoglobulin-like Receptor (KIR), with a very complex organization, is very important in the education and control of the NK cells by the union to their ligands, most of them, HLA class I molecules. This study aimed to investigate the contribution of certain KIR functional polymorphisms to the susceptibility to BD. A total of 466 BD patients and 444 healthy individuals were genotyped in HLA class I (A, B, and C). The set of KIR genes and the functional variants of KIR3DL1/DS1 and KIR2DS4 were also determined. Frequency of KIR3DL1*004 was lower in patients than in controls (0.15 vs. 0.20, P = 0.005, Pc = 0.015; OR = 0.70; 95% CI 0.54-0.90) in both B51 positive and negative individuals. KIR3DL1*004, which encodes a misfolded protein, is included in a common telomeric haplotype with only one functional KIR gene, KIR3DL2. Both, KIR3DL1 and KIR3DL2 sense pathogen-associated molecular patterns but they have different capacities to eliminate them. The education of the NK cells depending on the HLA, the balance of KIR3DL1/KIR3DL2 licensed NK cells and the different capacities of these receptors to eliminate pathogens could be involved in the etiopathogenesis of BD.
Prognostic factors and analysis of mortality due to brain haemorrhages associated with vitamin K antagonist oral anticoagulants. Results from the TAC registry
(Elsevier, 2018-09) Zapata-Wainberg, G; Quintas, S; Ximenez-Carrillo Rico, A; Benavente Fernandez, L; Masjuan Vallejo, J; Gallego Cullere, Jaime; Freijo Guerrero, Maria del Mar; Egido, Jose; Gomez Sanchez, JC; Martinez Domeno, A; Purroy, F; Vives Pastor, Barbara; Rodriguez Yanez, M; Vivancos, J; Grp Investigadores Estudio TAC
Introduction: Intracranial haemorrhages (ICH) represent a severe and frequently lethal complication in patients treated with vitamin K antagonists (VKA). The purpose of our study is to describe the factors and clinical features associated with mortality in these patients. Methods: We conducted an observational, retrospective, multi-centre study based on prospective stroke registries in Spain. We included all patients admitted to neurology departments during a one-year period who met the following inclusion criteria: being 18 or older, having a diagnosis of ICH, and receiving VKA. Clinical and radiological parameters and 3-month outcomes were analysed. Results: A total of 235 patients from 21 hospitals were included. Mortality rate at 90 days was 42.6%. Bivariate analysis showed a significant association between death and the following factors: median NIHSS score at admission (5 [IQR = 9] vs 17 [IQR = 14] points, P < .01) and presence of an extensive hemispheric haemorrhage (4.9% vs 35%, P < .01; chi(2)). Extensive hemispheric haemorrhages, in addition to being the most lethal type, were associated with a shorter time to death (mean of 16.5 days; 95% CI: 7.1-26). A logistic regression model showed that only baseline NIHSS scores independently predicted death (odds ratio =1.13 [95% CI: 1.08-1.17] for each point in the scale). Conclusion: ICH in patients treated with VKA is associated with high mortality rates; mortality in these patients is mainly and independently associated with the clinical situation at stroke onset.
Idiopathic Pulmonary Fibrosis: Epidemiology, Natural History, Phenotypes.
(2018) Sauleda, Jaume; Núñez, Belén; Sala, Ernest; Soriano, Joan B
Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It is characterized by a chronic, progressive, fibrotic interstitial lung disease of unknown cause that occurs primarily in older adults. Its prevalence and incidence have appeared to be increasing over the last decades. Despite its unknown nature, several genetic and environmental factors have been associated with IPF. Moreover, its natural history is variable, but could change depending on the currently suggested phenotypes: rapidly progressive IPF, familial, combined pulmonary fibrosis and emphysema, pulmonary hypertension, and that associated with connective tissue diseases. Early recognition and accurate staging are likely to improve outcomes and induce a prompt initiation of antifibrotics therapy. Treatment is expected to be more effective in the early stages of the disease, while developments in treatment aim to improve the current median survival of 3?4 years after diagnosis.
Large-scale external validation and comparison of prognostic models: an application to chronic obstructive pulmonary disease
(BioMed Central (BMC), 2018-03-02) Guerra, Beniamino; Haile, Sarah R; Lamprecht, Bernd; Ramirez, Ana S; Martinez-Camblor, Pablo; Kaiser, Bernhard; Alfageme, Inmaculada; Almagro, Pere; Casanova, Ciro; Esteban-Gonzalez, Cristobal; Soler-Cataluna, Juan J; de-Torres, Juan P; Miravitlles, Marc; Celli, Bartolome R; Marin, Jose M; ter Riet, Gerben; Sobradillo, Patricia; Lange, Peter; Garcia-Aymerich, Judith; Anto, Josep M; Turner, Alice M; Han, Meilan K; Langhammer, Arnulf; Leivseth, Linda; Bakke, Per; Johannessen, Ane; Oga, Toru; García-Cosío, Borja; Ancochea-Bermudez, Julio; Echazarreta, Andres; Roche, Nicolas; Burgel, Pierre-Regis; Sin, Don D; Soriano, Joan B; Puhan, Milo A; 3CIA Collaboration
Background: External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. Methods: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. Results: Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUC(ADO) - AUC(BODE) = 0.015 [95% confidence interval (CI) = - 0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUCBODE updated - AUCBODE = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. Conclusions: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research.
Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease
(Elsevier, 2017-12-01) Smid, Dionne E; Franssen, Frits M. E; Gonik, Maria; Miravitlles, Marc; Casanova, Ciro; García-Cosío, Borja; de Lucas, Pilar; Marin, Jose M; Martinez, Cristina; Mir, Isabel; Soriano, Joan B; De Torres Tajes, Juan Pablo; Agusti, Alvar; Atalay, Nart B; Billington, Julia; Boutou, Afroditi K; Brighenti-Zogg, Stefanie; Chaplin, Emma; Coster, Samantha; Dodd, James W; Durr, Selina; Fernandez-Villar, Alberto; Groenen, Miriam T. J; Guimaraes, Miguel; Hejduk, Karel; Higgins, Victoria; Hopkinson, Nicholas S; Horita, Nobuyuki; Houben-Wilke, Sarah; Janssen, Daisy J. A; Jehn, Melissa; Joerres, Rudolf; Karch, Annika; Kelly, Julia L; Kim, Yu-Il; Kimura, Hiroshi; Koblizek, Vladimir; Kocks, Janwillem H; Kon, Samantha S. C; Kwon, Namhee; Ladeira, Ines; Lee, Sang-Do; Leuppi, Joerg D; Locantore, Nicholas; Lopez-Campos, Jose Luis; Man, William D-C; Maricic, Lana; Mendoza, Laura; Miedinger, David; Mihaltan, Florin; Minami, Seigo; van der Molen, Thys; Murrells, Trevor J; Nakken, Nienke; Nishijima, Yu; Norman, Ian J; Novotna, Barbora; O'Donnell, Denis E; Ogata, Yoshitaka; Pereira, Eanes D; Piercy, James; Price, David; Pothirat, Chaicharn; Raghavan, Natya; Ringbaek, Thomas; Sajkov, Dimitar; Sigari, Naseh; Singh, Sally; Small, Mark; da Silva, Guilherme F; Tanner, Rebecca J; Tsiligianni, Ioanna G; Tulek, Baykal; Tzanakis, Nikolaos; Vanfleteren, Lowie E. G. W; Watz, Henrik; Webb, Katherine A; Wouters, Emiel F. M; Xie, Guogang G; Yoshikawa, Masanori; Spruit, Martijn A
Background: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. Methods: After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, post-bronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. Main outcomes: Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. Findings: A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. Conclusions: The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed.
Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach
(Nature Publishing Group, 2017-08-16) Burillo-Sanz, Sergio; Montes-Cano, Marco-Antonio; Garcia-Lozano, Jose-Raul; Ortiz-Fernandez, Lourdes; Ortego-Centeno, Norberto; Garcia-Hernandez, Francisco-Jose; Espinosa, Gerard; Grana-Gil, Genaro; Sanchez-Burson, Juan; Rosa Julia, Maria; Solans, Roser; Blanco, Ricardo; Barnosi-Marin, Ana-Celia; Gomez de la Torre, Ricardo; Fanlo Mateo, Patricia; Rodriguez-Carballeira, Monica; Rodriguez-RodigGuez, Luis; Camps, Teresa; Castaneda, Santos; Alegre-Sancho, Juan-Jose; Martin, Javier; Gonzalez-Escribano, Maria-Francisca
Behcet's disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(alpha) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(alpha) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.
Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea
(Wiley, 2017-05) Serrano Pariente, José; Plaza, V; Soriano, Joan B; Mayos, M; Lopez-Vina, A; Picado, C; Vigil, L; CPASMA Trial Grp
BackgroundContinuous positive airway pressure (CPAP) in asthma patients with concomitant obstructive sleep apnea syndrome (OSAS) seems to have a favorable impact on asthma, but data are inconsistent due to methodological limitations of previous studies. MethodsProspective, multicenter study. We examined asthma outcomes after 6 months of CPAP in 99 adult asthma patients (mean age 57 years) with OSAS (respiratory disturbance index 20). Asthma control and quality of life were assessed with the Asthma Control Questionnaire (ACQ) and the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), respectively. Data were analyzed by intention-to-treat basis. ResultsThe mean SD score of the ACQ decreased from 1.39 +/- 0.91 at baseline to 1.0 +/- 0.78 at 6 months (P = 0.003), the percentage of patients with uncontrolled asthma from 41.4% to 17.2% (P = 0.006), and the percentage of patients with asthma attacks in the 6 months before and after treatment from 35.4% to 17.2% (P = 0.015). The score of the mAQLQ increased from 5.12 +/- 1.38 to 5.63 +/- 1.17 (P = 0.009). There were also significant improvements in symptoms of gastroesophageal reflux and rhinitis, bronchial reversibility, and exhaled nitric oxide values (all P < 0.05). No significant changes were observed in drug therapy for asthma or their comorbidities nor in the patients' weight. ConclusionsAsthma control (both actual and future risk), quality of life, and lung function improved after starting continuous positive airway pressure in asthmatics with moderate to severe obstructive sleep apnea syndrome.
Noninvasive ventilation during the weaning process in chronically critically ill patients.
(2016) Sancho, Jesus; Servera, Emilio; Jara-Palomares, Luis; Barrot, Emilia; Sanchez-Oro-Gomez, Raque; Gomez de Terreros, F Javier; Martin-Vicente, M Jesus; Utrabo, Isabel; Núñez, Belén; Binimelis Varella, Alicia; Sala, Ernest; Zamora, Enrique; Segrelles, Gonzalo; Ortega-Gonzalez, Angel; Masa, Fernando
Chronically critically ill patients often undergo prolonged mechanical ventilation. The role of noninvasive ventilation (NIV) during weaning of these patients remains unclear. The aim of this study was to determine the value of NIV and whether a parameter can predict the need for NIV in chronically critically ill patients during the weaning process. We conducted a prospective study that included chronically critically ill patients admitted to Spanish respiratory care units. The weaning method used consisted of progressive periods of spontaneous breathing trials. Patients were transferred to NIV when it proved impossible to increase the duration of spontaneous breathing trials beyond 18 h. 231 chronically critically ill patients were included in the study. 198 (85.71%) patients achieved weaning success (mean weaning time 25.45�16.71 days), of whom 40 (21.4%) needed NIV during the weaning process. The variable which predicted the need for NIV was arterial carbon dioxide tension at respiratory care unit admission (OR 1.08 (95% CI 1.01-1.15), p=0.013), with a cut-off point of 45.5 mmHg (sensitivity 0.76, specificity 0.67, positive predictive value 0.76, negative predictive value 0.97). NIV is a useful tool during weaning in chronically critically ill patients. Hypercapnia despite mechanical ventilation at respiratory care unit admission is the main predictor of the need for NIV during weaning.

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