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1. A Pilot Study on Proteomic Predictors of Mortality in Stable COPD

Author: Cesar Jessé Enríquez-Rodríguez, Carme Casadevall, Rosa Faner, Sergi Pascual-Guardia, Ady Castro-Acosta, José Luis López-Campos, Germán Peces-Barba, Luis Seijo, Oswaldo Antonio Caguana-Vélez, Eduard Monsó, Diego Rodríguez-Chiaradia, Esther Barreiro, Borja G. Cosío, Alvar Agustí, Joaquim Gea, and on behalf of the BIOMEPOC Group
Subjects: COPD, mortality, prognosis, proteomic fingerprint, immunity, hemostasis, Cytology, QH573-671
Abstract: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of global mortality. Despite clinical predictors (age, severity, comorbidities, etc.) being established, proteomics offers comprehensive biological profiling to obtain deeper insights into COPD pathophysiology and survival prognoses. This pilot study aimed to identify proteomic footprints that could be potentially useful in predicting mortality in stable COPD patients. Plasma samples from 40 patients were subjected to both blind (liquid chromatography–mass spectrometry) and hypothesis-driven (multiplex immunoassays) proteomic analyses supported by artificial intelligence (AI) before a 4-year clinical follow-up. Among the 34 patients whose survival status was confirmed (mean age 69 ± 9 years, 29.5% women, FEV1 42 ± 15.3% ref.), 32% were dead in the fourth year. The analysis identified 363 proteins/peptides, with 31 showing significant differences between the survivors and non-survivors. These proteins predominantly belonged to different aspects of the immune response (12 proteins), hemostasis (9), and proinflammatory cytokines (5). The predictive modeling achieved excellent accuracy for mortality (90%) but a weaker performance for days of survival (Q2 0.18), improving mildly with AI-mediated blind selection of proteins (accuracy of 95%, Q2 of 0.52). Further stratification by protein groups highlighted the predictive value for mortality of either hemostasis or pro-inflammatory markers alone (accuracies of 95 and 89%, respectively). Therefore, stable COPD patients’ proteomic footprints can effectively forecast 4-year mortality, emphasizing the role of inflammatory, immune, and cardiovascular events. Future applications may enhance the prognostic precision and guide preventive interventions.
Published: 2024
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2. Update on metabolomic findings in COPD patients

Author: Joaquim Gea, César J. Enríquez-Rodríguez, Bella Agranovich, and Sergi Pascual-Guardia
Subjects: Medicine
Abstract: COPD is a heterogeneous disorder that shows diverse clinical presentations (phenotypes and “treatable traits”) and biological mechanisms (endotypes). This heterogeneity implies that to carry out a more personalised clinical management, it is necessary to classify each patient accurately. With this objective, and in addition to clinical features, it would be very useful to have well-defined biological markers. The search for these markers may either be done through more conventional laboratory and hypothesis-driven techniques or relatively blind high-throughput methods, with the omics approaches being suitable for the latter. Metabolomics is the science that studies biological processes through their metabolites, using various techniques such as gas and liquid chromatography, mass spectrometry and nuclear magnetic resonance. The most relevant metabolomics studies carried out in COPD highlight the importance of metabolites involved in pathways directly related to proteins (peptides and amino acids), nucleic acids (nitrogenous bases and nucleosides), and lipids and their derivatives (especially fatty acids, phospholipids, ceramides and eicosanoids). These findings indicate the relevance of inflammatory-immune processes, oxidative stress, increased catabolism and alterations in the energy production. However, some specific findings have also been reported for different COPD phenotypes, demographic characteristics of the patients, disease progression profiles, exacerbations, systemic manifestations and even diverse treatments. Unfortunately, the studies carried out to date have some limitations and shortcomings and there is still a need to define clear metabolomic profiles with clinical utility for the management of COPD and its implicit heterogeneity.
Published: 2023
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3. Proteomic Blood Profiles Obtained by Totally Blind Biological Clustering in Stable and Exacerbated COPD Patients

Author: Cesar Jessé Enríquez-Rodríguez, Sergi Pascual-Guardia, Carme Casadevall, Oswaldo Antonio Caguana-Vélez, Diego Rodríguez-Chiaradia, Esther Barreiro, and Joaquim Gea
Subjects: COPD, exacerbation, proteins, inflammation, immune response, lipid profile, Cytology, QH573-671
Abstract: Although Chronic Obstructive Pulmonary Disease (COPD) is highly prevalent, it is often underdiagnosed. One of the main characteristics of this heterogeneous disease is the presence of periods of acute clinical impairment (exacerbations). Obtaining blood biomarkers for either COPD as a chronic entity or its exacerbations (AECOPD) will be particularly useful for the clinical management of patients. However, most of the earlier studies have been characterized by potential biases derived from pre-existing hypotheses in one or more of their analysis steps: some studies have only targeted molecules already suggested by pre-existing knowledge, and others had initially carried out a blind search but later compared the detected biomarkers among well-predefined clinical groups. We hypothesized that a clinically blind cluster analysis on the results of a non-hypothesis-driven wide proteomic search would determine an unbiased grouping of patients, potentially reflecting their endotypes and/or clinical characteristics. To check this hypothesis, we included the plasma samples from 24 clinically stable COPD patients, 10 additional patients with AECOPD, and 10 healthy controls. The samples were analyzed through label-free liquid chromatography/tandem mass spectrometry. Subsequently, the Scikit-learn machine learning module and K-means were used for clustering the individuals based solely on their proteomic profiles. The obtained clusters were confronted with clinical groups only at the end of the entire procedure. Although our clusters were unable to differentiate stable COPD patients from healthy individuals, they segregated those patients with AECOPD from the patients in stable conditions (sensitivity 80%, specificity 79%, and global accuracy, 79.4%). Moreover, the proteins involved in the blind grouping process to identify AECOPD were associated with five biological processes: inflammation, humoral immune response, blood coagulation, modulation of lipid metabolism, and complement system pathways. Even though the present results merit an external validation, our results suggest that the present blinded approach may be useful to segregate AECOPD from stability in both the clinical setting and trials, favoring more personalized medicine and clinical research.
Published: 2024
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4. Influence of COPD systemic environment on the myogenic function of muscle precursor cells in vitro

Author: Carme Casadevall, Antonio Sancho-Muñoz, Ignacio Vicente, Sergi Pascual-Guardia, Mireia Admetlló, and Joaquim Gea
Subjects: COPD systemic environment, Muscle precursor cells, Myogenic capacity, Gene expression, Diseases of the respiratory system, RC705-779
Abstract: Abstract Background: Loss of muscle mass and function are well-recognized systemic manifestations of chronic obstructive pulmonary disease (COPD). Acute exacerbations, in turn, significantly contribute to upgrade these systemic comorbidities. Involvement of myogenic precursors in muscle mass maintenance and recovery is poorly understood. The aim of the present study was to investigate the effects of the vascular systemic environment from stable and exacerbated COPD patients on the myogenic behavior of human muscle precursor cells (MPC) in vitro. Methods: Serum from healthy controls and from stable and exacerbated COPD patients (before and after Methylprednisolone treatment) was used to stimulate human MPC cultures. Proliferation analysis was assessed through BrdU incorporation assays. MPC differentiation was examined through real-time RT-PCR, western blot and immunofluorescence analysis. Results: Stimulation of MPCs with serum obtained from stable COPD patients did not affect myogenic precursor cell function. The vascular systemic environment during an acute exacerbation exerted a mitotic effect on MPCs without altering myogenic differentiation outcome. After Methylprednisolone treatment of acute exacerbated COPD patients, however, the mitotic effect was further amplified, but it was followed by a deficient differentiation capacity. Moreover, these effects were prevented when cells were co-treated with the glucocorticoid receptor antagonist Mifepristone. Conclusion: Our findings suggest that MPC capacity is inherently preserved in COPD patients, but is compromised after systemic administration of MP. This finding strengthens the concept that glucocorticoid treatment over the long term can negatively impact myogenic stem cell fate decisions and interfere with muscle mass recovery.
Published: 2022
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5. Adaptive NKG2C+ natural killer cells are related to exacerbations and nutritional abnormalities in COPD patients

Author: Sergi Pascual-Guardia, Michelle Ataya, Isabel Ramírez-Martínez, José Yélamos, Roberto Chalela, Salomé Bellido, Miguel López-Botet, and Joaquim Gea
Subjects: Human Cytomegalovirus, NK cells, NKG2C, Chronic obstructive pulmonary disease, Exacerbation, Nutritional status, Diseases of the respiratory system, RC705-779
Abstract: Abstract Chronic obstructive pulmonary disease (COPD) is a chronic and often progressive disorder with a heterogeneous presentation and frequent systemic manifestations. Several aspects like persistence in smoking habit, continuous exacerbations, alpha-1-antitrypsin deficiency and inflammatory-immune response, are involved in the pathophysiology and progression of the disease. However, the role of natural killer (NK) cells remains controversial. Otherwise, human cytomegalovirus (HCMV) infection has been reported to induce an adaptive differentiation and expansion of an NK cell subset which carries the CD94/NKG2C receptor, which may contribute to an upset immune defense. For these reasons, our objective is to assess the distribution of NK cells and their subset in COPD patients and some of its phenotypes. Methods Peripheral blood samples were obtained from 66 COPD patients. HCMV serology and the proportions of total NK cells and the NKG2C+ and NKG2A+ subsets were evaluated by flow cytometry. The NKG2C genotype was also assessed. Results Eighty-eight per cent of COPD patients were HCMV(+), and the proportions of total NK cells were higher in patients with severe-very severe airway obstruction than in those with only mild-moderate involvement. There were no differences in the proportions of NKG2C+ cells between controls and COPD, either among COPD patients classified by severity of the disease. However, the percentage of NKG2C+ cells were higher in COPD patients with frequent exacerbations than in occasional exacerbators, and higher in cases with reduced lean mass (Fat free mass index) than in those with normal nutritional status. Conclusion These results suggest a relationship between levels of NKG2C+ cells in COPD patients and clinical variables closely linked to a poor/worse prognosis.
Published: 2020
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6. Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD

Author: Sandra Casas-Recasens, Nuria Mendoza, Alejandra López-Giraldo, Tamara Garcia, Borja G. Cosio, Sergi Pascual-Guardia, Ady Acosta-Castro, Alicia Borras-Santos, Joaquim Gea, Gloria Garrabou, Alvar Agusti, and Rosa Faner
Subjects: telomeres, mitochondrial DNA, chronic bronchitis, emphysema, ageing, Medicine (General), R5-920
Abstract: Accelerated ageing is implicated in the pathogenesis of respiratory diseases as chronic obstructive pulmonary disease (COPD), but recent evidence indicates that the COPD can have roots early in life. Here we hypothesise that the accelerated ageing markers might have a role in the pathobiology of young COPD. The objective of this study was to compare two hallmarks of ageing, telomere length (TL), and mitochondrial DNA copy number (mtDNA-CN, as a surrogate marker of mitochondrial dysfunction) in young (≤ 50 years) and old (>50 years) smokers, with and without COPD. Both, TL and mtDNA-CN were measured in whole blood DNA by quantitative PCR [qPCR] in: (1) young ever smokers with (n = 81) or without (n = 166) COPD; and (2) old ever smokers with (n = 159) or without (n = 29) COPD. A multivariable linear regression was used to assess the association of TL and mtDNA-CN with lung function. We observed that in the entire study population, TL and mtDNA-CN decreased with age, and the former but not the latter related to FEV1/FVC (%), FEV1 (% ref.), and DLCO (% ref.). The short telomeres were found both in the young and old patients with severe COPD (FEV1
Published: 2021
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7. Metabolomics in COPD

Author: Joaquim Gea, César J. Enríquez-Rodríguez, and Sergi Pascual-Guardia
Subjects: Pulmonary and Respiratory Medicine
Published: 2023
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8. Efficacy of FF/UMEC/VI compared with FF/VI and UMEC/VI in patients with COPD: subgroup analysis of the Spain cohort in IMPACT

Author: José M. Marín, Luis Mateos, Juan Roldán, José M. Echave-Sustaeta, Sergi Pascual-Guardia, Maria V. Pardo, Beatriz Velasco, C. Elaine Jones, Sally Kilbride, and David A. Lipson
Subjects: Diseases of the respiratory system, RC705-779
Abstract: Objectives: The IMPACT trial has compared the benefit in the reduction of moderate/severe exacerbations of single inhaler triple therapy (SITT) with fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus dual therapy with FF/VI (ICS/LABA) and UMEC/VI (LAMA/LABA) in the treatment of patients with chronic obstructive disease (COPD). This study performs a subgroup analysis of the cohort from Spain in the IMPACT study. Materials and Methods: In IMPACT, a 52-week randomized, double-blind, parallel-group, multicenter study ( N = 10,355), patients ⩾40 years of age with COPD and ⩾1 moderate/severe exacerbations in the previous year were randomized 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg or UMEC/VI 62.5/25 µg administered via the Ellipta inhaler. Here, we present a subgroup analysis of the 499 patients from Spain, included in the intent-to-treat (ITT) population in the study. Endpoint assessed included exposure-adjusted rate of moderate and severe exacerbations. Results: In the Spain cohort, the exposure-adjusted rate of on-treatment moderate/severe COPD exacerbations per year for FF/UMEC/VI was 1.31 versus 1.43 and 1.57 for FF/VI and UMEC/VI, respectively. No new adverse events were identified. The results are consistent with those observed in the overall ITT study population. Conclusion: In the Spain cohort of the IMPACT study, patients receiving triple therapy with FF/UMEC/VI had a lower exposure-adjusted rate of exacerbations compared with FF/VI and UMEC/VI, similar to the overall population. Study Title: A Phase III, 52 Week, Randomized, Double-blind, 3-arm Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination FF/UMEC/VI With the Fixed Dose Dual Combinations of FF/VI and UMEC/VI, All Administered Once-daily in the Morning Via a Dry Powder Inhaler in Subjects With Chronic Obstructive Pulmonary Disease URL : https://www.clinicaltrialsregister.eu/ctr-search/search?query=CTT116855/ https://clinicaltrials.gov/ct2/show/NCT02164513 Registration number : GSK (CTT116855/NCT02164513). The reviews of this paper are available via the supplemental material section.
Published: 2020
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9. Phenotypic characterisation of early COPD: a prospective case–control study

Author: Borja G. Cosío, Sergi Pascual-Guardia, Alicia Borras-Santos, Germán Peces-Barba, Salud Santos, Laura Vigil, Juan José Soler-Cataluña, Cristina Martínez-González, Ciro Casanova, Pedro J. Marcos, Carlos J. Alvarez, José Luis López-Campos, Joaquim Gea, Judith Garcia-Aymerich, Jesús Molina, Miguel Román, Jorge Moises, Viktoria Szabo, Elizabeth A. Reagan, Raúl San José Estépar, George Washko, Alvar Agustí, Rosa Faner, Full list of field participating investigators in the study:, Borja G. Cosio, Rocío Cordova Diaz, María Magdalena Pan Naranjo, Joan Palmer Sancho, Miguel Román Rodríguez, Rosa Faner Canet, Joan Albert Barberà, Josep Roca Torrent, Yolanda Torralba Garcia, Jorge Moises Lafuente, Anna Maria Pedro Pijoan, Amparo Hervas Docón, Carmen Herranz, Núria Sanchez Ruano, Diego A ChiaradíaRodríguez, Anna Rodó-Pin, Clara Martín-Ontiyuelo, Mireia Admetlló, Concepción Ballano Castro, Laura Gutiérrez Martín, JoséIgnacio Aoiz Linares, Marta Mourelo Cereijo, Germán Peces-Barba Romero, José Fernández Arias, Carolina Gotera Rivera, Manuel Martin Bernal, Guillermo Gallardo Madueño, Andrés Alcázar Peral, Carmelo Palacios Miras, Maria Teresa Pinedo Moraleda, Maria Belén Torres Labandeira, Mercedes Colomo Rodríguez, María Concepción Rodríguez Gallego, Carmen Lobon Agundez, Mónica Nácher Conches, María José Mansilla, Rosario Serrano Martín, Carlos J. Álvarez Martínez, Marta Padilla Bernáldez, Jesús Molina París, Laura Vigil Giménez, Eduard Monsó Molas, Laia Seto Gort, Mañas Montserrat Baré, Anna Maria Fabra Noguera, JoséLuís López Campos, Carmen Calero Acuña, Laura Carrasco Hernández, Salud Santos Perez, Montserrat Navarro, Elisabeth Serra, Ferran Ferrer Keysers, Damaris Batallé, M Dolores Peleato Catalan, Albert Dorca, Javier Burgos, Juan José, Soler-Cataluña Noelia González García, Lourdes Sánchez Sánchez, Cristina Martínez González, Amador Prieto Fernández, Susana Martínez González, Ciro Casanova Macario, Delia Mayato, Pedro J Marcos Rodriguez, Luis Domínguez Juncal, Rosario Timiraos Carrasco, and Rosa Garcia Palenzuela
Subjects: Medicine
Abstract: The phenotypic characteristics of chronic obstructive pulmonary disease (COPD) in individuals younger than 50 years of age (early COPD) are not well defined. This prospective, multicentre, case–control study sought to describe these characteristics and compare them with those of smokers (≥10 pack-years) of similar age with normal spirometry (controls). We studied 92 cases (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)
Published: 2020
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10. Immunologic resilience and COVID-19 survival advantage

Author: Grace C. Lee, Marcos I. Restrepo, Nathan Harper, Muthu Saravanan Manoharan, Alisha M. Smith, Justin A. Meunier, Sandra Sanchez-Reilly, Aamir Ehsan, Anne P. Branum, Caitlyn Winter, Lauryn Winter, Fabio Jimenez, Lavanya Pandranki, Andrew Carrillo, Graciela L. Perez, Antonio Anzueto, Hanh Trinh, Monica Lee, Joan M. Hecht, Celida Martinez-Vargas, Raj T. Sehgal, Jose Cadena, Elizabeth A. Walter, Kimberly Oakman, Raymond Benavides, Jacqueline A. Pugh, Scott Letendre, Maristella Steri, Valeria Orrù, Edoardo Fiorillo, Francesco Cucca, Alvaro G. Moreira, Nu Zhang, Elizabeth Leadbetter, Brian K. Agan, Douglas D. Richman, Weijing He, Robert A. Clark, Jason F. Okulicz, Sunil K. Ahuja, Mohamed I. Abdalla, Sandra G. Adams, Joseph Agnew, Saleem Ali, Jennifer Barker, Angela Birdwell, Stephen Bradford, Heather Briggs, Judith Marin Corral, Jennifer J. Dacus, Patrick J. Danaher, Scott A. DePaul, Jill Dickerson, Jollynn Doanne, Samantha Elbel, Corina Escamilla, Robert Farrar, David Feldman, Julianne Flynn, Delvina Ford, Joanna D. Foy, Megan Freeman, Samantha Galley, Maritza Garza, Sherraine Gilman, Jennifer Gomez, Varun K. Goyal, Sally Grassmuck, Joshua Hanson, Brande Harris, Gabrielyd Hastings, Audrey Haywood, Cecilia Hinojosa, Tony T. Ho, Teri Hopkins, Pamela Jewell, Thomas B. Johnson, Vasiliki Kotogiannes, Austin C. Lawler, Chadwick S. Lester, Stephanie M. Levine, Haidee V. Lewis, Angel Louder, Charmaine Mainor, Rachel Maldonado, Yvette Martinez, Neil McElligott, Laura Medlin, Myra Mireles, Kathleen Morneau, Samuel B. Munro, Anoop Nambiar, Daniel Nassery, Robert Nathanson, Jane O’Rorke, Cheryl Padgett, Sergi Pascual-Guardia, Marisa Patterson, Rogelio Perez, Robert E. Phillips, Patrick B. Polk, Michael A. Pomager, Kristy J. Preston, Kevin C. Proud, Michelle Rangel, Temple A. Ratcliffe, Renee L. Reichelderfer, Evan M. Renz, Jeanette Ross, Teresa Rudd, Maria E. Sanchez, Tammy Sanders, Kevin C. Schindler, David Schmit, Claudio Solorzano, Nilam Soni, Win S. Tam, Edward J. Tovar, Anna R. Tyler, Anjuli Vasquez, Maria C. Veloso, Steven G. Venticinque, Jorge A. Villalpando, Melissa Villanueva, Lauren Villegas, Andrew Wallace, Emily Wang, Andreia Williamson, Sadie A. Trammell Velasquez, Andrea Yunes, and Katharine H. Zentner
Subjects: Oncology, medicine.medical_specialty, business.industry, Immunology, Hazard ratio, Odds ratio, medicine.disease, Rate ratio, Framingham Heart Study, Acquired immunodeficiency syndrome (AIDS), Interquartile range, Internal medicine, Cohort, medicine, Immunology and Allergy, Immunocompetence, business
Abstract: Background The risk of severe COVID-19 varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). Objective To examine whether deficits in IR that antedate or are induced by SARS-CoV-2 infection independently predict COVID-19 mortality. Methods IR levels were quantified with two novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n=522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n=13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to clinical outcomes. Results IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection associated with underrepresentation of IHG-I (21%) vs. overrepresentation (77%) of IHG-II or IHG-IV, especially in males vs. females (P Conclusion Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19. Clinical implications Biomarkers tracking immunologic resilience may have broad prognostic utility, as they associated with longevity, as well as resistance to a progressive disease course during SARS-CoV-2, influenza, or HIV infection.
Published: 2021
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11. Health care-associated infections in patients with COVID-19 pneumonia in COVID critical care areas

Author: Joan R. Masclans, C. Vilà, Marcos I. Restrepo, Sergi Pascual-Guardia, M Picornell, M Acer, Francisco Álvarez-Lerma, C. Climent, R. Muñoz-Bermúdez, Anna Salazar-Degracia, and Judith Marin-Corral
Subjects: medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MEDLINE, Critical Care and Intensive Care Medicine, medicine.disease, Health care associated, Pneumonia, medicine, In patient, Carta Científica, Intensive care medicine, business
Published: 2022
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12. Consensus on the Management of the COPD Patient in the COVID-19 Setting: COPD Forum Working Group

Author: Myriam Calle Rubio, José Luis López-Campos, José Luis Izquierdo Alonso, Dolores Martínez Pitarch, Milagros Iriberri Pascual, Bernardino Alcázar Navarrete, Manuel Valle Falcones, María Jesús Avilés Inglés, Carlos Cabrera López, Carlos José Álvarez Martínez, Francisco Ortega Ruiz, Rafael Golpe, Antònia Fuster Gomila, Sergi Pascual Guardia, Juan Antonio Riesco Miranda, Germán Peces-Barba, Francisco García-Río, Manuel Ángel Martínez Muñiz, Borja G. Cosío, and Chiesi Limited
Subjects: Pulmonary and Respiratory Medicine, COVID-19 (Malaltia), Pulmons--Malalties obstructives
Abstract: This study was funded by Chiesi.
Published: 2022

13. Bacterial Patterns and Empiric Antibiotic Use in COPD Patients With Community-Acquired Pneumonia

Author: Sergi Pascual-Guardia, Francesco Amati, Judith Marin-Corral, Stefano Aliberti, Joaquim Gea, Nilam J. Soni, Alejandro Rodriguez, Oriol Sibila, Francisco Sanz, Giovanni Sotgiu, Pedro J. Marcos, Ane Uranga, Branislava Milenkovic, Christian N. Meyer, Martin Kolditz, Antonio R. Anzueto, and Marcos I. Restrepo
Subjects: Pulmonary and Respiratory Medicine
Abstract: Chronic obstructive pulmonary disease (COPD) is strongly associated with the development of community-acquired pneumonia (CAP). Limited data are available on risk factors for difficult to manage bacteria such as Pseudomonas aeruginosa in COPD patients with CAP. Our objective was to assess the microbiological patterns associated with risk factors that determine empiric antibiotic therapy in hospitalized COPD patients with CAP.We performed a secondary data analysis of an international, multicenter, observational, point-prevalence study involving hospitalized COPD patients with CAP from March to June 2015. After identifying the risk factors associated with different microorganisms, we developed a scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy in this population.We enrolled 689 hospitalized COPD patients with CAP with documented microbiological testing. The most frequent microorganisms isolated were Streptococcus pneumoniae (8%) and Gram-negative bacteria (8%), P. aeruginosa (7%) and Haemophilus influenzae (3%). We developed a scoring system incorporating the variables independently associated with P. aeruginosa that include a previous P. aeruginosa isolation or infection (OR 14.2 [95%CI 5.7-35.2]), hospitalization in the past 12 months (OR 3.7 [1.5-9.2]), and bronchiectasis (OR 3.2 [1.4-7.2]). Empiric anti-pseudomonal antibiotics were overutilized in COPD patients with CAP. The new scoring system has the potential to reduce empiric anti-pseudomonal antibiotic use from 54.1% to 6.2%.COPD patients with CAP present different microbiological profiles associated with unique risk factors. Anti-pseudomonal treatment is a critical decision when selecting empiric antibiotic therapy. We developed a COPD scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy.
Published: 2022

14. Non-typeable Haemophilus influenzae-Moraxella catarrhalis vaccine for the prevention of exacerbations in chronic obstructive pulmonary disease: a multicentre, randomised, placebo-controlled, observer-blinded, proof-of-concept, phase 2b trial

Author: Stefan Andreas, Marco Testa, Laurent Boyer, Guy Brusselle, Wim Janssens, Edward Kerwin, Alberto Papi, Bonavuth Pek, Luis Puente-Maestu, Dinesh Saralaya, Henrik Watz, Tom M A Wilkinson, Daniela Casula, Gennaro Di Maro, Maria Lattanzi, Luca Moraschini, Sonia Schoonbroodt, Annaelisa Tasciotti, Ashwani K Arora, François Maltais, Jean-Louis Corhay, Eduard Janssens, Mathias Leys, Murdo Ferguson, Mark Fitzgerald, Irvin Mayers, Shelly McNeil, Arnaud Bourdin, Francis Couturaud, Luc Dussart, Gabriele Illies, Andreas Eich, Andrea Ludwig-Sengpiel, Francesco Blasi, Stefano Centanni, Carlo Pomari, José Maria Echave-Sustaeta, Eleuterio Llorca Martínez, Silvia Narejos Pérez, Sergi Pascual-Guardia, Mercè Pérez Vera, Manuel Terns Riera, William Anderson, Gourab Choudhury, Anthony De-Soyza, Tom MA Wilkinson, Joseph Boscia III, Kenneth Chinsky, Leonard Dunn, David Erb, Charles Fogarty, Herman Jackson Downey, Craig Kunz, Terry Poling, Richard Sellman, Barry Sigal, John Southard, Selwyn Spangenthal, Ziad Tannous, Georg-August-University = Georg-August-Universität Göttingen, GlaxoSmithKline [Siena, Italy] (GSK), Hôpital Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Ghent University Hospital, University Hospitals Leuven [Leuven], Università degli Studi di Ferrara = University of Ferrara (UniFE), Centre Hospitalier Régional de Lanaudiere, Joliette, Quebec, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, University of Southampton, GlaxoSmithKline Pharmaceuticals [Rixensart] (GSK), Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and NTHi-Mcat-002 study group Guy Brusselle Jean-Louis Corhay Eduard Janssens Wim Janssens Mathias Leys Murdo Ferguson Mark Fitzgerald François Maltais Irvin Mayers Shelly McNeil Bonavuth Pek Arnaud Bourdin Laurent Boyer Francis Couturaud Luc Dussart Stefan Andreas Gabriele Illies Andreas Eich Andrea Ludwig-Sengpiel Henrik Watz Francesco Blasi Stefano Centanni Alberto Papi Carlo Pomari José Maria Echave-Sustaeta Eleuterio Llorca Martínez Silvia Narejos Pérez Sergi Pascual-Guardia Mercè Pérez Vera Luis Puente-Maestu Manuel Terns Riera William Anderson Gourab Choudhury Anthony De-Soyza Dinesh Saralaya Tom MA Wilkinson Joseph Boscia III Kenneth Chinsky Leonard Dunn David Erb Charles Fogarty Herman Jackson Downey Edward Kerwin Craig Kunz Terry Poling Richard Sellman Barry Sigal John Southard Selwyn Spangenthal Ziad Tannous Marco Testa Daniela Casula Gennaro Di Maro Maria Lattanzi Luca Moraschini Sonia Schoonbroodt Annaelisa Tasciotti Ashwani K Arora
Subjects: Pulmonary and Respiratory Medicine, Adult, Vaccines, [SDV]Life Sciences [q-bio], Sputum, Socio-culturale, Haemophilus influenzae, Pulmonary Disease, Chronic Obstructive, Double-Blind Method, vaccine, Chronic obstructive pulmonary disease (COPD) exacerbations, Haemophilus influenzae, Moraxella catarrhalis, vaccine, Humans, Moraxella catarrhalis, Chronic obstructive pulmonary disease (COPD) exacerbations
Abstract: International audience; BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with changes in the sputum microbiome, including an increased prevalence of pathogenic bacteria. Vaccination against the most frequent bacteria identified in AECOPD might reduce exacerbation frequency. We assessed the efficacy, safety, and immunogenicity of a candidate vaccine containing surface proteins from non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) in patients with COPD.MethodsThis multicentre, randomised, observer-blinded, placebo-controlled, proof-of-concept, phase 2b trial recruited patients with stable COPD, moderate-to-very severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2, 3, or 4), at 67 clinical sites in Belgium, Canada, France, Germany, Italy, Spain, UK, and USA. Eligible patients were aged 40–80 years and had a history of at least one moderate or severe exacerbation in the previous year. Patients were allocated (1:1) using a minimisation algorithm to receive two intramuscular injections of NTHi–Mcat vaccine or placebo 60 days apart, in addition to standard care. The allocation algorithm considered age category, number of previous exacerbations, COPD severity at study entry, and country as minimisation factors, to guarantee treatment balance within each factor. Vaccine recipients and those responsible for evaluating study endpoints were masked to group allocation. In the analysis of efficacy, the primary outcome was the rate of any moderate or severe AECOPD occurring within a 1-year period, starting 1 month after the second dose in patients who received two vaccine doses (modified total vaccinated cohort). Safety was assessed in the total vaccinated cohort. The trial is registered with ClinicalTrials.gov, number NCT03281876, and is complete.FindingsBetween Nov 27, 2017, and Nov 30, 2018, 606 adults were enrolled and included in the total vaccinated cohort (304 in the NTHi–Mcat vaccine group, 302 in the placebo group); 571 received two doses and were included in the primary efficacy analysis (279 in the NTHi–Mcat vaccine group, 292 in the placebo group). 23 participants dropped-out in the NTHi–Mcat vaccine group and 39 in the placebo group; this included 4 patients in the NTHi–Mcat vaccine group and 15 in the placebo group who withdrew from the study because of an adverse event. The primary analysis included 340 exacerbations (in follow-up time 102 123 days) in the NTHi–Mcat vaccine group and 333 (in 104 443 days) in the placebo group, with a yearly rate of moderate or severe AECOPD of 1·22 in the NTHi–Mcat vaccine group and 1·17 in the placebo group, with vaccine efficacy in reducing the yearly rate of moderate or severe AECOPD estimated to be zero (vaccine efficacy point estimate 2·26% [87% CI –18·27 to 11·58]; p=0·82). Solicited local adverse events were more frequent in the NTHi–Mcat vaccine group (216 [72%] of 301 patients) than with placebo (34 [11%] of 299 patients), and the frequency of solicited general adverse events was similar between groups (239 [79%] of 301 vs 235 [79%] of 299 patients). There was one death in the NTHi–Mcat vaccine group (acute respiratory failure, not related to vaccination) and ten in the placebo group (seven due in part to COPD or respiratory failure). There were 158 serious adverse events (89 [29%] of 304 patients) in the NTHi–Mcat vaccine group, not related to vaccination, and 214 (99 [33%] of 302 patients) in the placebo group.InterpretationNTHi–Mcat vaccine administered to patients with COPD did not show efficacy in reducing the yearly rate of moderate or severe exacerbations. No safety concerns were identified.
Published: 2021
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15. Impact of a Non-Invasive Respiratory Support Strategy and Switches in Therapy During Acute Respiratory Failure Due to SARS-CoV-2

Author: Judith Marin-Corral, FJ Parrilla, Andrea Castellví, Purificación Pérez-Terán, Lucía Picazo, Sergi Pascual-Guardia, Alejandro Rodriguez Oviedo, Juan Carlos Ballesteros, Susana Sancho, Lorenzo Socias, Emili Díaz, Antonio Albaya Moreno, Candelaria de Haro, Oriol Roca, Marcos I. Restrepo, and Joan Ramón Masclans
Subjects: History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published: 2022
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16. Accelerated aging biomarkers in young, old, mild and severe COPD

Author: Sandra Casas Recasens, Borja Garcia Cosio, Sergi Pascual-Guardia, Ady Acosta-Castro, Alicia Borras-Santos, Joaquim Gea, Alvar Agustí, and Rosa Faner, Early Study Group
Subjects: medicine.medical_specialty, business.industry, Internal medicine, medicine, Severe copd, business, Accelerated aging
Published: 2021
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17. Determinants of the Appearance and Progression of Early-Onset Chronic Obstructive Pulmonary Disease in Young Adults. A Case–Control Study With Follow-Up

Author: Laura Vigil Giménez, Miguel Román Rodríguez, Judith Garcia-Aymerich, Diego Agustin Rodriguez Chiaradía, Joaquim Gea Guiral, Borja G. Cosío, Carlos J. Álvarez Martínez, Cristina Martínez-González, José Luis López-Campos, Pedro Jorge Marcos Rodríguez, Juan José Soler-Cataluña, Sergi Pascual-Guardia, Germán Peces-Barba, Joan Albert Barberà, en representación del Grupo Investigador del estudio Early Copd, Ciro Casanova Macario, Rosa Faner, Jesús Molina París, Alícia Borràs-Santos, Salud Santos-Pérez, Laura Carrasco Hernández, and Alvar Agusti
Subjects: medicine.medical_specialty, COPD, education.field_of_study, business.industry, Population, Case-control study, General Medicine, Disease, medicine.disease, Logistic regression, respiratory tract diseases, Pulmonary function testing, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Internal medicine, Cohort, medicine, Young adult, business, education
Abstract: Introduction and objectives: Determinants of chronic obstructive pulmonary disease (COPD) in the early stages of its natural history are not well known. Improving our knowledge of these factors will help to design interventions that can modify prognosis. Study objectives are: a) to characterize a COPD population of young adults aged 35-50 years from a multidimensional point of view; b) to compare these patients with smokers with normal lung function: and c) to create a cohort of young adults aged 35-50 years (smokers or former smokers), with and without COPD, who will be followed in the future to improve understanding of the natural history of the disease. Participants and method: This is a case-control multicenter study aimed at establishing a well characterized cohort of young adults, smokers or former-smokers, with and without COPD, for subsequent follow-up. A total of 311 participants (101 cases and 210 controls) were selected from approximately 30 primary care settings and 12 hospitals in 8 Spanish regions. Subjects were smokers or former smokers (> 10 pack-years) aged 35-50 years. Diagnosis of COPD was based on a post-bronchodilator result of FEV1/FVC < 70%. The main study variables were: questionnaires on health, symptoms, exacerbations and daily physical activity, lung function tests, blood and sputum samples, and low-dose computed tomography. In the statistical analysis, COPD patient characteristics will be described and compared with control subjects using a logistic regression analysis. (C) 2018 SEPAR. Published by Elsevier Espana, S.L.U. All rights reserved.
Published: 2019
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18. EARLY COPD: determinantes de la aparición y progresión de la enfermedad pulmonar obstructiva crónica en adultos jóvenes. Protocolo de un estudio caso-control con seguimiento

Author: Joan Albert Barberà, Pedro Jorge Marcos Rodríguez, Laura Carrasco Hernández, Judith Garcia-Aymerich, Joaquim Gea Guiral, Laura Vigil Giménez, Juan José Soler-Cataluña, José Luis López-Campos, Rosa Faner, Carlos J. Álvarez Martínez, Alvar Agusti, Cristina Martínez-González, Borja G. Cosío, Ciro Casanova Macario, Alícia Borràs-Santos, Miguel Román Rodríguez, Jesús Molina París, Sergi Pascual-Guardia, Salud Santos-Pérez, Germán Peces-Barba, and Diego Agustin Rodriguez Chiaradía
Subjects: Pulmonary and Respiratory Medicine, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, business.industry, Medicine, business, Humanities
Abstract: Resumen Introduccion y objetivos Los determinantes en fases iniciales de la historia natural de la enfermedad pulmonar obstructiva cronica (EPOC) son poco conocidos. Entenderlos mejor es de capital importancia para poder disenar intervenciones dirigidas a modificar su pronostico. Los principales objetivos del estudio son: a) caracterizar a una poblacion de adultos jovenes con EPOC de forma multidimensional; b) comparar estos pacientes con sujetos fumadores con funcion pulmonar normal; y c) establecer una cohorte de adultos jovenes con y sin EPOC, que pueda ser seguida a largo plazo para conocer mejor la historia natural de la enfermedad. Participantes y metodo EARLY COPD es un estudio multicentrico de casos y controles que permitira establecer una cohorte de sujetos para su seguimiento posterior. Se seleccionaron 311 (101 casos y 210 controles) participantes reclutados en una treintena de centros de atencion primaria y 12 hospitales de 8 comunidades autonomas espanolas. Los participantes eran fumadores o exfumadores (> 10 paquetes ano) de entre 35-50 anos de edad. Los casos presentaban una espirometria obstructiva con un FEV1/FVC
Published: 2019
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19. Diagnosis and Initial Investigation of Bronchiectasis

Author: Francesco Blasi, Stefano Aliberti, Marco Mantero, Edoardo Simonetta, Pieter Goeminne, Martina Santambrogio, Tommaso Pilocane, Antonio Voza, Sergi Pascual-Guardia, Francesco Amati, Martina Oriano, and Andrea Gramegna
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Endotype, Bronchiectasis, business.industry, Respiratory disease, Disease, Critical Care and Intensive Care Medicine, medicine.disease, Review article, Pulmonary function testing, 03 medical and health sciences, 0302 clinical medicine, Phenotype, 030228 respiratory system, Health care, Etiology, Medicine, Humans, 030212 general & internal medicine, business, Intensive care medicine, Lung
Abstract: Bronchiectasis refers to both the name of a disease and a single radiological appearance that may, or may not, be associated with disease. As chronic respiratory disease, bronchiectasis is characterized by a variable range of signs and symptoms that may overlap with other chronic respiratory conditions. The proper identification of bronchiectasis as a disease in both primary and secondary care is of paramount importance. However, a standardized definition of radiologically and clinically significant bronchiectasis is still missing. Disease heterogeneity is a hallmark of bronchiectasis and applies not only to radiological features and clinical manifestations but also to other aspects of the disease, including the etiological and microbiological diagnosis as well as the evaluation of pulmonary function. Although the guidelines suggest a “minimum bundle” of tests, the diagnostic approach to bronchiectasis is challenging and may be driven by the “treatable traits” approach based on endotypes and biological characteristics. A broad spectrum of diagnostic tests could be used to investigate the etiology of bronchiectasis as well as other pulmonary, extrapulmonary, and environmental traits. Individualizing bronchiectasis workup according to the site of care (e.g., primary, secondary, and tertiary care) could help optimize patients' management and reduce healthcare costs.
Published: 2021

20. Metabolic Signatures Associated with Severity in Hospitalized COVID-19 Patients

Author: Joan R. Masclans, Sergi Pascual-Guardia, Alex Gomez-Gomez, Judith Marin-Corral, Marcos I. Restrepo, Noemí Haro, Jose Rodríguez-Morató, R. Muñoz-Bermúdez, Oscar J. Pozo, Purificación Pérez-Terán, Olha Khymenets, and Anna Salazar-Degracia
Subjects: Adult, Male, medicine.medical_specialty, QH301-705.5, severity, macromolecular substances, Severity of Illness Index, Catalysis, Article, Inorganic Chemistry, Internal medicine, Severity of illness, Medicine, Humans, Prospective Studies, Physical and Theoretical Chemistry, Biology (General), Prospective cohort study, Molecular Biology, QD1-999, Spectroscopy, Oxygen saturation (medicine), Aged, ceramides, business.industry, SARS-CoV-2, Organic Chemistry, Tryptophan, COVID-19, General Medicine, Middle Aged, medicine.disease, Obesity, metabolomics, Pathophysiology, Computer Science Applications, kynurenine, Hospitalization, Pneumonia, Chemistry, Blood pressure, Metabolome, Observational study, Female, business, Biomarkers
Abstract: The clinical evolution of COVID-19 pneumonia is poorly understood. Identifying the metabolic pathways that are altered early with viral infection and their association with disease severity is crucial to understand COVID-19 pathophysiology, and guide clinical decisions. This study aimed at assessing the critical metabolic pathways altered with disease severity in hospitalized COVID-19 patients. Forty-nine hospitalized patients with COVID-19 pneumonia were enrolled in a prospective, observational, single-center study in Barcelona, Spain. Demographic, clinical, and analytical data at admission were registered. Plasma samples were collected within the first 48 h following hospitalization. Patients were stratified based on the severity of their evolution as moderate (N = 13), severe (N = 10), or critical (N = 26). A panel of 221 biomarkers was measured by targeted metabolomics in order to evaluate metabolic changes associated with subsequent disease severity. Our results show that obesity, respiratory rate, blood pressure, and oxygen saturation, as well as some analytical parameters and radiological findings, were all associated with disease severity. Additionally, ceramide metabolism, tryptophan degradation, and reductions in several metabolic reactions involving nicotinamide adenine nucleotide (NAD) at inclusion were significantly associated with respiratory severity and correlated with inflammation. In summary, assessment of the metabolomic profile of COVID-19 patients could assist in disease severity stratification and even in guiding clinical decisions.
Published: 2021

21. The Effect of Incidental Consolidation on Management and Outcomes in COPD Exacerbations: Data from the European COPD Audit

Author: MEHMET POLATLI, Vasileios Kouranos, Manuel Angel Villanueva, Maciej Ciebiada, José Luis López-Campos Bodineau, CRISTOBAL ESTEBAN, Aarash Saleh, Parthiban Nadarajan, EYLEM SERCAN OZGUR, Cristina Represas-Represas, DOLORES CORBACHO, Christopher Roberts, Antonio López-Quílez, William MacNee, Wim Janssens, Martin Brutsche, Sibel Naycı, Inmaculada Alfageme, Sebastian Majewski, Bernardino Alcázar-Navarrete, Nawar Diar Bakerly, Sergi Pascual-Guardia, Fotis Perlikos, Małgorzata Czajkowska-Malinowska, Carlos Cenjor Español, ERDOGAN ÇETINKAYA, Georgios Kaltsakas, Eddie Moloney, Otmar Schindler, ALBERTO FERNANDEZ-VILLAR, Ady Angelica Castro-Acosta, Otto Burghuber, Mina Gaga, Daiana Stolz, Silke Ryan, Lourdes Cañón-Barroso, Luis Borderias, Universitat de Barcelona, Kostikas, Konstantinos, and Janssens, Wim
Subjects: Male, Spirometry, medicine.medical_specialty, lcsh:Medicine, 610 Medicine & health, Pneumònia, Audit, Pulmonary Disease, Chronic Obstructive, Epidemiology, medicine, Pulmonary diseases, Humans, Chronic obstructive pulmonary diseases, Intensive care medicine, lcsh:Science, Survival rate, Malalties pulmonars obstructives cròniques, Aged, Aged, 80 and over, Medical Audit, COPD, Multidisciplinary, medicine.diagnostic_test, business.industry, lcsh:R, Age Factors, Sputum, Esput, Pneumonia, Middle Aged, medicine.disease, Europe, Survival Rate, Malalties dels pulmons, Radiological weapon, Female, lcsh:Q, Guideline Adherence, Radioscopic diagnosis, medicine.symptom, Chest radiograph, business, Research Article, Follow-Up Studies, Diagnòstic radiològic
Abstract: Objective There is controversy regarding the significance of radiological consolidation in the context of COPD exacerbation (eCOPD). While some studies into eCOPD exclude these cases, consolidation is a common feature of eCOPD admissions in real practice. This study aims to address the question of whether consolidation in eCOPD is a distinct clinical phenotype with implications for management decisions and outcomes. Patients and Methods The European COPD Audit was carried out in 384 hospitals from 13 European countries between 2010 and 2011 to analyze guideline adherence in eCOPD. In this analysis, admissions were split according to the presence or not of consolidation on the admission chest radiograph. Groups were compared in terms of clinical and epidemiological features, existing treatment, clinical care utilized and mortality. Results 14,111 cases were included comprising 2,714 (19.2%) with consolidation and 11,397 (80.8%) without. The risk of radiographic consolidation increased with age, female gender, cardiovascular diseases, having had two or more admissions in the previous year, and sputum color change. Previous treatment with inhaled steroids was not associated. Patients with radiographic consolidation were significantly more likely to receive antibiotics, oxygen and non-invasive ventilation during the admission and had a lower survival from admission to 90-day follow-up. Conclusions Patients admitted for COPD exacerbation who have radiological consolidation have a more severe illness course, are treated more intensively by clinicians and have a poorer prognosis. We recommend that these patients be considered a distinct subset in COPD exacerbation.
Published: 2021
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22. Aspiration Risk Factors, Microbiology, and Empiric Antibiotics for Patients Hospitalized With Community-Acquired Pneumonia

Author: Judith Marin-Corral, Sergi Pascual-Guardia, Francesco Amati, Stefano Aliberti, Joan R Masclans, Nilam Soni, Alejandro Rodriguez, Oriol Sibila, Francisco Sanz, Giovanni Sotgiu, Antonio Anzueto, Katerina Dimakou, Roberta Petrino, Ewoudt van de Garde, Marcos I Restrepo, GLIMP investigators, Patricia Karina Aruj, Silvia Attorri, Enrique Barimboim, Juan Pablo Caeiro, María I Garzón, Victor Hugo Cambursano, V H Dr Cazaux A Adrian Ceccato, Julio Chertcoff, Florencia Lascar, Fernando Di Tulio, Ariel Cordon Díaz, Lautaro de Vedia, Maria Cristina Ganaha, Sandra Lambert, Gustavo Lopardo, Carlos M Luna, Alessio Gerardo Malberti, Nora Morcillo, Silvina Tartara, Claudia Pensotti, Betiana Pereyra, Pablo Gustavo Scapellato, Juan Pablo Stagnaro, Sonali Shah, Felix Lötsch, Florian Thalhammer, Kurt Anseeuw, Camille A Francois, Eva Van Braeckel, Jean Louis Vincent, Marcel Zannou Djimon, Jules Bashi, Roger Dodo, Simone Aranha Nouér, Peter Chipev, Milena Encheva, Darina Miteva, Diana Petkova, Adamou Dodo Balkissou, Eric Walter Pefura Yone, Bertrand Hugo Mbatchou Ngahane, Ning Shen, Jin-Fu Xu, Carlos Andres Bustamante Rico, Ricardo Buitrago, Fernando Jose Pereira Paternina, Jean-Marie Kayembe Ntumba, Vesna Vladic Carevic, Marko Jakopovic, Mateja Jankovic, Zinka Matkovic, Ivan Mitrecic, Marie-Laure Bouchy Jacobsson, Anette Bro Christensen, Uffe Christian Heitmann Bødtger, Christian Niels Meyer, Andreas Vestergaard Jensen, Gertrud Baunbæk-Knudsen, Pelle Trier Petersen, Stine Andersen, Ibrahim El-Said Abd El-Wahhab, Nesreen Elsayed Morsy, Hanaa Shafiek, Eman Sobh, Kedir Abdella Abdulsemed, Fabrice Bertrand, Christian Brun-Buisson, Etienne de Montmollin, Muriel Fartoukh, Jonathan Messika, Pierre Tattevin, Abdo Khoury, Bernard Ebruke, Michael Dreher, Martin Kolditz, Matthias Meisinger, Mathias W Pletz, Stefan Hagel, Jan Rupp, Tom Schaberg, Marc Spielmanns, Petra Creutz, Norton Suttorp, Beatrice Siaw-Lartey, Dimosthenis Papapetrou, Evdoxia Tsigou, Dimitrios Ampazis, Evangelos Kaimakamis, Mohit Bhatia, Raja Dhar, George D'Souza, Rajiv Garg, Parvaiz A Koul, P A Mahesh, B S Jayaraj, Kiran Vishnu Narayan, Hirennappa B Udnur, Shashi Bhaskara Krishnamurthy, Surya Kant, Rajesh Swarnakar, Sneha Limaye, Sundeep Salvi, Keihan Golshani, Vera M Keatings, Ignacio Martin-Loeches, Yasmin Maor, Jacob Strahilevitz, Paola Faverio, Salvatore Battaglia, Maria Carrabba, Piero Ceriana, Marco Confalonieri, Antonella d'Arminio Monforte, Bruno Del Prato, Marino De Rosa, Riccardo Fantini, Giuseppe Fiorentino, Maria Antonia Gammino, Francesco Menzella, Giuseppe Milani, Stefano Nava, Gerardo Palmiero, Barbra Gabrielli, Paolo Rossi, Claudio Sorino, Gundi Steinhilber, Alessandro Zanforlin, Ospedale San Luca, Fabio Franzetti, Manuela Carugati, Manuela Morosi, Elisa Monge, Mauro Carone, Vincenzo Patella, Simone Scarlata, Andrea Comel, Kiyoyasu Kurahashi, Zeina Aoun Bacha, Daniel Barajas Ugalde, Omar Ceballos Zuñiga, José F Villegas, Milic Medenica, Deebya Raj Mihsra, Poojan Shrestha, Elliott Ridgeon, Babatunde Ishola Awokola, Ogonna N O Adefuye Bolanle Olufunlola, Segaolu Olumide, Kingsley N Ukwaja, Muhammad Irfan, Lukasz Minarowski, Skoczyński Szymon, Felipe Froes, Pedro Leuschner, Mariana Meireles, Cláudia Ferrão, João Neves, Abel Salazar, Sofia B Ravara, Victoria Brocovschii, Doina Rusu, Cristina Toma, Daniela Chirita, Carmen Mihaela Dorobat, Alexei Birkun, Anna Kaluzhenina, Abdullah Almotairi, Zakeya Abdulbaqi Ali Bukhary, Jameela Edathodu, Amal Fathy, Abdullah Mushira Abdulaziz Enani, Nazik Eltayeb Mohamed, Jawed Ulhadi Memon, Abdelhaleem Bella, Serbia Nada Bogdanović, Branislava Milenkovic, Dragica Pesut, Luis Borderìas, Noel Manuel Bordon Garcia, Hugo Cabello Alarcón, Catia Cilloniz, Antoni Torres, Vicens Diaz-Brito, Xavier Casas, Alicia Encabo González, Maria Luisa Fernández-Almira, Medicina Interna, Miguel Gallego, Inmaculada Gaspar-GarcÍa, Juan González Del Castillo, Patricia Javaloyes Victoria, Elena Laserna Martínez, Rosa Malo de Molina, Pedro J Marcos, Rosario Menéndez, Ana Pando-Sandoval, Cristina Prat Aymerich, Alicia Lacoma de la Torre, Ignasi García-Olivé, Jordi Rello, Silvia Moyano, Ana Rodrigo-Troyano, Jordi Solé-Violán, Ane Uranga, Job Fm van Boven, Ester Vendrell Torra, Jordi Almirall Pujol, Charles Feldman, Ho Kee Yum, Inje Univ Arnauld Attannon Fiogbe, Ferdaous Yangui, Semra Bilaceroglu, Izmir Dr Levent Dalar, Ufuk Yilmaz, Artemii Bogomolov, Naheed Elahi, Devesh J Dhasmana, Andrew Feneley, Adam T Hill, Banu Rudran, Silvia Ruiz-Buitrago, Marion Campbell, Paul Whitaker, Alexander Youzguin, Anika Singanayagam, C Hancock, David Villafuerte, Karen S Allen, Veronica Brito, Jessica Dietz, Claire E Dysart, Susan M Kellie, Clement J Ricardo A Franco-Sadud, Garnet Meier, Mina Gaga, Thomas L Holland, Stephen P Bergin, Fayez Kheir, Mark Landmeier, Manuel Lois, Girish B Nair, Hemali Patel, Katherine Reyes, William Rodriguez-Cintron, Shigeki Saito, Julio Noda, Cecilia I Hinojosa, Stephanie M Levine, Luis F Reyes, Luis F Angel, K Scott Whitlow, John Hipskind, Kunal Sukhija, Vicken Totten, Richard G Wunderink, Ray D Shah, Kondwelani John Mateyo, Lorena Noriega, Ezequiel Alvarado, Mohamed Aman, Lucía Labra, Marin-Corral J., Pascual-Guardia S., Amati F., Aliberti S., Masclans J.R., Soni N., Rodriguez A., Sibila O., Sanz F., Sotgiu G., Anzueto A., Dimakou K., Petrino R., van de Garde E., Restrepo M.I., Aruj P.K., Attorri S., Barimboim E., Caeiro J.P., Garzon M.I., Cambursano V.H., Adrian Ceccato V.H.D.C.A., Chertcoff J., Lascar F., Di Tulio F., Diaz A.C., de Vedia L., Ganaha M.C., Lambert S., Lopardo G., Luna C.M., Malberti A.G., Morcillo N., Tartara S., Pensotti C., Pereyra B., Scapellato P.G., Stagnaro J.P., Shah S., Lotsch F., Thalhammer F., Anseeuw K., Francois C.A., Van Braeckel E., Vincent J.L., Djimon M.Z., Bashi J., Dodo R., Nouer S.A., Chipev P., Encheva M., Miteva D., Petkova D., Balkissou A.D., Pefura Yone E.W., Mbatchou Ngahane B.H., Shen N., Xu J.-F., Bustamante Rico C.A., Buitrago R., Pereira Paternina F.J., Kayembe Ntumba J.-M., Carevic V.V., Jakopovic M., Jankovic M., Matkovic Z., Mitrecic I., Bouchy Jacobsson M.-L., Christensen A.B., Heitmann Bodtger U.C., Meyer C.N., Jensen A.V., Baunbaek-knudsen G., Petersen P.T., Andersen S., El-Said Abd El-Wahhab I., Morsy N.E., Shafiek H., Sobh E., Abdulsemed K.A., Bertrand F., Brun-Buisson C., de Montmollin E., Fartoukh M., Messika J., Tattevin P., Khoury A., Ebruke B., Dreher M., Kolditz M., Meisinger M., Pletz M.W., Hagel S., Rupp J., Schaberg T., Spielmanns M., Creutz P., Suttorp N., Siaw-Lartey B., Papapetrou D., Tsigou E., Ampazis D., Kaimakamis E., Bhatia M., Dhar R., D'Souza G., Garg R., Koul P.A., Mahesh P.A., Jayaraj B.S., Narayan K.V., Udnur H.B., Krishnamurthy S.B., Kant S., Swarnakar R., Limaye S., Salvi S., Golshani K., Keatings V.M., Martin-Loeches I., Maor Y., Strahilevitz J., Faverio P., Battaglia S., Carrabba M., Ceriana P., Confalonieri M., Monforte A.D., Del Prato B., De Rosa M., Fantini R., Fiorentino G., Gammino M.A., Menzella F., Milani G., Nava S., Palmiero G., Gabrielli B., Rossi P., Sorino C., Steinhilber G., Zanforlin A., San Luca O., Franzetti F., Carugati M., Morosi M., Monge E., Carone M., Patella V., Scarlata S., Comel A., Kurahashi K., Bacha Z.A., Ugalde D.B., Zuniga O.C., Villegas J.F., Medenica M., Mihsra D.R., Shrestha P., Ridgeon E., Awokola B.I., Adefuye Bolanle Olufunlola O.N.O., Olumide S., Ukwaja K.N., Irfan M., Minarowski L., Szymon S., Froes F., Leuschner P., Meireles M., Ferrao C., Neves J., Abel Salazar, Ravara S.B., Brocovschii V., Rusu D., Toma C., Chirita D., Dorobat C.M., Birkun A., Kaluzhenina A., Almotairi A., Ali Bukhary Z.A., Edathodu J., Fathy A., Abdulaziz Enani A.M., Mohamed N.E., Memon J.U., Bella A., Bogdanovic S.N., Milenkovic B., Pesut D., Borderias L., Bordon Garcia N.M., Alarcon H.C., Cilloniz C., Torres A., Diaz-Brito V., Casas X., Gonzalez A.E., Fernandez-Almira M.L., Interna M., Gallego M., Gaspar-GarcIa I., Gonzalez del Castillo J., Victoria P.J., Martinez E.L., Malo de Molina R., Marcos P.J., Menendez R., Pando-Sandoval A., Aymerich C.P., Lacoma de la Torre A., Garcia-Olive I., Rello J., Moyano S., Rodrigo-Troyano A., Sole-Violan J., Uranga A., van Boven J.F., Torra E.V., Pujol J.A., Feldman C., Yum H.K., Arnauld Attannon Fiogbe I.U., Yangui F., Bilaceroglu S., Levent Dalar I.D., Yilmaz U., Bogomolov A., Elahi N., Dhasmana D.J., Feneley A., Hill A.T., Rudran B., Ruiz-Buitrago S., Campbell M., Whitaker P., Youzguin A., Singanayagam A., Hancock C., Villafuerte D., Allen K.S., Brito V., Dietz J., Dysart C.E., Kellie S.M., Ricardo A. Franco-Sadud C.J., Meier G., Gaga M., Holland T.L., Bergin S.P., Kheir F., Landmeier M., Lois M., Nair G.B., Patel H., Reyes K., Rodriguez-Cintron W., Saito S., Noda J., Hinojosa C.I., Levine S.M., Reyes L.F., Angel L.F., Whitlow K.S., Hipskind J., Sukhija K., Totten V., Wunderink R.G., Shah R.D., Mateyo K.J., Noriega L., Alvarado E., Aman M., Labra L., Marin-Corral, Judith, Pascual-Guardia, Sergi, Amati, Francesco, Aliberti, Stefano, R Masclans, Joan, Soni, Nilam, Rodriguez, Alejandro, Sibila, Oriol, Sanz, Francisco, Sotgiu, Giovanni, Anzueto, Antonio, Dimakou, Katerina, Petrino, Roberta, van de Garde, Ewoudt, I Restrepo, Marco, Investigators, Glimp, Karina Aruj, Patricia, Attorri, Silvia, Barimboim, Enrique, Pablo Caeiro, Juan, I Garzón, María, Hugo Cambursano, Victor, A Adrian Ceccato, V H Dr Cazaux, Chertcoff, Julio, Lascar, Florencia, Di Tulio, Fernando, Cordon Díaz, Ariel, de Vedia, Lautaro, Cristina Ganaha, Maria, Lambert, Sandra, Lopardo, Gustavo, M Luna, Carlo, Gerardo Malberti, Alessio, Morcillo, Nora, Tartara, Silvina, Pensotti, Claudia, Pereyra, Betiana, Gustavo Scapellato, Pablo, Pablo Stagnaro, Juan, Shah, Sonali, Lötsch, Felix, Thalhammer, Florian, Anseeuw, Kurt, A Francois, Camille, Van Braeckel, Eva, Louis Vincent, Jean, Zannou Djimon, Marcel, Bashi, Jule, Dodo, Roger, Aranha Nouér, Simone, Chipev, Peter, Encheva, Milena, Miteva, Darina, Petkova, Diana, Dodo Balkissou, Adamou, Walter Pefura Yone, Eric, Hugo Mbatchou Ngahane, Bertrand, Shen, Ning, Xu, Jin-Fu, Andres Bustamante Rico, Carlo, Buitrago, Ricardo, Jose Pereira Paternina, Fernando, Kayembe Ntumba, Jean-Marie, Vladic Carevic, Vesna, Jakopovic, Marko, Jankovic, Mateja, Matkovic, Zinka, Mitrecic, Ivan, Bouchy Jacobsson, Marie-Laure, Bro Christensen, Anette, Christian Heitmann Bødtger, Uffe, Niels Meyer, Christian, Vestergaard Jensen, Andrea, Baunbæk-Knudsen, Gertrud, Trier Petersen, Pelle, Andersen, Stine, El-Said Abd El-Wahhab, Ibrahim, Elsayed Morsy, Nesreen, Shafiek, Hanaa, Sobh, Eman, Abdella Abdulsemed, Kedir, Bertrand, Fabrice, Brun-Buisson, Christian, de Montmollin, Etienne, Fartoukh, Muriel, Messika, Jonathan, Tattevin, Pierre, Khoury, Abdo, Ebruke, Bernard, Dreher, Michael, Kolditz, Martin, Meisinger, Matthia, W Pletz, Mathia, Hagel, Stefan, Rupp, Jan, Schaberg, Tom, Spielmanns, Marc, Creutz, Petra, Suttorp, Norton, Siaw-Lartey, Beatrice, Papapetrou, Dimostheni, Tsigou, Evdoxia, Ampazis, Dimitrio, Kaimakamis, Evangelo, Bhatia, Mohit, Dhar, Raja, D'Souza, George, Garg, Rajiv, A Koul, Parvaiz, A Mahesh, P, S Jayaraj, B, Vishnu Narayan, Kiran, B Udnur, Hirennappa, Bhaskara Krishnamurthy, Shashi, Kant, Surya, Swarnakar, Rajesh, Limaye, Sneha, Salvi, Sundeep, Golshani, Keihan, M Keatings, Vera, Martin-Loeches, Ignacio, Maor, Yasmin, Strahilevitz, Jacob, Faverio, Paola, Battaglia, Salvatore, Carrabba, Maria, Ceriana, Piero, Confalonieri, Marco, d'Arminio Monforte, Antonella, Del Prato, Bruno, De Rosa, Marino, Fantini, Riccardo, Fiorentino, Giuseppe, Antonia Gammino, Maria, Menzella, Francesco, Milani, Giuseppe, Nava, Stefano, Palmiero, Gerardo, Gabrielli, Barbra, Rossi, Paolo, Sorino, Claudio, Steinhilber, Gundi, Zanforlin, Alessandro, San Luca, Ospedale, Franzetti, Fabio, Carugati, Manuela, Morosi, Manuela, Monge, Elisa, Carone, Mauro, Patella, Vincenzo, Scarlata, Simone, Comel, Andrea, Kurahashi, Kiyoyasu, Aoun Bacha, Zeina, Barajas Ugalde, Daniel, Ceballos Zuñiga, Omar, F Villegas, José, Medenica, Milic, Raj Mihsra, Deebya, Shrestha, Poojan, Ridgeon, Elliott, Ishola Awokola, Babatunde, O Adefuye Bolanle Olufunlola, Ogonna N, Olumide, Segaolu, N Ukwaja, Kingsley, Irfan, Muhammad, Minarowski, Lukasz, Szymon, Skoczyński, Froes, Felipe, Leuschner, Pedro, Meireles, Mariana, Ferrão, Cláudia, Neves, João, Salazar, Abel, B Ravara, Sofia, Brocovschii, Victoria, Rusu, Doina, Toma, Cristina, Chirita, Daniela, Mihaela Dorobat, Carmen, Birkun, Alexei, Kaluzhenina, Anna, Almotairi, Abdullah, Abdulbaqi Ali Bukhary, Zakeya, Edathodu, Jameela, Fathy, Amal, Mushira Abdulaziz Enani, Abdullah, Eltayeb Mohamed, Nazik, Ulhadi Memon, Jawed, Bella, Abdelhaleem, Nada Bogdanović, Serbia, Milenkovic, Branislava, Pesut, Dragica, Borderìas, Lui, Manuel Bordon Garcia, Noel, Cabello Alarcón, Hugo, Cilloniz, Catia, Torres, Antoni, Diaz-Brito, Vicen, Casas, Xavier, Encabo González, Alicia, Luisa Fernández-Almira, Maria, Interna, Medicina, Gallego, Miguel, Gaspar-GarcÍa, Inmaculada, González Del Castillo, Juan, Javaloyes Victoria, Patricia, Laserna Martínez, Elena, Malo de Molina, Rosa, J Marcos, Pedro, Menéndez, Rosario, Pando-Sandoval, Ana, Prat Aymerich, Cristina, Lacoma de la Torre, Alicia, García-Olivé, Ignasi, Rello, Jordi, Moyano, Silvia, Rodrigo-Troyano, Ana, Solé-Violán, Jordi, Uranga, Ane, Fm van Boven, Job, Vendrell Torra, Ester, Almirall Pujol, Jordi, Feldman, Charle, Kee Yum, Ho, Univ Arnauld Attannon Fiogbe, Inje, Yangui, Ferdaou, Bilaceroglu, Semra, Dr Levent Dalar, Izmir, Yilmaz, Ufuk, Bogomolov, Artemii, Elahi, Naheed, J Dhasmana, Devesh, Feneley, Andrew, T Hill, Adam, Rudran, Banu, Ruiz-Buitrago, Silvia, Campbell, Marion, Whitaker, Paul, Youzguin, Alexander, Singanayagam, Anika, Hancock, C, Villafuerte, David, S Allen, Karen, Brito, Veronica, Dietz, Jessica, E Dysart, Claire, M Kellie, Susan, A Franco-Sadud, Clement J Ricardo, Meier, Garnet, Gaga, Mina, L Holland, Thoma, P Bergin, Stephen, Kheir, Fayez, Landmeier, Mark, Lois, Manuel, B Nair, Girish, Patel, Hemali, Reyes, Katherine, Rodriguez-Cintron, William, Saito, Shigeki, Noda, Julio, I Hinojosa, Cecilia, M Levine, Stephanie, F Reyes, Lui, F Angel, Lui, Scott Whitlow, K, Hipskind, John, Sukhija, Kunal, Totten, Vicken, G Wunderink, Richard, D Shah, Ray, John Mateyo, Kondwelani, Noriega, Lorena, Alvarado, Ezequiel, Aman, Mohamed, Labra, Lucía, Marin-Corral, J, Pascual-Guardia, S, Amati, F, Aliberti, S, Masclans, J, Soni, N, Rodriguez, A, Sibila, O, Sanz, F, Sotgiu, G, Anzueto, A, Dimakou, K, Petrino, R, van de Garde, E, Restrepo, M, Aruj, P, Attorri, S, Barimboim, E, Caeiro, J, Garzon, M, Cambursano, V, Adrian Ceccato, V, Chertcoff, J, Lascar, F, Di Tulio, F, Diaz, A, de Vedia, L, Ganaha, M, Lambert, S, Lopardo, G, Luna, C, Malberti, A, Morcillo, N, Tartara, S, Pensotti, C, Pereyra, B, Scapellato, P, Stagnaro, J, Shah, S, Lotsch, F, Thalhammer, F, Anseeuw, K, Francois, C, Van Braeckel, E, Vincent, J, Djimon, M, Bashi, J, Dodo, R, Nouer, S, Chipev, P, Encheva, M, Miteva, D, Petkova, D, Balkissou, A, Pefura Yone, E, Mbatchou Ngahane, B, Shen, N, Xu, J, Bustamante Rico, C, Buitrago, R, Pereira Paternina, F, Kayembe Ntumba, J, Carevic, V, Jakopovic, M, Jankovic, M, Matkovic, Z, Mitrecic, I, Bouchy Jacobsson, M, Christensen, A, Heitmann Bodtger, U, Meyer, C, Jensen, A, Baunbaek-knudsen, G, Petersen, P, Andersen, S, El-Said Abd El-Wahhab, I, Morsy, N, Shafiek, H, Sobh, E, Abdulsemed, K, Bertrand, F, Brun-Buisson, C, de Montmollin, E, Fartoukh, M, Messika, J, Tattevin, P, Khoury, A, Ebruke, B, Dreher, M, Kolditz, M, Meisinger, M, Pletz, M, Hagel, S, Rupp, J, Schaberg, T, Spielmanns, M, Creutz, P, Suttorp, N, Siaw-Lartey, B, Papapetrou, D, Tsigou, E, Ampazis, D, Kaimakamis, E, Bhatia, M, Dhar, R, D'Souza, G, Garg, R, Koul, P, Mahesh, P, Jayaraj, B, Narayan, K, Udnur, H, Krishnamurthy, S, Kant, S, Swarnakar, R, Limaye, S, Salvi, S, Golshani, K, Keatings, V, Martin-Loeches, I, Maor, Y, Strahilevitz, J, Faverio, P, Battaglia, S, Carrabba, M, Ceriana, P, Confalonieri, M, Monforte, A, Del Prato, B, De Rosa, M, Fantini, R, Fiorentino, G, Gammino, M, Menzella, F, Milani, G, Nava, S, Palmiero, G, Gabrielli, B, Rossi, P, Sorino, C, Steinhilber, G, Zanforlin, A, San Luca, O, Franzetti, F, Carugati, M, Morosi, M, Monge, E, Carone, M, Patella, V, Scarlata, S, Comel, A, Kurahashi, K, Bacha, Z, Ugalde, D, Zuniga, O, Villegas, J, Medenica, M, Mihsra, D, Shrestha, P, Ridgeon, E, Awokola, B, Adefuye Bolanle Olufunlola, O, Olumide, S, Ukwaja, K, Irfan, M, Minarowski, L, Szymon, S, Froes, F, Leuschner, P, Meireles, M, Ferrao, C, Neves, J, Abel, S, Ravara, S, Brocovschii, V, Rusu, D, Toma, C, Chirita, D, Dorobat, C, Birkun, A, Kaluzhenina, A, Almotairi, A, Ali Bukhary, Z, Edathodu, J, Fathy, A, Abdulaziz Enani, A, Mohamed, N, Memon, J, Bella, A, Bogdanovic, S, Milenkovic, B, Pesut, D, Borderias, L, Bordon Garcia, N, Alarcon, H, Cilloniz, C, Torres, A, Diaz-Brito, V, Casas, X, Gonzalez, A, Fernandez-Almira, M, Interna, M, Gallego, M, Gaspar-GarcIa, I, Gonzalez del Castillo, J, Victoria, P, Martinez, E, Malo de Molina, R, Marcos, P, Menendez, R, Pando-Sandoval, A, Aymerich, C, Lacoma de la Torre, A, Garcia-Olive, I, Rello, J, Moyano, S, Rodrigo-Troyano, A, Sole-Violan, J, Uranga, A, van Boven, J, Torra, E, Pujol, J, Feldman, C, Yum, H, Arnauld Attannon Fiogbe, I, Yangui, F, Bilaceroglu, S, Levent Dalar, I, Yilmaz, U, Bogomolov, A, Elahi, N, Dhasmana, D, Feneley, A, Hill, A, Rudran, B, Ruiz-Buitrago, S, Campbell, M, Whitaker, P, Youzguin, A, Singanayagam, A, Villafuerte, D, Allen, K, Brito, V, Dietz, J, Dysart, C, Kellie, S, Ricardo, A, Meier, G, Gaga, M, Holland, T, Bergin, S, Kheir, F, Landmeier, M, Lois, M, Nair, G, Patel, H, Reyes, K, Rodriguez-Cintron, W, Saito, S, Noda, J, Hinojosa, C, Levine, S, Reyes, L, Angel, L, Whitlow, K, Hipskind, J, Sukhija, K, Totten, V, Wunderink, R, Shah, R, Mateyo, K, Noriega, L, Alvarado, E, Aman, M, and Labra, L
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.drug_class, Aspiration risk, Antibiotics, Nursing home resident, Settore MED/10 - Malattie Dell'Apparato Respiratorio, Critical Care and Intensive Care Medicine, Microbiology, anaerobic, aspiration, bacteria, pneumonia, risk factors, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Community-acquired pneumonia, Taverne, Anti-Bacterial Agent, medicine, Humans, Community-Acquired Infection, 030212 general & internal medicine, Stroke, Aged, Aged, 80 and over, business.industry, Respiratory Aspiration, Middle Aged, medicine.disease, Antibiotic coverage, Anti-Bacterial Agents, Community-Acquired Infections, Hospitalization, Pneumonia, 030228 respiratory system, Risk factors, risk factor, Female, Underweight, medicine.symptom, business, Cardiology and Cardiovascular Medicine
Abstract: Background: Aspiration community-acquired pneumonia (ACAP) and community-acquired pneumonia (CAP) in patients with aspiration risk factors (AspRFs) are infections associated with anaerobes, but limited evidence suggests their pathogenic role. Research Question: What are the aspiration risk factors, microbiology patterns, and empiric anti-anaerobic use in patients hospitalized with CAP? Study Design and Methods: This is a secondary analysis of GLIMP, an international, multicenter, point-prevalence study of adults hospitalized with CAP. Patients were stratified into three groups: (1) ACAP, (2) CAP/AspRF+ (CAP with AspRF), and (3) CAP/AspRF- (CAP without AspRF). Data on demographics, comorbidities, microbiological results, and anti-anaerobic antibiotics were analyzed in all groups. Patients were further stratified in severe and nonsevere CAP groups. Results: We enrolled 2,606 patients with CAP, of which 193 (7.4%) had ACAP. Risk factors independently associated with ACAP were male, bedridden, underweight, a nursing home resident, and having a history of stroke, dementia, mental illness, and enteral tube feeding. Among non-ACAP patients, 1,709 (70.8%) had CAP/AspRF+ and 704 (29.2%) had CAP/AspRF-. Microbiology patterns including anaerobes were similar between CAP/AspRF-, CAP/AspRF+ and ACAP (0.0% vs 1.03% vs 1.64%). Patients with severe ACAP had higher rates of total gram-negative bacteria (64.3% vs 44.3% vs 33.3%, P =.021) and lower rates of total gram-positive bacteria (7.1% vs 38.1% vs 50.0%, P 50% in all groups) independent of AspRFs or ACAP received specific or broad-spectrum anti-anaerobic coverage antibiotics. Interpretation: Hospitalized patients with ACAP or CAP/AspRF+ had similar anaerobic flora compared with patients without aspiration risk factors. Gram-negative bacteria were more prevalent in patients with severe ACAP. Despite having similar microbiological flora between groups, a large proportion of CAP patients received anti-anaerobic antibiotic coverage.
Published: 2021

23. Protein profile of COPD patients with Pseudomonas in their airway secretions

Author: Eduard Monsó, Germán Peces-Barba, Borja G. Cosío, Alvar Agusti, Rosa Faner, Sergi Pascual-Guardia, Adi Castro-Acosta, Joaquim Gea Guiral, and Rut Mas
Subjects: biology, Copd patients, business.industry, Pseudomonas, Immunology, Medicine, Protein profile, Airway, biology.organism_classification, business
Published: 2020
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24. Novel Pseudomonas aeruginosa scoring system to guide empiric anti-pseudomonal therapy in COPD patients with community-acquired pneumònia

Author: Nilam J. Soni, Marcos I. Restrepo, Giovanni Sotgiu, Joaquim Gea, Judith Marin Corral, Francesco Amati, Martin Kolditz, Francisco Sanz, Pedro J. Marcos, Alejandro Rodriguez, Anzueto Antonio, Sergi Pascual Guardia, Oriol Sibila, and Stefano Aliberti
Subjects: COPD, medicine.medical_specialty, Scoring system, Bronchiectasis, business.industry, Copd patients, medicine.drug_class, Pseudomonas aeruginosa, Antibiotics, medicine.disease, medicine.disease_cause, Pneumonia, Community-acquired pneumonia, Internal medicine, Medicine, business
Abstract: Background: COPD is associated with the development of Community-Acquired Pneumonia (CAP). Limited data are available regarding the association of P. aeruginosa (PA) risk factors as predictors of appropriate selection of anti-PA antibiotics. Our aim was to developed a novel PA scoring system based on risk factors to guide appropriate selection of empiric anti-PA antibiotics in hospitalized COPD patients with CAP. Methods: This pre-planned analysis of an international, multicenter, point-prevalence study included immunocompetent COPD patients hospitalized with CAP. We developed a scoring system of independently associated risk factors for PA-CAP. The primary outcomes were prevalence of PA-CAP and the appropriate selection of empiric anti-PA antibiotics. Results: We enrolled 689 hospitalized COPD patients with CAP, with a prevalence of PA-CAP of 7% (n=45). The variables independently associated with PA-CAP were a previous PA infection or colonization (OR 14.2 [95%CI 5.7-35.2] – 3 points), hospitalization in the past 12 months (OR 3.7 [1.5-9.2] – 1 point), and the presence of bronchiectasis (OR 3.2 [1.4-7.2] - 1 point). The PA score-COPD (PAS-COPD) was stratified in 0, 1, 2, or ≥3 points with a PA-CAP prevalence of 2%, 5%, 20% and 50%, respectively. Current anti-PA empiric antibiotics overuse occurs in 54% of the patients, but after the application of the PAS-COPD the overuse of anti-PA empiric antibiotics may ideally drop to 6%. Conclusions: We developed a novel PAS-COPD that accurately identified the risk of PA-CAP and is able to assist providers in the appropriate use of anti-PA antibiotics in COPD patients hospitalized with CAP.
Published: 2020
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25. Anti-Pseudomonas antibiotic use for hospitalized patients with community-acquired pneumonia

Author: Oriol Sibila, Manuela Carugati, Marcos I. Restrepo, Alejandro Rodriguez, Judith Marin-Corral, Glimp Investigators, Stefano Aliberti, Francisco Sanz, Martin Kolditz, Giovanni Sotgiu, and Sergi Pascual-Guardia
Subjects: medicine.medical_specialty, biology, Community-acquired pneumonia, Hospitalized patients, business.industry, Internal medicine, Pseudomonas, medicine, Antibiotic use, biology.organism_classification, medicine.disease, business
Published: 2020
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26. International Guideline concordance of empiric antibiotic use in community-acquired pneumonia

Author: Judith Marin-Corral, Giovanni Sotgiu, Stefano Aliberti, Martin Kolditz, Francisco Sanz, Manuela Carugati, Marcos I. Restrepo, Sergi Pascual Guardia, Pedro J. Marcos, and Oriol Sibila
Subjects: medicine.medical_specialty, medicine.drug_class, business.industry, Concordance, Antibiotics, Guideline, medicine.disease, Intensive care unit, law.invention, Pneumonia, Community-acquired pneumonia, law, Emergency medicine, medicine, Antimicrobial stewardship, business, Cause of death
Abstract: Community-acquired pneumonia (CAP) is the leading infectious cause of death worldwide and its empiric treatment is a critical decision. Several guidelines recommend the appropriate use of antibiotics for patients with CAP, but evidence regarding guideline concordance (GC) is limited to local or regional studies. Our aim was to evaluate the national and international GC of empiric antibiotic selection for hospitalized patients with CAP. Methods: We used the platform of an international, multicenter, point-prevalence study of hospitalized immunocompetent patients with CAP. We analyzed the continental GC according to the recommendations by ERS-2011, ATS/IDSA-2007, and ALAT-2004, and by national guidelines from Portugal, United Kingdom, Pakistan, Spain, India, Germany and Croatia. We stratified the patients according to the site of care in ward or intensive care unit (ICU) admission. Results: We enrolled 3,019 patients with 83% admitted from the ward and 17% from the ICU. At a global level GC was 42%, highest in European countries according to the ERS-2011 (53%), followed by North America (35%) according to ATS/IDSA 2007 guidelines and 33% of South American countries according to ALAT-2004, respectively (p value Conclusions: Adherence to CAP guidelines is suboptimal among the majority of participating countries or at the continental level. Antimicrobial stewardship programs should focus on improving adherence of empiric antibiotic selection in clinical practice.
Published: 2020
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27. Absence of Relevant Clinical Effects of SARS-COV-2 on the Affinity of Hemoglobin for O

Author: Elvira Tejedor, Diego A Rodríguez-Chiaradía, Óscar Díaz, Antonio O. Caguana, Antoni Ferrer, Joaquim Gea, Sergi Pascual-Guardia, and Salomé Bellido-Calduch
Subjects: Pulmonary and Respiratory Medicine, Hemoglobina, Coronavirus disease 2019 (COVID-19), Original, SARS-CoV-2, business.industry, Oxígeno, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, Oxygen, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Carta al Director, Medicine, In patient, Hemoglobin, business, Humanities, ComputingMethodologies_COMPUTERGRAPHICS
Abstract: Graphical abstract, La afectación pulmonar por COVID-19 se asocia frecuentemente con alteraciones en la oxigenación. La presión parcial arterial de oxígeno (PaO2) es la variable más utilizada clínicamente para valorar dicha oxigenación, ya que influye decisivamente en el oxígeno transportado por la hemoglobina (expresado por porcentaje de saturación, SaO2). Sin embargo, dos estudios recientes realizados respectivamente in silico y mediante técnicas ómicas en hematíes de pacientes han sugerido que SARS-CoV-2 podría disminuir la afinidad del oxígeno por la hemoglobina (lo que implicaría que la PaO2 sobrevaloraría la SaO2 real), e incluso reduciría la cantidad de esta molécula transportadora. Objetivo Evaluar dicha hipótesis en muestras gasométricas de pacientes con COVID-19. Métodos Se incluyeron las gasometrías de todos los pacientes con COVID-19 realizadas en nuestro laboratorio, así como las de dos grupos control: pacientes sincrónicos con PCR negativa (GCS) y grupo histórico (GCH). Se compararon por separado las SaO2 y saturaciones venosas (SvO2), medidas por cooximetría (COX) con las calculadas mediante las ecuaciones de Kelman (K), Severinghaus (SV) y Siggaard-Andersen (SA) en cada grupo. Resultados Las cifras de SaO2 y SvO2 medidas y calculadas fueron prácticamente superponibles en todos los grupos. Así, los coeficientes de correlación intraclase (CCI) en COVID-19 para SaO2 fueron 0,993 en COX-K y 0,992 en COX-SV y COX-SA; siendo 0,995 para SvO2 tanto en COX-K como en COX-SV y COX-SA. La hemoglobina y la ferritina resultaron algo superiores en el grupo COVID-19 respecto de GCS y GCH (hemoglobina, p < 0,001 en ambos; ferritina, p < 0,05 para GCS y p < 0,001 para GCH). Conclusiones En condiciones clínicas, el SARS-CoV-2 no influye de forma apreciable en la afinidad del oxígeno por la hemoglobina, ni tampoco en los niveles de esta última. Por tanto, la PaO2 es un buen marcador de oxigenación sanguínea también en COVID-19.
Published: 2020

28. Incidence of pulmonary embolism in patients with non-invasive respiratory support during COVID-19 outbreak

Author: Juan José. Rodriguez‐Sevilla, Salome Bellido Calduch, Sergi Pascual-Guardia, Purificación Pérez Terán, Cinta Cumplí Gargallo, Marisol Domínguez-Álvarez, Ricardo J. Aguilar Colindres, Mariela Alvarado Miranda, Francisco José Parrilla-Gómez, Juana Martínez-Llorens, Karys Khilzi, Roberto Chalela, Diana Badenes Bonet, Pilar Ausin Herrero, Nuria Grau, Oswaldo Antonio Caguana Velez, Antonio Sancho-Muñoz, Joaquim Gea, Jose Gregorio González-García, Mariela Arita Guevara, Diego Rodríguez-Chiaradia, Judith Marin Corral, Albert Sánchez-Font, and Mónica Sánchez Ortiz
Subjects: Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, medicine.medical_treatment, Short Communication, Context (language use), 03 medical and health sciences, 0302 clinical medicine, CPAP, Internal medicine, medicine, Humans, Cumulative incidence, 030212 general & internal medicine, Continuous positive airway pressure, COVID-19 pneumonia, Non-invasive respiratory support (NIS), Severe COVID-19, Retrospective Studies, Mechanical ventilation, Noninvasive Ventilation, Continuous Positive Airway Pressure, business.industry, Incidence (epidemiology), Incidence, Pulmonary embolism, COVID-19, Retrospective cohort study, Middle Aged, medicine.disease, 030228 respiratory system, Spain, Female, Airway, business
Abstract: While the incidence of thrombotic complications in critically ill patients is very high, in patients under non-invasive respiratory support (NIS) is still unknown. The specific incidence of thrombotic events in each of the clinical scenarios within the broad spectrum of severity of COVID-19, is not clearly established, and this has not allowed the implementation of thromboprophylaxis or anticoagulation for routine care in COVID-19. Patients admitted in a semi-critical unit treated initially with NIS, especially Continuous-Positive Airway Pressure (CPAP), were included in the study. The cumulative incidence of pulmonary embolism was analyzed and compared between patients with good response to NIS and patients with clinical deterioration that required orotracheal intubation. 93 patients were included and 16% required mechanical ventilation (MV) after the NIS. The crude cumulative incidence of the PE was 14% (95%, CI 8-22) for all group. In patients that required orotracheal intubation and MV, the cumulative incidence was significantly higher [33% (95%, CI 16-58)] compared to patients that continued with non-invasive support [11% (CI 5-18)] (Log-Rank, p = 0.013). Patients that required mechanical ventilation were at higher risk of PE for a HR of 4.3 (95%CI 1.2-16). In conclusion, cumulative incidence of PE is remarkably higher in critically patients with a potential impact in COVID-19 evolution. In this context, patients under NIS are a very high-risk group for developing PE without a clear strategy regarding thromboprophylaxis.
Published: 2020

29. Differences in micro-RNA expression profile between vastus lateralis samples and myotubes in COPD cachexia

Author: Esther Barreiro, Sergi Pascual-Guardia, Joaquim Gea, Ester Puig-Vilanova, Carme Casadevall, Antonio Sancho-Muñoz, and Anna Salazar-Degracia
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Cachexia, Muscle specimens, Physiology, Muscle Fibers, Skeletal, Pulmonary disease, Muscle-enriched micro-RNAs, Severe copd, Quadriceps Muscle, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, Lower limb muscle atrophy, 0302 clinical medicine, Lower-limb muscle atrophy, In vivo, Physiology (medical), microRNA, medicine, Humans, Caquèxia, Prospective Studies, Cells, Cultured, Adiposity, Aged, COPD, Myogenesis, business.industry, Middle Aged, medicine.disease, MicroRNAs, Cross-Sectional Studies, 030104 developmental biology, 030228 respiratory system, Case-Control Studies, Myotubes, Body Composition, Female, Severe COPD, Transcriptome, business
Abstract: Quadriceps muscle weakness and wasting are common comorbidities in chronic obstructive pulmonary disease (COPD). Micro-RNA expression upregulation may favor muscle mass growth and differentiation. We hypothesized that the profile of muscle-enriched micro-RNAs in cultured myotubes differs between patients with COPD of a wide range of body composition and healthy controls and that expression levels of those micro-RNAs from patients with COPD and controls differ between in vivo and in vitro conditions. Twenty-nine patients with COPD [ n = 15 with muscle wasting and fat-free mass index (FFMI) 15 kg/m2 and n = 14 with normal body composition and FFMI 18 kg/m2] and 10 healthy controls (FFMI 19 kg/m2) were consecutively recruited. Biopsies from the vastus lateralis muscle were obtained in all study subjects. A fragment of each biopsy was used to obtain primary cultures, in which muscle cells were first proliferated to be then differentiated into actual myotubes. In both sets of experiments (in vivo biopsies and in vitro myotubes) the following muscle-enriched micro-RNAs from all the study subjects were analyzed using quantitative real-time PCR amplification: micro-RNA (miR)-1, miR-133a, miR-206, miR-486, miR-29b, miR-27a, and miR-181a. Whereas the expression of miR-1, miR-206, miR-486, and miR-29b was upregulated in the muscle biopsies of patients with COPD compared with those of healthy controls, levels of none of the studied micro-RNAs in the myotubes (primary cultured cells) significantly differed between patients with COPD and the controls. We conclude from these findings that environmental factors (blood flow, muscle metabolism, and inflammation) taking place in vivo (biopsies) in muscles may account for the differences observed in micro-RNA expression between patients with COPD and controls. In the myotubes, however, the expression of the same micro-RNAs did not differ between the study subjects as such environmental factors were not present. These findings suggest that therapeutic strategies should rather target environmental factors in COPD muscle wasting as the profile of micro-RNA expression in myotubes was similar in patients to that observed in the healthy controls. NEW & NOTEWORTHY Environmental factors taking place in vivo (biopsies) in the muscles may explain differences observed in micro-RNA expression between patients with chronic obstructive pulmonary disease (COPD) and controls. In the myotubes, however, the expression of the same micro-RNAs did not differ between the study subjects as such environmental factors were not present. These findings suggest that therapeutic strategies should rather target environmental factors in COPD muscle wasting and cachexia as micro-RNA expression profile in myotubes was similar between patients and controls. This study was supported by Centro de Investigación en Red de Enfermedades Respiratorias, Fondo de Investigación Sanitaria (FIS) 14/00713 [Fondo Europeo de Desarrollo Regional (FEDER)], FIS 18/00075 (FEDER), Grant SAF2014-54371, Sociedad Española de Neumología y Cirugía Torácica (SEPAR) 2016, SEPAR 2018, Fundació Catalana de Pneumologia 2016, and an unrestricted grant from Menarini SA 2018 (Spain). E. Barreiro was a recipient of the European Respiratory Society COPD Research Award 2008.
Published: 2019
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30. Aspiration Risks Factors, Microbiology and Empiric Antibiotics for Patients Hospitalized with Community Acquired Pneumonia

Author: Stefano Aliberti, Nilam J. Soni, Glimp Study Grp, Eva Van Braeckel, Marcos I. Restrepo, Sergi Pascual-Guardia, Francesco Amati, Alejandro Rodriguez, and Judith Marin-Corral
Subjects: medicine.medical_specialty, Community-acquired pneumonia, medicine.drug_class, business.industry, Antibiotics, Medicine and Health Sciences, medicine, medicine.disease, Intensive care medicine, business
Published: 2020
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31. Benralizumab for the Prevention of COPD Exacerbations

Author: Criner, G. J., Celli, B. R., Brightling, C. E., Agusti, A., Papi, A., Singh, D., Sin, D. D., Vogelmeier, C. F., Sciurba, F. C., Bafadhel, M., Backer, V., Kato, M., Ramirez-Venegas, A., Wei, Y. -F., Bjermer, L., Shih, V. H., Jison, M., O'Quinn, S., Makulova, N., Newbold, P., Goldman, M., Martin, U. J., GALATHEA Study Investigators, TERRANOVA Study Investigators, Otto, Burghuber, Bernhard, Forstner, Gerhard, Köberl, Bernd, Lamprecht, Judith, Löffler-Ragg, Horst, Olschewski, Michael, Studnicka, Francois, Beaucage, Guy, Chouinard, Anthony, Dechant, Anthony, Dowell, Jacques, Hebert, Sohail, Khattak, Kieran, Killian, William, Killorn, Andy, Lam, Francois, Maltais, Darcy, Marciniuk, Lyle, Melenka, Bonavuth, Pek, Jeremy, Road, Donald, Sin, Alain, Vaugeois, Brandie, Walker, Tomas, Dvorak, Stanislav, Holub, Otakar, Hokynar, Vitezslav, Kolek, Daniela, Kopecka, Jan, Krepelka, Jaroslav, Mares, Josef, Veverka, Vladimir, Zindr, Sabine, Ballenberger, Rolf, Dichmann, Christian, Geßner, Margret, Jandl, Claus, Keller, Joachim, Kirschner, Marc, Kornmann, Petra, Mikloweit, Ingomar, Naudts, Axel, Overlack, Isabelle, Schenkenberger, Volker, Schlegel, Lutz Von Versen, Claus Franz Vogelmeier, Stefan, Zielen, István, Albert, Beatrix, Bálint, Mária Csilla Hangonyi, Teréz, Kecskés, Anikó, Kurucz, Balázs, Medgyasszay, Lajos, Molnár, János, Mucsi, Márta, Papp, Magdolna, Póczi, Éva, Radeczky, Zsolt Pápai Székely, Csilla, Szabó, Gyöngyi, Szabó, Melinda, Szabó, Alfredo Antonio Chetta, Giuseppe Di Maria, Giulio, Donazzan, Federica, Meloni, Elisabetta, Pace, Pierluigi, Paggiaro, Alberto, Papi, Ricciardolo, Fabio Luigi Massimo, Antonio, Spanevello, Fumiaki, Aoki, Ryosuke, Eda, Takeo, Endo, Yasushi, Fukushima, Kenichi, Gemba, Naoki, Hagimoto, Hiromasa, Harada, Yasuko, Harada, Norihiko, Hata, Osamu, Hataji, Nobuo, Hatakeyama, Takahiko, Horiguchi, Gen, Ideura, Motoyasu, Iikura, Azusa, Ikegami, Shirou, Imokawa, Yoshikazu, Inoue, Takeshi, Isobe, Ryoji, Ito, Susumu, Iwata, Tadashi, Kamei, Motokazu, Kato, Hideki, Katsura, Yuji, Kawarada, Norio, Kihara, Masaharu, Kinoshita, Takashi, Kinoshita, Tomoo, Kishaba, Hideo, Kita, Arihiro, Kiyosue, Shigeru, Komatsu, Kazuki, Konishi, Sekiya, Koyama, Makoto, Kudo, Kazuhiko, Machida, Hironi, Makita, Hiroto, Matsuse, Naoki, Miyazawa, Hiroyuki, Nakamura, Yuji, Nakatani, Kazuyuki, Nishimura, Takashi, Nishimura, Junichi, Ogawa, Hiroyuki, Ohbayashi, Tetsuro, Ohdaira, Tsukasa, Ohnishi, Kazuhiko, Oki, Masahiko, Saito, Kenji, Sakamoto, Osamu, Sakamoto, Hisakuni, Sekino, Noriharu, Shijubo, Masaharu, Shinkai, Hideo, Soto, Yoshitaka, Sugawara, Noriaki, Suko, Hisaho, Takahashi, Masamitsu, Takahashi, Tsuneyuki, Takahashi, Hiroshi, Tanaka, Hiroyuki, Taniguchi, Tadayuki, Terada, Takao, Tochigi, Kazuyo, Tohyama, Hirokazu, Tokuyasu, Keisuke, Tomii, Tomomasa, Tsuboi, Mitsuyoshi, Utsugi, Katsumaru, Yamamoto, Michiko, Yamamoto, Shuichi, Yano, Makoto, Yoshida, Frank, Custers, Richard, Dekhuijzen, Remco, Djamin, Jan Willem Van Dan Berg, Lowie, Vanfleteren, Pascal, Wielders, Bogusława, Cimoszko, Anna, Doboszyńska, Andrzej, Dyczek, Andrzej, Fal, Krystyna, Folcik, Łukasz, Goliński, Marek, Jutel, Andrzej, Kolczyński, Piotr, Kuna, Ewa, Łączyńska, Wojciech, Machowiak, Maciej, Marczak, Joanna, Markiewicz, Janusz, Milanowski, Grzegorz, Mincewicz, Maria, Nittner-Marszalska, Wojciech, Papiewski, Małgorzata, Pawlukiewicz, Witold, Pomiećko, Barbara, Rewerska, Cezary, Rybacki, Wojciech, Skucha, Ewa, Trębas-Pietraś, Ewa, Uhryn, Małgorzata, Żurowska-Gębala, Laurentia, Andrei, Traian, Mihaescu, Stefan, Mihaicuta, Eniko Vera Pall, Ioan, Petrui, Angelica, Savu, Claudia, Toma, Ana, Trailescu, Vladimir, Abrosimov, Nataliya, Astafyeva, Evgenyi, Bazdyrev, Nadezhda, Berdnikova, Laura, Bolieva, Ekaterina, Bukreeva, Valery, Chistyakov, Anna, Galustyan, Halida, Gantseva, Svetlana, Goncharova, Sergey, Grigoriev, Galina, Ignatova, Inna, Ilyashevich, Nadezhda, Izmozherova, Magomed, Kamalov, Yaroslava, Khovaeva, Natalia, Kuzubova, Lyudmila, Kvitkova, Liudmila, Lenskaya, Igor, Leshchenko, Olga, Magnitskaya, Boris, Molotilov, Artem, Molotkov, Svetlana, Myasoedova, Sergey, Nedogoda, Vladimir, Nosov, Marina, Osipenko, Andrey, Peskov, Veronika, Popova, Oksana, Ratushnay, Irina, Ryzhova, Olga, Shangina, Natalia, Shaporova, Evgeny, Shmelev, Lybov, Shpagina, Alexander, Shutkin, Yuri, Shvarts, Mikhail, Smirnov, Irina, Stitsenko, Maksim, Vasilev, Arkadiy, Vertkin, Elena, Vishneva, Alexander, Vizel, Anna, Zateyschikova, Mohamed, Abdool-Gaffar, Ismail, Abdullah, Axel, Bruning, Nyda, Fourie, Michael, Greenblatt, Mohammed, Tayob, Venter, K, An Soo Jang, Kwan Ho Lee, Sang Haak Lee, Sook Young Lee, Suk Joong Yong, Kwang Ha Yoo, Soo Taek Uh, Ramón Agüero Balbín, David Ramos Barbón, Álvar Agustí García-Navarro, José Luis Velasco Garrido, Sergi Pascual Guardia, Eduard Monso Molas, Luis De Teresa Parreño, Borja García-Cosio Piqueras, German Peces-Barba Romero, Myriam Calle Rubio, Fernando Sánchez-Toril López, Alicia Marín Tapia, Heidi Martin Braschler, Martin, Brutsche, Michael, Grob, Jörg, Leuppi, Daiana, Stolz, Alexander, Turk, Nawar, Bakerley, Mona, Bafadhel, Christopher, Brightling, Rekha, Chaudhuri, Gourab, Choudhury, Graham, Devereux, Imran, Hussain, Kai, Lee, William, Macnee, Ravindran, Mahadeva, Matthew, Masoli, Monica, Nordstrom, Manish, Patel, Allan, Reid, Dinesh, Saralaya, Tariq, Sethi, Sukh Dave Singh, Anthony, G de Soyza, Tom, Wilkinson, Alice, Turner, Helen, Ward, Chandar, Abboy, Ivan, Ackerman, Idalia, Acosta, Arun, Adlakha, Bassil, Aish, Mohamed, Ali, Charles, Andrews, Robby, Ayoub, Anil, Badhwar, Dennis, Bassetti, Sherif El Bayadi, Richard, Beasley, Shashi, Bellam, Jonathan, Bernstein, Maria, Blahey, Scott, Bloom, Eugene, Bleecker, Wesley, Bray, Johnathan, Brewer, Robert, Buynak, William, Calhoun, Edward, Campbell, Anthony, Captain, Birjis, Chinoy, Kenneth, Chinsky, Geoffrey, Chupp, Arsenio, Columbie, Clinton, Corder, Gerard, Criner, Humberto, Cruz, Edward, Cullen, Kevin, Deboer, Michael, Denenberg, Mark, Dransfield, Leonard, Dunn, Miles, Elmore, David, Erb, Faisal, Fakih, Gary, Ferguson, Charles, Fogarty, Mark, Freed, Stephen, Fritz, David, Fuentes, Shariar, Cohen-Gadol, Robert, Garver, John, Given, Luis Ramos Gonez, Raul Ebran Gonzalez, Robert, Gordon, Gregory, Gottschlich, Donald, Graham, David, Grant, Gary, Greenwald, James, Greenwald, Kenneth, Haft, Gregory, Hammond, Nadia, Hansel, Jeffrey, Harris, Humberto, Hernandez, Marvin, Heuer, Albrecht, Heyder, David, Hill, Willis, Holloway, Octavian, Ioachimescu, Richard, Jackson, Ajay, Jain, Nan, Jiang, Thomas, Kaelin, Adolfo, Kaplan, Mitchell, Kaye, Akram, Khan, Yekaterina, Khronusova, Ryan, Klein, Joel, Kline, Firas, Koura, Ritsu, Kuno, Ware, Kuschner, Jean Claude Labissiere, David Laman Jr, John, Lee, Mitchell, Lee, Lawrence, Levinson, Njira, Lugogo, Mador, M, Nathaniel, Marchetti, Rafael, Martinez, Richard, Martinez, Peter, Mattar, David, Maybee, Dennis, Mcgraw, Michael, Mcguire, Curtis, Mello, Aaron, Milstone, John, Mitchell, Wendy, Moore, Timothy, Moriarty, Cheta, Nand, Brooke, Nevins, Ikeadi, Ndukwu, Rachel, Nisbet, David, Nyanjom, Maria, Nualart, Thomas, O'Brien, Mikhail, Palatnik, Gnyandev, Patel, Amit, Patel, Guido, Perez, Christopher, Perry, Michael, Pfeffer, Krishna, Pudi, Marina, Raikhel, Murali, Ramaswamy, Joe, Ramsdell, Donato, Ricci, Gary, Richmond, Eugene, Ryan, Fadi, Saba, Boris, Sagalovich, C Andrew Schroeder, Timothy, Scialla, Frank, Sciurba, Amit, Shah, Nirav, Shah, Zeeshan, Shaikh, Akhtar, Siddiqui, Barry, Sigal, Thomas, Siler, Howard, Silverboard, William, Sims, Clyde, Southwell, Selwyn, Spangenthal, Peruvemba, Sriram, James, Stocks, Tony, Su, John, Suen, Robert, Sussman, Horia, Tatu, Antonio, Terrelonge, Alan, Thomas, Mario, Torres, Rodolfo, Trejo, Miguel, Trevino, Banks, Turner, Manuel, Villareal, Janine, Vintch, Neal, Warshoff, Jan, Westerman, Philip, Wexler, Thomas, Yunger, Amir, Zeki, Mariano Fernandez Acquier, Norma, Aramayo, German, Arce, Juan, Belloni, Víctor, Cambursano, Carlos De La Vega, Fernando Rodriguez Chariarse, Pedro, Elias, Marcelo, Fernández, Ana, Lopez, Andrea, Medina, María, Otaola, Maria Salazan Saez, Maria De Salvo, Fernando, Scherbovsky, Ana, Stok, Jorge, Taborda, Alberto, Tolcachier, Fernando, Verra, Carlos, Victorio, Rita Gisela Delgado Vizcarra, Philip, Bardin, Peter, Bremner, Martin, Phillips, John, Upham, Peter, Wark, Antoine, Bolly, Alain, Delobbe, Peter, Driesen, Eduard, Janssens, Wim, Janssens, Olivier, Michel, Bernard, Vandooren, Martti, Antila, Jussara, Fiterman, Carlos, Fritscher, Jorge, Hetzel, Jose, Jardim, Waldo De Mattos, Rafael, Martins, Maria Eunice De Oliveira, Andreia, Pez, Maria, Sales, Rafael, Stelmach, Priscila, Wolff, Svetla, Andreeva, Reneta, Antonova, Ana, Dancheva, Yuliya, Ivanova, Slavcho, Ivanov, Hristo, Metev, Iveta, Naydenova, Tatyana, Petkova, Galina, Petrova, Kostadinka, Sotirova, Mariyana, Stoyanova, Rumen, Tiholov, Iliyana, Valkanova, Oleg, Yakov, Rosa, Feijoo, Juana, Pavie, Patricia, Schönffeldt, Absalon, Silva, Victor, Martinez, David, Espinosa, Alejandro, Londono, Dora, Molina, Gonzalo, Prada, Andrés, Rico, Gregorio Sanchez Vallejo, Alvaro, Urbina, Ana, Vanegas, Maria, Villegas, Josip, Aralica, Gordana, Stjepanovic, Vibeke, Backer, Uffe, Bødtger, Christian, Meyer, Læge Sven Nielsen, Anders Loekke Ottesen, Ingrid, Titlestad, Nathalie, Bautin, Arnaud, Bourdin, Pascal, Chanez, Francis, Couturaud, Antoine, Cuvelier, Gilles, Devouassoux, Pierre-Olivier, Girodet, Jean-François, Muir, Jean-Louis, Pépin, Alain, Proust, Azzedine, Yaici, Yochai, Adir, Gershon, Fink, Zvi, Fridlender, Gabriel, Izbicki, Mordechai, Kramer, Yehuda, Schwartz, Juan Moreno Hoyos Abril, Ricardo Campos Cerda, Efraín Montaño Gonzalez, Ricardo Ramirez Terrones, Rodolfo Posadas Valay, Alejandra, Ramirez-Venegas, Paul, Dawkins, Syed, Hussain, Benedict, Brockway, John, Richmond, Colin, Helm, Catherina, Chang, Jørn, Ahlqvist, Terje, Tollåli, Tadeusz, Tomala, Socorro, Castro, William, Chavez, Octavio, Cubas, Rolando, Estrella, Efrain, Felix, Ronal, Gamarra, Alfredo, Guerreros, Alberto, Matsuno, Danilo, Salazar, Miguel, Tsukayama, Albert Albay Jr, Teresita, Aquino, Tito, Atienza, Joven Roque Gonong, Ronnie, Samoro, Joel, Santiaguel, Beata, Asankowicz-Bargiel, Ewa, Pisarczyk-Bogacka, Renata, Bijata-Bronisz, Marta, Chełmińska, Małgorzata, Dobryniewska, Anna, Olech-Cudzik, Tomasz, Fijołek, Krzysztof, Filipek, Agata, Kot, Bożena, Kucińska, Krzysztof, Lis, Elżbieta, Rybicka-Liszewska, Marzenna, Tarnowska-Matusiak, Robert, Mróz, Piotr, Napora, Wojciech, Naumnik, Artur, Niemiec, Władysław, Pierzchała, Grzegorz, Przybylski, Katarzyna, Styka, Danuta, Wrońska, Branislava, Milenkovic, Dobrivoje, Novkovic, Matijaz, Flezar, Niksa, Segota, Snezana Ulcar Kostic, Albert, Klobucar, Leif, Bjermer, Dan, Curiac, Christer, Janson, Pekka, Koskinen, Lundback, Bo, Åke, Olsson, Shih-Lung, Cheng, Ming-Lin, Ho, Jeng-Yuan, Hsu, Wu-Huei, Hsu, Ping-Hung, Kuo, Chin-Chou, Wang, Yu-Feng, Wei, Kuang-Yao, Yang, Watchara, Boonsawat, Somchai, Chantarothorn, Warangkana, Keeratichananont, Kittipong, Maneechotesuwan, Kanok, Pipatvech, Piamlarp, Sangsayunh, Sibel, Arinc, Sermin, Borekci, Arzu Kaner Erturk, Filiz, Kosar, Hakan, Gunen, Ismail, Hanta, Pinar Akin Kabalak, Tunc Alp Demir, Sibel, Nayci, Serir Aktogu Ozkan, Abdullah, Sayiner, Esra, Uzaslan, Viktor, Blazhko, Volodymyr, Gavrysyuk, Olena, Golub, Liudmyla, Iashyna, Tetiana, Ilashchuk, Volodymyr, Koshlia, Olena, Krakhmalova, Vitali, Kryvenko, Lesia, Kuryk, Olena, Levchenko, Yuriy, Mostovoy, Mykola, Ostrovskyy, Tetyana, Pertseva, Olena, Piura, Nadiya, Rudnytska, Ganna, Stupnytska, Nataliia, Velychko, Oleh, Yakovenko, Lilia Rodriguez Ables, Roger, Abrahams, Jose, Alvarez, Fernando, Arencibia, Chander, Arora, Samir, Arora, Francis, Averill, Kwabena, Ayesu, Stephen, Basheda, Steven, Bauer, Jose, Bautista, Matthew, Beacom, Hernando, Bernal, Subodh, Bhuchar, J'Cinda, Bitters, John, Burk, Elizabeth, Burkett, James, Cain, Robert, Call, Christopher, Chappel, Bartolome, Celli, Tom, Christensen, Jeremy, Cole, Jerome, Daniel, Nguyen, Dang, Enrique, Davis, Samuel, Deleon, Robert, Deluca, Ernesto, Diaz, Anthony, Dimarco, Calvin, Dixon, Ankur, Doshi, Hugh, Durrence, Alain, Eid, John, Elsen, Herbon, Fleming, May, Flores, Scott, Franczek, Gregory, Funk, Stuart, Garay, Bernard, Garcia, Joseph, Graif, Carl, Griffin, Yamirka Duardo Guerra, David, Headley, Mitzie, Hewitt, Susan, Hole, Robert, Holladay, Ira, Horowitz, Yu-Luen, Hsu, Jonathan, Ilowite, Stephen, Jones, Ravindra, Kashyap, Edward, Kerwin, Ahtaram, Khan, Nicole, Kimzey, James, Krainson, Flory, Kreutter, Kannappan, Krishnaswamy, Shahrukh, Kureishy, Albert, Lai, Alex, Lechin, Daria, Lee, Marcus, Lee, Williams, Leeds, Joseph, Lillo, Edward, Lisberg, Lawrence, Madoff, Narendra, Maheskwari, Mujibur, Majumder, Sashi, Makam, Douglas, Mapel, Matthew, Mardiney, Jennifer, Martin, Isaac, Melamed, Elvin, Mendez, Stuart, Millstone, Joseph, Montes, Lee, Morrow, Frank, Murphy, Dany, Obeid, France, Occy, Godson, Oguchi, Juan, Ortiz, Francisco, Padron, Ward, Paine, James, Pearle, Enrique, Pelayo, Vandely, Perez, David, Pham, Carlos, Piniella, Kevin, Pritchett, Padmashri, Rastogi, Stephen, Ryan, Syed, Rehman, Jackson, Rhudy, Eustace, Riley, James, Riser, Clifford, Risk, Emory, Robinette, Christopher, Roney, Gary, Ruoff, David, Russian, Mercedes, Samson, Jay, Sandberg, Jose, Santiago, William, Sargeant, Alan, Schecter, Jeffrey, Scott, Ilia, Segal, Sudhir, Sehgal, Frederic, Seifer, Sudhir, Sekhsaria, Richard, Sellman, Paul, Shapero, Jeffrey, Shea, Lawrence, Sher, John, Sibille, Jawed, Siddiqui, Toniya, Singh, Deren, Sinkowitz, Denise, Smyth, Daniel, Soteres, Daniel, Sousa, Ralph, Steele, Thomas, Stern, Jose, Suarez, Sever, Surdulescu, Ricardo, Tan, Tonny, Tanus, Raymond, Tidman, Aurelio, Torres-Consuegra, Barry, Troyan, John, Updegrove, Sanjay, Vadgama, Armando, Pineda-Velez, Eduardo, Viera, Andrew, Wachtel, Ralph, Wade, Jimin, Wang, Dave, Webster, Paul, Weinberg, Terry, Wells, Jeffrey, White, Bram, Wieskopf, Hugh, Windom, Patrick, Wright, David, Wyatt, Bassam, Yousef, Zahid, Zafar, Chau, Ngo, Huong, Le, Lan, Nguyen, Thanh, Nguyen, Nhung, Nguyen, SALAS, Danielle, Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Harvard Medical School [Boston] (HMS), University of Leicester, University of Barcelona, Università degli Studi di Ferrara = University of Ferrara (UniFE), University of Manchester [Manchester], St. Paul’s Hospital - University of British Columbia [Vancouver, BC, Canada] (SPH-UBC), Philipps Universität Marburg = Philipps University of Marburg, University of Pittsburgh School of Medicine, University of Oxford, Bispebjerg University Hospital [Copenhagen, Denmark] (BUH), Kishiwada City Hospital [Osaka, Japan] (KCH), Instituto Nacional de Enfermedades Respiratorias [México, Mexico], I-Shou University [Kaohsiung, Taiwan] (ISU), Lund University [Lund], AstraZeneca [Gaithersburg, MD, USA] (AZ), Hypoxie et PhysioPathologie (HP2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), and Otto Burghuber, Bernhard Forstner, Gerhard Köberl, Bernd Lamprecht, Judith Löffler-Ragg, Horst Olschewski, Michael Studnicka, Francois Beaucage, Guy Chouinard, Anthony Dechant, Anthony Dowell, Jacques Hebert, Sohail Khattak, Kieran Killian, William Killorn, Andy Lam, Francois Maltais, Darcy Marciniuk, Lyle Melenka, Bonavuth Pek, Jeremy Road, Donald Sin, Alain Vaugeois, Brandie Walker, Tomas Dvorak, Stanislav Holub, Otakar Hokynar, Vitezslav Kolek, Daniela Kopecka, Jan Krepelka, Jaroslav Mares, Josef Veverka, Vladimir Zindr, Sabine Ballenberger, Rolf Dichmann, Christian Geßner, Margret Jandl, Claus Keller, Joachim Kirschner, Marc Kornmann, Petra Mikloweit, Ingomar Naudts, Axel Overlack, Isabelle Schenkenberger, Volker Schlegel, Lutz Von Versen, Claus Franz Vogelmeier, Stefan Zielen, István Albert, Beatrix Bálint, Mária Csilla Hangonyi, Teréz Kecskés, Anikó Kurucz, Balázs Medgyasszay, Lajos Molnár, János Mucsi, Márta Papp, Magdolna Póczi, Éva Radeczky, Zsolt Pápai Székely, Csilla Szabó, Gyöngyi Szabó, Melinda Szabó, Alfredo Antonio Chetta, Giuseppe Di Maria, Giulio Donazzan, Federica Meloni, Elisabetta Pace, Pierluigi Paggiaro, Alberto Papi, Fabio Luigi, Massimo Ricciardolo, Antonio Spanevello, Fumiaki Aoki, Ryosuke Eda, Takeo Endo, Yasushi Fukushima, Kenichi Gemba, Naoki Hagimoto, Hiromasa Harada, Yasuko Harada, Norihiko Hata, Osamu Hataji, Nobuo Hatakeyama, Takahiko Horiguchi, Gen Ideura, Motoyasu Iikura, Azusa Ikegami, Shirou Imokawa, Yoshikazu Inoue, Takeshi Isobe, Ryoji Ito, Susumu Iwata, Tadashi Kamei, Motokazu Kato, Hideki Katsura, Yuji Kawarada, Norio Kihara, Masaharu Kinoshita, Takashi Kinoshita, Tomoo Kishaba, Hideo Kita, Arihiro Kiyosue, Shigeru Komatsu, Kazuki Konishi, Sekiya Koyama, Makoto Kudo, Kazuhiko Machida, Hironi Makita, Hiroto Matsuse, Naoki Miyazawa, Hiroyuki Nakamura, Yuji Nakatani, Kazuyuki Nishimura, Takashi Nishimura, Junichi Ogawa, Hiroyuki Ohbayashi, Tetsuro Ohdaira, Tsukasa Ohnishi, Kazuhiko Oki, Masahiko Saito, Kenji Sakamoto, Osamu Sakamoto, Hisakuni Sekino, Noriharu Shijubo, Masaharu Shinkai, Hideo Soto, Yoshitaka Sugawara, Noriaki Suko, Hisaho Takahashi, Masamitsu Takahashi, Tsuneyuki Takahashi, Hiroshi Tanaka, Hiroyuki Taniguchi, Tadayuki Terada, Takao Tochigi, Kazuyo Tohyama, Hirokazu Tokuyasu, Keisuke Tomii, Tomomasa Tsuboi, Mitsuyoshi Utsugi, Katsumaru Yamamoto, Michiko Yamamoto, Shuichi Yano, Makoto Yoshida, Frank Custers, Richard Dekhuijzen, Remco Djamin, Jan Willem Van Dan Berg, Lowie Vanfleteren, Pascal Wielders, Bogusława Cimoszko, Anna Doboszyńska, Andrzej Dyczek, Andrzej Fal, Krystyna Folcik, Łukasz Goliński, Marek Jutel, Andrzej Kolczyński, Piotr Kuna, Ewa Łączyńska, Wojciech Machowiak, Maciej Marczak, Joanna Markiewicz, Janusz Milanowski, Grzegorz Mincewicz, Maria Nittner-Marszalska, Wojciech Papiewski, Małgorzata Pawlukiewicz, Witold Pomiećko, Barbara Rewerska, Cezary Rybacki, Wojciech Skucha, Ewa Trębas-Pietraś, Ewa Uhryn, Małgorzata Żurowska-Gębala, Laurentia Andrei, Traian Mihaescu, Stefan Mihaicuta, Eniko Vera Pall, Ioan Petrui, Angelica Savu, Claudia Toma, Ana Trailescu, Vladimir Abrosimov, Nataliya Astafyeva, Evgenyi Bazdyrev, Nadezhda Berdnikova, Laura Bolieva, Ekaterina Bukreeva, Valery Chistyakov, Anna Galustyan, Halida Gantseva, Svetlana Goncharova, Sergey Grigoriev, Galina Ignatova, Inna Ilyashevich, Nadezhda Izmozherova, Magomed Kamalov, Yaroslava Khovaeva, Natalia Kuzubova, Lyudmila Kvitkova, Liudmila Lenskaya, Igor Leshchenko, Olga Magnitskaya, Boris Molotilov, Artem Molotkov, Svetlana Myasoedova, Sergey Nedogoda, Vladimir Nosov, Marina Osipenko, Andrey Peskov, Veronika Popova, Oksana Ratushnay, Irina Ryzhova, Olga Shangina, Natalia Shaporova, Evgeny Shmelev, Lybov Shpagina, Alexander Shutkin, Yuri Shvarts, Mikhail Smirnov, Irina Stitsenko, Maksim Vasilev, Arkadiy Vertkin, Elena Vishneva, Alexander Vizel, Anna Zateyschikova, Mohamed Abdool-Gaffar, Ismail Abdullah, Axel Bruning, Nyda Fourie, Michael Greenblatt, Mohammed Tayob, K Venter, An Soo Jang, Kwan Ho Lee, Sang Haak Lee, Sook Young Lee, Suk Joong Yong, Kwang Ha Yoo, Soo Taek Uh, Ramón Agüero Balbín, David Ramos Barbón, Álvar Agustí García-Navarro, José Luis Velasco Garrido, Sergi Pascual Guardia, Eduard Monso Molas, Luis De Teresa Parreño, Borja García-Cosio Piqueras, German Peces-Barba Romero, Myriam Calle Rubio, Fernando Sánchez-Toril López, Alicia Marín Tapia, Heidi Martin Braschler, Martin Brutsche, Michael Grob, Jörg Leuppi, Daiana Stolz, Alexander Turk, Nawar Bakerley, Mona Bafadhel, Christopher Brightling, Rekha Chaudhuri, Gourab Choudhury, Graham Devereux, Imran Hussain, Kai Lee, William MacNee, Ravindran Mahadeva, Matthew Masoli, Monica Nordstrom, Manish Patel, Allan Reid, Dinesh Saralaya, Tariq Sethi, Sukh Dave Singh, Anthony G de Soyza, Tom Wilkinson, Alice Turner, Helen Ward, Chandar Abboy, Ivan Ackerman, Idalia Acosta, Arun Adlakha, Bassil Aish, Mohamed Ali, Charles Andrews, Robby Ayoub, Anil Badhwar, Dennis Bassetti, Sherif El Bayadi, Richard Beasley, Shashi Bellam, Jonathan Bernstein, Maria Blahey, Scott Bloom, Eugene Bleecker, Wesley Bray, Johnathan Brewer, Robert Buynak, William Calhoun, Edward Campbell, Anthony Captain, Birjis Chinoy, Kenneth Chinsky, Geoffrey Chupp, Arsenio Columbie, Clinton Corder, Gerard Criner, Humberto Cruz, Edward Cullen, Kevin Deboer, Michael Denenberg, Mark Dransfield, Leonard Dunn, Miles Elmore, David Erb, Faisal Fakih, Gary Ferguson, Charles Fogarty, Mark Freed, Stephen Fritz, David Fuentes, Shariar Cohen-Gadol, Robert Garver, John Given, Luis Ramos Gonez, Raul Ebran Gonzalez, Robert Gordon, Gregory Gottschlich, Donald Graham, David Grant, Gary Greenwald, James Greenwald, Kenneth Haft, Gregory Hammond, Nadia Hansel, Jeffrey Harris, Humberto Hernandez, Marvin Heuer, Albrecht Heyder, David Hill, Willis Holloway, Octavian Ioachimescu, Richard Jackson, Ajay Jain, Nan Jiang, Thomas Kaelin, Adolfo Kaplan, Mitchell Kaye, Akram Khan, Yekaterina Khronusova, Ryan Klein, Joel Kline, Firas Koura, Ritsu Kuno, Ware Kuschner, Jean Claude Labissiere, David Laman Jr, John Lee, Mitchell Lee, Lawrence Levinson, Njira Lugogo, M Mador, Nathaniel Marchetti, Rafael Martinez, Richard Martinez, Peter Mattar, David Maybee, Dennis McGraw, Michael McGuire, Curtis Mello, Aaron Milstone, John Mitchell, Wendy Moore, Timothy Moriarty, Cheta Nand, Brooke Nevins, Ikeadi Ndukwu, Rachel Nisbet, David Nyanjom, Maria Nualart, Thomas O'Brien, Mikhail Palatnik, Gnyandev Patel, Amit Patel, Guido Perez, Christopher Perry, Michael Pfeffer, Krishna Pudi, Marina Raikhel, Murali Ramaswamy, Joe Ramsdell, Donato Ricci, Gary Richmond, Eugene Ryan, Fadi Saba, Boris Sagalovich, C Andrew Schroeder, Timothy Scialla, Frank Sciurba, Amit Shah, Nirav Shah, Zeeshan Shaikh, Akhtar Siddiqui, Barry Sigal, Thomas Siler, Howard Silverboard, William Sims, Clyde Southwell, Selwyn Spangenthal, Peruvemba Sriram, James Stocks, Tony Su, John Suen, Robert Sussman, Horia Tatu, Antonio Terrelonge, Alan Thomas, Mario Torres, Rodolfo Trejo, Miguel Trevino, Banks Turner, Manuel Villareal, Janine Vintch, Neal Warshoff, Jan Westerman, Philip Wexler, Thomas Yunger, Amir Zeki, Mariano Fernandez Acquier, Norma Aramayo, German Arce, Juan Belloni, Víctor Cambursano, Carlos De La Vega, Fernando Rodriguez Chariarse, Pedro Elias, Marcelo Fernández, Ana Lopez, Andrea Medina, María Otaola, Maria Salazan Saez, Maria De Salvo, Fernando Scherbovsky, Ana Stok, Jorge Taborda, Alberto Tolcachier, Fernando Verra, Carlos Victorio, Rita Gisela Delgado Vizcarra, Philip Bardin, Peter Bremner, Martin Phillips, John Upham, Peter Wark, Antoine Bolly, Alain Delobbe, Peter Driesen, Eduard Janssens, Wim Janssens, Olivier Michel, Bernard Vandooren, Martti Antila, Jussara Fiterman, Carlos Fritscher, Jorge Hetzel, Jose Jardim, Waldo De Mattos, Rafael Martins, Maria Eunice De Oliveira, Andreia Pez, Maria Sales, Rafael Stelmach, Priscila Wolff, Svetla Andreeva, Reneta Antonova, Ana Dancheva, Yuliya Ivanova, Slavcho Ivanov, Hristo Metev, Iveta Naydenova, Tatyana Petkova, Galina Petrova, Kostadinka Sotirova, Mariyana Stoyanova, Rumen Tiholov, Iliyana Valkanova, Oleg Yakov, Rosa Feijoo, Juana Pavie, Patricia Schönffeldt, Absalon Silva, Victor Martinez, David Espinosa, Alejandro Londono, Dora Molina, Gonzalo Prada, Andrés Rico, Gregorio Sanchez Vallejo, Alvaro Urbina, Ana Vanegas, Maria Villegas, Josip Aralica, Gordana Stjepanovic, Vibeke Backer, Uffe Bødtger, Christian Meyer, Læge Sven Nielsen, Anders Loekke Ottesen, Ingrid Titlestad, Nathalie Bautin, Arnaud Bourdin, Pascal Chanez, Francis Couturaud, Antoine Cuvelier, Gilles Devouassoux, Pierre-Olivier Girodet, Jean-François Muir, Jean-Louis Pépin, Alain Proust, Azzedine Yaici, Yochai Adir, Gershon Fink, Zvi Fridlender, Gabriel Izbicki, Mordechai Kramer, Yehuda Schwartz, Juan Moreno Hoyos Abril, Ricardo Campos Cerda, Efraín Montaño Gonzalez, Ricardo Ramirez Terrones, Rodolfo Posadas Valay, Alejandra Ramirez-Venegas, Paul Dawkins, Syed Hussain, Benedict Brockway, John Richmond, Colin Helm, Catherina Chang, Jørn Ahlqvist, Terje Tollåli, Tadeusz Tomala, Socorro Castro, William Chavez, Octavio Cubas, Rolando Estrella, Efrain Felix, Ronal Gamarra, Alfredo Guerreros, Alberto Matsuno, Danilo Salazar, Miguel Tsukayama, Albert Albay Jr, Teresita Aquino, Tito Atienza, Joven Roque Gonong, Ronnie Samoro, Joel Santiaguel, Beata Asankowicz-Bargiel, Ewa Pisarczyk-Bogacka, Renata Bijata-Bronisz, Marta Chełmińska, Małgorzata Dobryniewska, Anna Olech-Cudzik, Tomasz Fijołek, Krzysztof Filipek, Agata Kot, Bożena Kucińska, Krzysztof Lis, Elżbieta Rybicka-Liszewska, Marzenna Tarnowska-Matusiak, Robert Mróz, Piotr Napora, Wojciech Naumnik, Artur Niemiec, Władysław Pierzchała, Grzegorz Przybylski, Katarzyna Styka, Danuta Wrońska, Branislava Milenkovic, Dobrivoje Novkovic, Matijaz Flezar, Niksa Segota, Snezana Ulcar Kostic, Albert Klobucar, Leif Bjermer, Dan Curiac, Christer Janson, Pekka Koskinen, Bo Lundback, Åke Olsson, Shih-Lung Cheng, Ming-Lin Ho, Jeng-Yuan Hsu, Wu-Huei Hsu, Ping-Hung Kuo, Chin-Chou Wang, Yu-Feng Wei, Kuang-Yao Yang, Watchara Boonsawat, Somchai Chantarothorn, Warangkana Keeratichananont, Kittipong Maneechotesuwan, Kanok Pipatvech, Piamlarp Sangsayunh, Sibel Arinc, Sermin Borekci, Arzu Kaner Erturk, Filiz Kosar, Hakan Gunen, Ismail Hanta, Pinar Akin Kabalak, Tunc Alp Demir, Sibel Nayci, Serir Aktogu Ozkan, Abdullah Sayiner, Esra Uzaslan, Viktor Blazhko, Volodymyr Gavrysyuk, Olena Golub, Liudmyla Iashyna, Tetiana Ilashchuk, Volodymyr Koshlia, Olena Krakhmalova, Vitali Kryvenko, Lesia Kuryk, Olena Levchenko, Yuriy Mostovoy, Mykola Ostrovskyy, Tetyana Pertseva, Olena Piura, Nadiya Rudnytska, Ganna Stupnytska, Nataliia Velychko, Oleh Yakovenko, Lilia Rodriguez Ables, Roger Abrahams, Bassil Aish, Jose Alvarez, Fernando Arencibia, Chander Arora, Samir Arora, Francis Averill, Kwabena Ayesu, Stephen Basheda, Steven Bauer, Jose Bautista, Matthew Beacom, Richard Beasley, Hernando Bernal, Subodh Bhuchar, J'Cinda Bitters, John Burk, Elizabeth Burkett, James Cain, Robert Call, Christopher Chappel, Bartolome Celli, Tom Christensen, Jeremy Cole, Jerome Daniel, Nguyen Dang, Enrique Davis, Samuel Deleon, Robert DeLuca, Ernesto Diaz, Anthony DiMarco, Calvin Dixon, Ankur Doshi, Hugh Durrence, Alain Eid, John Elsen, Herbon Fleming, May Flores, Charles Fogarty, Scott Franczek, Stephen Fritz, Gregory Funk, Stuart Garay, Bernard Garcia, Luis Ramos Gonez, Gregory Gottschlich, Joseph Graif, Carl Griffin, Yamirka Duardo Guerra, David Headley, Mitzie Hewitt, Susan Hole, Robert Holladay, Ira Horowitz, Yu-Luen Hsu, Jonathan Ilowite, Stephen Jones, Ravindra Kashyap, Edward Kerwin, Ahtaram Khan, Nicole Kimzey, James Krainson, Flory Kreutter, Kannappan Krishnaswamy, Shahrukh Kureishy, Albert Lai, Alex Lechin, Daria Lee, Marcus Lee, Williams Leeds, Joseph Lillo, Edward Lisberg, Lawrence Madoff, Narendra Maheskwari, Mujibur Majumder, Sashi Makam, Douglas Mapel, Matthew Mardiney, Jennifer Martin, David Maybee, Isaac Melamed, Elvin Mendez, Stuart Millstone, Joseph Montes, Lee Morrow, Frank Murphy, Dany Obeid, France Occy, Godson Oguchi, Juan Ortiz, Francisco Padron, Ward Paine, James Pearle, Enrique Pelayo, Vandely Perez, David Pham, Carlos Piniella, Kevin Pritchett, Padmashri Rastogi, Stephen Ryan, Syed Rehman, Jackson Rhudy, Eustace Riley, James Riser, Clifford Risk, Emory Robinette, Christopher Roney, Gary Ruoff, David Russian, Mercedes Samson, Jay Sandberg, Jose Santiago, William Sargeant, Alan Schecter, Frank Sciurba, Jeffrey Scott, Ilia Segal, Sudhir Sehgal, Frederic Seifer, Sudhir Sekhsaria, Richard Sellman, Paul Shapero, Jeffrey Shea, Lawrence Sher, John Sibille, Jawed Siddiqui, William Sims, Toniya Singh, Deren Sinkowitz, Denise Smyth, Daniel Soteres, Daniel Sousa, Ralph Steele, Thomas Stern, Jose Suarez, Sever Surdulescu, Ricardo Tan, Tonny Tanus, Raymond Tidman, Aurelio Torres-Consuegra, Barry Troyan, John Updegrove, Sanjay Vadgama, Armando Pineda-Velez, Eduardo Viera, Andrew Wachtel, Ralph Wade, Jimin Wang, Dave Webster, Paul Weinberg, Terry Wells, Jeffrey White, Bram Wieskopf, Hugh Windom, Patrick Wright, David Wyatt, Bassam Yousef, Zahid Zafar, Chau Ngo, Huong Le, Lan Nguyen, Thanh Nguyen, Nhung Nguyen
Subjects: Male, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Anti-asthmatic Agent, law.invention, Pulmonary Disease, Chronic Obstructive, Leukocyte Count, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Monoclonal, Receptors, Medicine, Anti-Asthmatic Agents, 030212 general & internal medicine, Humanized, COPD Exacerbations, benralizumab, clinical trials, COPD, Subcutaneous, General Medicine, Middle Aged, anti–IL-5Rα, Benralizumab, Pulmonary Disease, Chronic Obstructive/drug therapy, [SDV] Life Sciences [q-bio], Female, Antibodies, Monoclonal, Humanized/administration & dosage, Chronic Obstructive, Benralizumab COPD exacerbations, Injections, Subcutaneous, Socio-culturale, Aged, Antibodies, Monoclonal, Humanized, Double-Blind Method, Eosinophils, Humans, Patient Acuity, Receptors, Interleukin-5, Antibodies, chronic obstructive pulmonary disease, Injections, Pulmonary Disease, 03 medical and health sciences, Phase III, Anti-Asthmatic Agents/administration & dosage, In patient, business.industry, Eosinophils/metabolism, medicine.disease, Clinical trial, Receptors, Interleukin-5/antagonists & inhibitors, chemistry, Multicenter study, randomized controlled trial, Immunology, Interleukin-5, business
Abstract: BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).
Published: 2019
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32. Efficacy of FF/UMEC/VI compared with FF/VI and UMEC/VI in patients with COPD: subgroup analysis of the Spain cohort in IMPACT

Author: José M Echave-Sustaeta, C. Elaine Jones, Beatriz Velasco, Sergi Pascual-Guardia, Sally Kilbride, José M Marín, Juan Roldán, Luis Mateos, David A. Lipson, and Maria V Pardo
Subjects: Male, Quinuclidines, Time Factors, law.invention, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Glucocorticoid, Randomized controlled trial, law, Medicine, Pharmacology (medical), 030212 general & internal medicine, Lung, Original Research, Aged, 80 and over, COPD, biology, LAMA, Middle Aged, Lama, Bronchodilator Agents, Drug Combinations, Treatment Outcome, Cohort, Disease Progression, Female, Randomized clinical trial, medicine.drug, Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, LABA, Subgroup analysis, Chronic obstructive pulmonary disease (COPD), Muscarinic Antagonists, Chlorobenzenes, Fluticasone propionate, 03 medical and health sciences, Double-Blind Method, Internal medicine, Administration, Inhalation, Humans, In patient, Triple therapy, Glucocorticoids, Benzyl Alcohols, Aged, lcsh:RC705-779, business.industry, Nebulizers and Vaporizers, Inhaler, Recovery of Function, lcsh:Diseases of the respiratory system, medicine.disease, biology.organism_classification, Androstadienes, 030228 respiratory system, Spain, business
Abstract: Objectives: The IMPACT trial has compared the benefit in the reduction of moderate/severe exacerbations of single inhaler triple therapy (SITT) with fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus dual therapy with FF/VI (ICS/LABA) and UMEC/VI (LAMA/LABA) in the treatment of patients with chronic obstructive disease (COPD). This study performs a subgroup analysis of the cohort from Spain in the IMPACT study. Materials and Methods: In IMPACT, a 52-week randomized, double-blind, parallel-group, multicenter study ( N = 10,355), patients ⩾40 years of age with COPD and ⩾1 moderate/severe exacerbations in the previous year were randomized 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg or UMEC/VI 62.5/25 µg administered via the Ellipta inhaler. Here, we present a subgroup analysis of the 499 patients from Spain, included in the intent-to-treat (ITT) population in the study. Endpoint assessed included exposure-adjusted rate of moderate and severe exacerbations. Results: In the Spain cohort, the exposure-adjusted rate of on-treatment moderate/severe COPD exacerbations per year for FF/UMEC/VI was 1.31 versus 1.43 and 1.57 for FF/VI and UMEC/VI, respectively. No new adverse events were identified. The results are consistent with those observed in the overall ITT study population. Conclusion: In the Spain cohort of the IMPACT study, patients receiving triple therapy with FF/UMEC/VI had a lower exposure-adjusted rate of exacerbations compared with FF/VI and UMEC/VI, similar to the overall population. Study Title: A Phase III, 52 Week, Randomized, Double-blind, 3-arm Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination FF/UMEC/VI With the Fixed Dose Dual Combinations of FF/VI and UMEC/VI, All Administered Once-daily in the Morning Via a Dry Powder Inhaler in Subjects With Chronic Obstructive Pulmonary Disease URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=CTT116855/ https://clinicaltrials.gov/ct2/show/NCT02164513 Registration number: GSK (CTT116855/NCT02164513). The reviews of this paper are available via the supplemental material section.
Published: 2020

33. Adaptive NKG2C+ Natural Killer Cells Increase in COPD Patients with Frequent Exacerbations

Author: Joaquim Gea, Miguel López-Botet, José Yélamos, I. Ramirez-Martinez, and Sergi Pascual-Guardia
Subjects: medicine.medical_specialty, business.industry, Copd patients, Internal medicine, Medicine, business
Published: 2019
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34. Correction to: Bacterial etiology of community-acquired pneumonia in immunocompetent hospitalized patients and appropriateness of empirical treatment recommendations: an international point-prevalence study

Author: Francesco Blasi, Martin Kolditz, Gerrit Woltmann, Thomas Holland, Gundi Steinhilber, Giuseppe Fiorentino, Roberta Petrino, Sergi Pascual-Guardia, Claudio Sorino, Pedro J Marcos, Chesov Ion, and Piero Ceriana
Subjects: Microbiology (medical), Infectious Diseases, General Medicine
Published: 2021
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35. 2019 ATS/IDSA CRITERIA TO IDENTIFY P. AERUGINOSA AND MRSA PROMOTE OVERUTILIZATION OF MRSA THERAPY IN NON-SEVERE CAP

Author: Francesco Blasi, Sergi Pascual-Guardia, Judith Marin-Corral, Stefano Aliberti, Marcos I. Restrepo, Francesco Amati, and Alexander Shaffer
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Internal medicine, Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, business
Published: 2020
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36. Bispectral index in hypercapnic encephalopathy associated with COPD exacerbation: a pilot study

Author: Joaquim Gea, Lluís Gallart, Sergi Pascual-Guardia, Roberto Chalela, Mauricio Orozco-Levi, and Antonio Sancho-Muñoz
Subjects: Male, Exacerbation, Conscious Sedation, Pilot Projects, Severity of Illness Index, Hypercapnia, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Level of consciousness, exacerbation, 030202 anesthesiology, hypercapnic encephalopathy, Prospective Studies, Original Research, COPD, Brain Diseases, Gypercapnic encephalopathy, Electroencephalography, General Medicine, Middle Aged, Prognosis, Hypercapnic encephalopathy, Treatment Outcome, Bispectral index, Anesthesia, Disease Progression, Female, Emergency Service, Hospital, Encephalopathy, International Journal of Chronic Obstructive Pulmonary Disease, Risk Assessment, 03 medical and health sciences, Consciousness Monitors, medicine, bispectral index, Humans, Glasgow Coma Scale, Aged, Monitoring, Physiologic, business.industry, medicine.disease, Intensity (physics), Early Diagnosis, Copd exacerbation, Case-Control Studies, business, 030217 neurology & neurosurgery
Abstract: Background Hypercapnic encephalopathy is relatively frequent in severe exacerbations of COPD (ECOPDs), with its intensity usually being evaluated through clinical scales. Bispectral index (BIS) is a relatively new technique, based on the analysis of the electroencephalographic signal, which provides a good approximation to the level of consciousness, having already been validated in anesthesia. Objective The objective of the study was to evaluate the utility of BIS in the assessment of the intensity of hypercapnic encephalopathy in ECOPD patients. Patients and methods A total of ten ECOPD patients were included, and the level of brain activity was assessed using BIS and different scales: Glasgow Coma Scale, Ramsay Sedation Scale (RSS), and Richmond Agitation–Sedation Scale. The evaluation was performed both in the acute phase and 3 months after discharge. Results BIS was recorded for a total of about 600 minutes. During ECOPD, BIS values ranged from 58.8 (95% CI: 48.6–69) for RSS score of 4 to 92.2 (95% CI: 90.1–94.3) for RSS score of 2. A significant correlation was observed between values obtained with BIS and those from the three scales, although the best fit was for RSS, followed by Glasgow and Richmond (r=−0.757, r=0.701, and r=0.615, respectively; P, Video abstract
Published: 2018

37. VENTILATOR-INDUCED DIAPHRAGM DYSFUNCTION IN BRAIN-DEAD AND MAASTRICHT III DONORS

Author: Lluis Cecchini, A. Zapatero, Irene Dot Jordana, Joan R. Masclans, Claravila Vilardell, Judith Marin Corral, Andrea Castellví, M Pilar Gracia Arnillas, Yolanda Diaz, Sergi Pascual-Guardia, Judit Boncompte Torres, and Marina Boguñá
Subjects: Pulmonary and Respiratory Medicine, Brain dead, medicine.medical_specialty, business.industry, Internal medicine, Cardiology, Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, business, Diaphragm (structural system)
Published: 2018
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38. EGFR and KRAS Mutations in the Non-Tumoral Lung. Prognosis in Patients with Adenocarcinoma

Author: Edurne Arriola, Diana Badenes-Bonet, Lara Pijuan, Albert Sánchez-Font, Víctor Curull, Sergi Pascual-Guardia, Joaquim Gea, Beatriz Bellosillo, Raquel Longarón, and Roberto Chalela
Subjects: medicine.medical_specialty, EGFR, lcsh:Medicine, Adenocarcinoma, medicine.disease_cause, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Parenchyma, KRAS, Medicine, In patient, Carcinogen, 030304 developmental biology, 0303 health sciences, Lung, Proportional hazards model, business.industry, lcsh:R, Confounding, General Medicine, Prognosis, medicine.disease, medicine.anatomical_structure, 030220 oncology & carcinogenesis, business, Mutations
Abstract: Tumor recurrence is frequent and survival rates remain extremely low in lung adenocarcinoma (ADC). We hypothesize that carcinogenic factors will promote loco-regional modifications not only in the future tumor, but throughout the exposed lung. Objective: To analyze whether the most prevalent mutations observed in ADC can also be observed in the non-neoplastic lung tissue, as well as the short-term prognosis implications of this finding. Methods: Non-tumoral lung parenchyma specimens obtained during surgery from 47 patients with EGFR and/or KRAS abnormalities in their ADC tumors underwent similar genomic testing. Short-term outcomes were also recorded. Results: The same mutations were present in the tumor and the histologically normal tissue in 21.3% of patients (SM group). Although local recurrences were similar in both groups, distant metastases were more frequent in the former (60 vs. 5.4%, p &lt, 0.001). Moreover, SM patients showed lower time-to-progression (8.5 vs. 11.7 months, p &lt, 0.001) and disease-free survival (8.5 vs. 11.2 months, p &lt, 0.001). COX regression showed a higher risk of progression or death (DFS) in the SM group (HR 5.94, p &lt, 0.01]. Similar results were observed when adjusting for potential confounding variables. Conclusions: These results confirm that genetic changes are present in the apparently normal lung in many ADC patients, and this finding has prognostic implications.
Published: 2019
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39. Diagnosis of Pulmonary Infarction by Thoracic Ultrasonography

Author: Sergi Pascual-Guardia, María Pilar Ausin-Herrero, and Enric Ripoll-Fuster
Subjects: General Medicine
Published: 2018
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40. Redox Balance and Carbonylated Proteins in Limb and Heart Muscles of Cachectic Rats

Author: Esther Barreiro, Francisco J. López-Soriano, Sílvia Busquets, Mireia Olivan, Josep M. Argilés, Cibely C. Fontes, Sergi Pascual-Guardia, Judith Marin-Corral, and Francisco Sanchez
Subjects: Electrophoresis, Male, medicine.medical_specialty, Cachexia, Physiology, Protein Carbonylation, Immunoblotting, Clinical Biochemistry, Oxidative phosphorylation, Protein oxidation, Biochemistry, chemistry.chemical_compound, Malondialdehyde, Internal medicine, medicine, Animals, Electrophoresis, Gel, Two-Dimensional, Glycolysis, Rats, Wistar, Muscle, Skeletal, Molecular Biology, General Environmental Science, Chemistry, Myocardium, Cell Biology, Metabolism, medicine.disease, Immunohistochemistry, Rats, Endocrinology, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, General Earth and Planetary Sciences, medicine.symptom, Oxidation-Reduction, Muscle contraction
Abstract: In fast- and slow-twitch limb and heart muscles of cachectic rats, redox balance and muscle structure were explored. The nature of the oxidatively modified proteins also was identified in these muscles. Reactive carbonyls, hydroxynonenal (HNE)- and malondialdehyde (MDA)-protein adducts, and antioxidant enzyme levels were determined in limb and heart muscles of cachectic (7 days after inoculation of Yoshida AH-130 ascites hepatoma) and control rats. Moreover, carbonylated proteins were identified (proteomics), and fiber-type composition evaluated (morphometry) in these muscles. In cachectic rats, compared with the controls: (a) HNE- and MDA-protein adducts levels were greater in gastrocnemius, tibialis anterior, soleus, and heart; (b) in the gastrocnemius, type II fiber size was reduced, and the intensity of carbonylated protein immunostaining was significantly greater in these fibers; and (c) proteins involved in glycolysis, ATP production and distribution, carbon dioxide hydration, muscle contraction, and mitochondrial metabolism were significantly more carbonylated in limb and heart muscles. Cancer cachexia alters redox balance in fast- and slow-twitch limb and heart muscles of rats, inducing increased oxidative modifications of key proteins involved in muscle structure and function. Additionally, it induces a reduction in type II fiber size in the gastrocnemius, which is associated with increased protein oxidation.
Published: 2010
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41. Antibiotic Prescription for COPD Exacerbations Admitted to Hospital: European COPD Audit

Author: José Luis López-Campos Bodineau, EYLEM SERCAN OZGUR, DOLORES CORBACHO, Christopher Roberts, and Sergi Pascual-Guardia
Subjects: Spirometry, medicine.medical_specialty, Multivariate analysis, Exacerbation, medicine.drug_class, Antibiotics, lcsh:Medicine, Audit, Pulmonary Disease, Chronic Obstructive, Drug Utilization Review, Patient Admission, medicine, Humans, Medical prescription, Intensive care medicine, lcsh:Science, COPD, Medical Audit, Multidisciplinary, medicine.diagnostic_test, business.industry, lcsh:R, medicine.disease, Anti-Bacterial Agents, Europe, lcsh:Q, business, Research Article
Abstract: Objective Appropriate use of antibiotics in the management of hospitalised patients with COPD exacerbations is defined within the GOLD strategy. This paper analyses the factors associated with antibiotic prescribing in patients to better understand how prescribing may be improved. Methods The European COPD audit was a study of clinical care in 384 hospitals from 13 European countries between 2010 and 2011 enrolling 16018 patients. Those admitted to hospital due to a clinician-made diagnosis of exacerbation of COPD at the time of discharge were audited. We defined antibiotic prescribing compliance as consistent with the GOLD 2010 recommendations. Two different multivariate models were used to evaluate factors associated with the prescription of antibiotics and the guideline-compliant prescriptions. Results Overall 86% of admissions were given antibiotics but only 61.4% cases met the GOLD recommendations. Antibiotics were more likely to be given in hospital and at discharge if received prior to admission. Antibiotic prescription was more likely in patients who met the GOLD recommendations and in those with radiological consolidation but there was also a significant use of antibiotics in patients who did not meet either criterion. Patients cared for on a Respiratory Ward were more likely to receive GOLD compliant antibiotic management. Conclusions The present study describes the audited in-hospital antibiotic prescription for COPD exacerbation across different European countries. In general, there is an apparent overuse of antibiotics likely to be associated with both patient and practice-related variables.
Published: 2015

42. Redox Balance and Carbonylated Proteins in Limb and Heart Muscles of Cachectic Rats.

Author: Judith Marin-Corral, Cibely C. Fontes, Sergi Pascual-Guardia, Francisco Sanchez, Mireia Olivan, Josep M. ArgilÃ©s, SÃlvia Busquets, Francisco J. LÃ³pez-Soriano, and Esther Barreiro
Published: 2010
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43. Clinical audit of COPD patients requiring hospital admissions in Spain: AUDIPOC Study

Author: Manuel Angel Villanueva, Anabel Forte, Maria Teresa Rio, Manuel Valle, José Luis López-Campos Bodineau, CRISTOBAL ESTEBAN, Víctor Abraira, Ferran Barbé, Cristina Represas-Represas, DOLORES CORBACHO, RUTH AYERBE GARCIA, Tomás Ruiz Albi, Nisa Boukichou Abdelkader, Beatriz Abascal-Bolado, Inmaculada Alfageme, Bernardino Alcázar-Navarrete, Jesus R. Hernandez Hernandez, Piedad Ussetti, Jose Antonio Cascante, Sergi Pascual-Guardia, Virginia Leiro-Fernández, Virginia Pajares, Paola Lisseth Ordóñez Gómez, Pedro J Marcos, Adolfo Doménech del Río, ALBERTO FERNANDEZ-VILLAR, Alvar Agusti Garcia-Navarro, José Antonio Gullón, Juan José Soler-Cataluña, Lourdes Cañón-Barroso, Rubén Andújar-Espinosa, Luis Borderias, Marta Garcia Clemente, Borja G Cosio, Universitat de Barcelona, AUDIPOC Study Group, [Pozo-Rodríguez,F, Álvarez-Martínez,CJ, Castro-Acosta,A] Instituto de Investigación, Hospital 12 de Octubre, Madrid Spain. [Pozo-Rodríguez,F, López-Campos,JL, Castro-Acosta,A, Cosío,BG, Agustí,A] Centre for Biomedical Research on Respiratory Diseases (CIBERES). Instituto de Salud Carlos III, Madrid,Spain. [López-Campos,JL] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Seville, Spain. [Agüero,J] Hospital Universitario Marqués de Valdecilla, Santander, Spain. [Hueto,J] Complejo Hospitalario de Navarra, Pamplona, Spain. [Hernández-Hernández,J] Hospital Nuestra Sra. de Sonsoles, Ávila, Spain. [Barrón,M] Complejo Hospitalario San Millán, Logroño, Spain. [Abraira,V] Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain. Centre for Biomedical Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain. [Forte,A] Department of Statistics and Operational Research, Universidad de Castellón, Castellón, Spain. [Sanchez Nieto,JM] Hospital Universitario Morales Meseguer, Murcia, Spain. [Lopez-Gabaldón,E] Hospital Virgen de la Salud, Toledo, Spain. [Cosío,BJ] Hospital Universitario Son Espases, Balearic Island, Spain. [Agustí,A] Instituto del Tórax, Hospital Clínic, Barcelona, Spain., and Fondo de Investigación Sanitaria (FIS), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI 08/90129, PI 90486, PI08/90578, PI 07/90503, PI 08/90251, PI 07/90516, PI 08/90529, PI 07/90309, PI 08/90457, PI 08/90129, PI 07/90721, PI 08/90550, PI08/90447, PI07/90403, PI 08/90486), Spanish Respiratory Society (SEPAR) and CIBER de Enfermedades Respiratorias (CIBERES).
Subjects: Clinical audit, auditoría clínica, Spatial Epidemiology, Exacerbation, Non-Clinical Medicine, Pulmonology, Chronic Obstructive Pulmonary Diseases, Epidemiology, humanos, España, Psychological intervention, Hospitalización, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Pulmonary Disease, Chronic Obstructive, análisis de regresión, guías de práctica clínica como asunto, Guías de Práctica Clínica como Asunto, Clinical Epidemiology, Análisis Multivariante, Malalties pulmonars obstructives cròniques, Análisis de Regresión, Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Hospitals [Medical Subject Headings], Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], COPD, education.field_of_study, Multidisciplinary, Mortality rate, Adhesión a Directriz, Hospitals, Humanos, Hospitalization, Practice Guidelines as Topic, Regression Analysis, Medicine, Health Care::Health Care Quality, Access, and Evaluation::Quality Assurance, Health Care::Guidelines as Topic::Practice Guidelines as Topic [Medical Subject Headings], Guideline Adherence, Health Services Research, Health Care::Health Care Facilities, Manpower, and Services::Health Services::Patient Care::Hospitalization [Medical Subject Headings], teorema de Bayes, Research Article, medicine.medical_specialty, Science, Auditoría Clínica, Health Care::Health Services Administration::Quality of Health Care::Guideline Adherence [Medical Subject Headings], Population, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Analysis of Variance::Multivariate Analysis [Medical Subject Headings], MEDLINE, Health Informatics, Audit, medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Bayes Theorem [Medical Subject Headings], Humans, hospitalización, Teorema de Bayes, Diseases::Respiratory Tract Diseases::Lung Diseases::Lung Diseases, Obstructive::Pulmonary Disease, Chronic Obstructive [Medical Subject Headings], análisis multifactorial, Espanya, Chronic obstructive pulmonary diseases, Intensive care medicine, education, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Regression Analysis [Medical Subject Headings], Health Care Policy, Clinical Audit, Auditoria, business.industry, Enfermedad Pulmonar Obstructiva Crónica, Health Services Administration and Management, Smoking Related Disorders, Bayes Theorem, Auditing, medicine.disease, Social Epidemiology, Survey Methods, Spain, Multivariate Analysis, Health Care::Health Services Administration::Quality of Health Care::Quality Assurance, Health Care::Clinical Audit [Medical Subject Headings], Health Statistics, business
Abstract: Backgrounds: AUDIPOC is a nationwide clinical audit that describes the characteristics, interventions and outcomes of patients admitted to Spanish hospitals because of an exacerbation of chronic obstructive pulmonary disease (ECOPD), assessing the compliance of these parameters with current international guidelines. The present study describes hospital resources, hospital factors related to case recruitment variability, patients' characteristics, and adherence to guidelines. Methodology/Principal Findings: An organisational database was completed by all participant hospitals recording resources and organisation. Over an 8-week period 11,564 consecutive ECOPD admissions to 129 Spanish hospitals covering 70% of the Spanish population were prospectively identified. At hospital discharge, 5,178 patients (45% of eligible) were finally included, and thus constituted the audited population. Audited patients were reassessed 90 days after admission for survival and readmission rates. A wide variability was observed in relation to most variables, hospital adherence to guidelines, and readmissions and death. Median inpatient mortality was 5% (across-hospital range 0-35%). Among discharged patients, 37% required readmission (0-62%) and 6.5% died (0-35%). The overall mortality rate was 11.6% (0-50%). Hospital size and complexity and aspects related to hospital COPD awareness were significantly associated with case recruitment. Clinical management most often complied with diagnosis and treatment recommendations but rarely (, This work was supported by Fondo de Investigacion Sanitaria (FIS), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion (PI 08/90129, PI 90486, PI08/90578, PI 07/90503, PI 08/90251, PI 07/90516, PI 08/90529, PI 07/90309, PI 08/90457, PI 08/90129, PI 07/90721, PI 08/90550, PI08/90447, PI07/90403, PI 08/90486), Spanish Respiratory Society (SEPAR) and CIBER de Enfermedades Respiratorias (CIBERES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

44. The phosphodiesterase-4 inhibitor roflumilast reverts proteolysis in skeletal muscle cells of patients with COPD cachexia

Author: Esther Barreiro, Ester Puig-Vilanova, Anna Salazar-Degracia, Carme Casadevall, Joaquim Gea, and Sergi Pascual-Guardia
Subjects: 0301 basic medicine, Cyclopropanes, Male, medicine.medical_specialty, Physiology, Proteolysis, Muscle Fibers, Skeletal, Aminopyridines, Muscle Proteins, COPD-induced muscle wasting, Cachexia, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, Physiology (medical), Internal medicine, Myosin, Gene expression, Antioxidant defense, medicine, Autophagy, Humans, Muscle, Skeletal, Roflumilast, COPD, Muscle Weakness, Myosin heavy chain myotubes, medicine.diagnostic_test, Myogenesis, business.industry, Skeletal muscle, Middle Aged, medicine.disease, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Cross-Sectional Studies, Case-Control Studies, Benzamides, Female, Phosphodiesterase 4 Inhibitors, business, Biomarkers, medicine.drug
Abstract: Peripheral muscle weakness and mass loss are characteristic features in severe chronic obstructive pulmonary disease (COPD). We hypothesized that the phosphodiesterase (PDE)-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 μM roflumilast N-oxide (RNO) for three time cohorts (1, 6, and 24 h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting. In COPD patients at 6 h RNO treatment, myotube tyrosine release, total protein ubiquitination, and tripartite motif-containing protein 32 levels were significantly lower than healthy controls, whereas at 24 h RNO treatment, myotube myosin heavy chain ( MyHC) -I and MyHC-IIx expression levels were upregulated in both patients and controls. In the 6-h RNO cohort, in patients and controls, myotube expression of nuclear factor (erythroid-derived 2)-like 2 ( NRF2) and its downstream antioxidants sirtuin-1, FGF-inducible 14, and insulin-like growth factor-1 was upregulated, whereas that of myocyte-specific enhancer factor 2C, myogenic differentiation, myogenin, myostatin, atrogin-1, and muscle RING-finger protein-1 was downregulated. In myotubes of severe COPD patients with cachexia, roflumilast-induced cAMP signaling exerts beneficial effects by targeting muscle protein breakdown (tyrosine release), along with reduced expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In both patients and controls, roflumilast also favored antioxidant defense through upregulation of the NRF2 pathway and that of the histone deacetylase sirtuin-1, whereas it improved the expression of slow- and fast-twitch myosin isoforms. These findings show that muscle dysfunction and wasting may be targeted by roflumilast-induced cAMP signaling in COPD. These results have potential therapeutic implications, as this PDE-4 inhibitor is currently available for the treatment of systemic inflammation and exacerbations in patients with severe COPD. NEW & NOTEWORTHY In myotubes of cachectic chronic obstructive pulmonary disease (COPD) patients, cAMP signaling exerted beneficial effects by targeting muscle proteolysis and reducing gene expression of proteolytic markers of the ubiquitin-proteasome system and that of myostatin. In myotubes of patients and controls, roflumilast also favored antioxidant defense through upregulation of the nuclear factor (erythroid-derived 2)-like 2 pathway, of sirtuin-1, and of gene expression of slow- and fast-twitch isoforms. These findings have potential clinical implications for the treatment of muscle wasting in patients with COPD and cachexia. Support for this study was provided by CIBERES, FIS 14/00713 (FEDER), SAF-2014-54371-R, SEPAR 2016, FUCAP 2016 (Spain), and an unrestricted grant from Takeda (Japan). E. Barreiro was a recipient of the ERS COPD Research Award 2008.

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