IDIVAL - Instituto de Investigación Marqués de Valdecilla (Cantabria)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16970

El IDIVAL con el impulso de sus Instituciones fundadoras, Consejería de Sanidad del Gobierno de Cantabria y Universidad de Cantabria, promueve y desarrolla la investigación y la innovación en el entorno biosanitario de Cantabria que tiene como epicentro al Hospital Universitario Marqués de Valdecilla, con vocación de buscar soluciones a los problemas de salud y de contribuir al desarrollo científico, docente, social y económico. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2015, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

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Calibration of Toenail Metal Concentrations for Sample Mass Heterogeneity and Between-Batch Variability: The COMET Approach
(National Institute of Environmental Health Sciences (NIEHS), 2025-04) Pastor-Barriuso, Roberto; Gutiérrez-González, Enrique; Varea-Jiménez, Elena; Gómez-Ariza, José Luis; Castaño-Vinyals, Gemma; Aragonés, Nuria; Molina, Antonio José; Dierssen-Sotos, Trinidad; Fernández-Tardón, Guillermo; Amiano, Pilar; Ederra-Sanz, María; Moreno, Victor; Jiménez-Moleón, José Juan; Molina-Barceló, Ana; Marcos-Gragera, Rafael; Casabonne, Delphine; Alguacil, Juan; Gómez-Gómez, Jesús Humberto; García-Barrera, Tamara; Kogevinas, Manolis; Pollan-Santamaria, Marina; Perez-Gomez, Beatriz; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer; Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública); Scientific Foundation
Background: Toenails are promising biomarkers of long-term metal exposure in epidemiological studies, but their accuracy may be compromised by systematic and random errors associated with heterogeneous toenail sample masses, as well as by substantial variability across laboratory batches. Objectives: We propose a novel modeling approach to calibrate toenail metal concentrations for the heterogeneity in sample masses and the variability between batches. Methods: We developed a heteroscedastic spline mixed model relating sample mass and laboratory batch with measured concentrations, allowing for an average bias in measurements over all batches as a smooth function of sample mass, random variation in mass-related biases across batches, and mass-related heterogeneity in within-batch error variance. The model allowed partitioning the total variance of measured concentrations into the extraneous variances (due to different sample masses and laboratory batches) and the intrinsic variance (resulting from distinct metal exposures). We derived calibrated metal concentrations from the model by removing both sources of extraneous variation and estimating the predicted concentrations had all toenail samples been analyzed in a single batch and of the same mass. We provide the R script COMET (COrrected METals) to fit the proposed model, extract variance components, and calibrate metal concentrations. Results: In a multicase-control study in Spain (MCC-Spain) with toenail determinations for 16 metals in 4,473 incident cases of five common cancers and 3,450 population controls, sample mass and batch accounted for 26%-60% of the total variance of measured concentrations for most metals. In comparison with calibrated concentrations, odds ratios for measured concentrations were biased by > 10% toward or away from the null in one-quarter of the estimated metal-cancer associations. Discussion: The proposed model allows correcting toenail metal concentrations for sample mass heterogeneity and between-batch variability and could be applied to other biological specimens of heterogeneous size, distinct laboratory techniques, and different study designs.
Epidemiological and clinical characterization of community, healthcare-associated and nosocomial colonization and infection due to carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in Spain
(Springer, 2024-12) Salamanca-Rivera, Elena; Palacios-Baena, Zaira R; Cañada-Garcia, Javier Enrique; Moure García, Zaira; Perez-Vazquez, Maria; Calvo-Montes, Jorge; Martínez-Martínez, Luis; Cantón, Rafael; Ruiz Carrascoso, Guillermo; Pitart, Cristina; Navarro, Ferran; Bou, Germán; Mulet, Xavier; González-López, Juan José; Sivianes, Fran; Delgado-Valverde, Mercedes; Pascual, Álvaro; Oteo-Iglesias, Jesus; Rodríguez-Baño, Jesús; GEMARA/GEIRAS-SEIMC/REIPI CARB-ES-19 Study Group; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Plan Nacional de I+D+i (España); Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: Community-acquired (CA) and healthcare-associated (HCA) infections caused by carbapenemase-producing Enterobacterales (CPE) are not well characterized. The objective was to provide detailed information about the clinical and molecular epidemiological features of nosocomial, HCA and CA infections caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp) and Escherichia coli (CP-Ec). Methods: A prospective cohort study was performed in 59 Spanish hospitals from February to March 2019, including the first 10 consecutive patients from whom CP-Kp or CP-Ec were isolated. Patients were stratified according to acquisition type. A multivariate analysis was performed to identify the impact of acquisition type in 30-day mortality. Results: Overall, 386 patients were included (363 [94%] with CP-Kp and 23 [6%] CP-Ec); in 296 patients (76.3%), the CPE was causing an infection. Acquisition was CA in 31 (8.0%) patients, HCA in 183 (47.4%) and nosocomial in 172 (48.3%). Among patients with a HCA acquisition, 100 (54.6%) had been previously admitted to hospital and 71 (38.8%) were nursing home residents. Urinary tract infections accounted for 19/23 (82.6%), 89/130 (68.5%) and 42/143 (29.4%) of CA, HCA and nosocomial infections, respectively. Overall, 68 infections (23%) were bacteremia (8.7%, 17.7% and 30.1% of CA, HCA and nosocomial, respectively). Mortality in infections was 28% (13%, 14.6% and 42.7% of CA, HCA and nosocomial, respectively). Nosocomial bloodstream infections were associated with increased odds for mortality (adjusted OR, 4.00; 95%CI 1.21-13.19). Conclusions: HCA and CA infections caused by CPE are frequent and clinically significant. This information may be useful for a better understanding of the epidemiology of CPE.
Novel risk loci for COVID-19 hospitalization among admixed American populations
(eLife Sciences Publications, 2024-10-03) Diz-de Almeida, Silvia; Cruz, Raquel; Luchessi, Andre D; Lorenzo-Salazar, José M; López de Heredia, Miguel; Quintela, Inés; González-Montelongo, Rafaela; Nogueira Silbiger, Vivian; Porras, Marta Sevilla; Tenorio Castaño, Jair Antonio; Nevado, Julián; Aguado, José María; Aguilar, Carlos; Aguilera-Albesa, Sergio; Almadana, Virginia; Almoguera, Berta; Alvarez, Nuria; Andreu-Bernabeu, Álvaro; Arana-Arri, Eunate; Arango, Celso; Arranz, María J; Artiga, Maria-Jesus; Baptista-Rosas, Raúl C; Barreda-Sánchez, María; Belhassen-García, Moncef; Bezerra, Joao F; Bezerra, Marcos A C; Boix-Palop, Lucía; Brion, María; Brugada, Ramón; Bustos, Matilde; Calderón, Enrique J; Carbonell, Cristina; Castano, Luis; Castelao, Jose E; Conde-Vicente, Rosa; Cordero-Lorenzana, M Lourdes; Cortes-Sanchez, Jose L; Corton, Marta; Darnaude, M Teresa; De Martino-Rodríguez, Alba; Del Campo-Pérez, Victor; Diaz de Bustamante, Aranzazu; Domínguez-Garrido, Elena; Eirós, Rocío; Fariñas, María Carmen; Fernandez-Nestosa, María J; Fernández-Robelo, Uxía; Fernandez-Rodriguez, Amanda; Fernández-Villa, Tania; Gago-Dominguez, Manuela; Gil-Fournier, Belén; Gómez-Arrue, Javier; González Álvarez, Beatriz; González Bernaldo de Quirós, Fernan; González-Neira, Anna; González-Peñas, Javier; Gutiérrez-Bautista, Juan F; Herrero, María José; Herrero-Gonzalez, Antonio; Jimenez-Sousa, Maria Angeles; Lattig, María Claudia; Liger Borja, Anabel; Lopez-Rodriguez, Rosario; Mancebo, Esther; Martín-López, Caridad; Martín, Vicente; Martinez-Nieto, Oscar; Martinez-Lopez, Iciar; Martinez-Resendez, Michel F; Martinez-Perez, Angel; Mazzeu, Juliana F; Merayo Macías, Eleuterio; Minguez, Pablo; Moreno Cuerda, Victor; Oliveira, Silviene F; Ortega-Paino, Eva; Pompa-Mera, Ericka N; Parellada, Mara; Paz-Artal, Estela; Santos, Ney PC; Pérez-Matute, Patricia; Perez, Patricia; Pérez-Tomás, M Elena; Perucho, Teresa; Pinsach-Abuin, Mel·lina; Pita, Guillermo; Porras-Hurtado, Gloria L; Pujol, Aurora; Ramiro León, Soraya; Resino, Salvador; Fernandes, Marianne R; Rodríguez-Ruiz, Emilio; Rodríguez-Artalejo, Fernando; Rodriguez-Garcia, José A; Ruiz-Cabello, Francisco; Ruiz-Hornillos, Javier; Ryan, Pablo; Soria, José Manuel; Souto, Juan Carlos; Tamayo, Eduardo; Tamayo-Velasco, Álvaro; Taracido-Fernandez, Juan Carlos; Teper, Alejandro; Torres-Tobar, Lilian; Urioste, Miguel; Valencia-Ramos, Juan; Yáñez, Zuleima; Zarate, Ruth; de Rojas, Itziar; Ruiz, Agustín; Sánchez, Pascual; Real, Luis Miguel; SCOURGE Cohort Group; Guillén-Navarro, Encarna; Ayuso, Carmen; Parra, Esteban; Riancho, José A; Rojas-Martinez, Augusto; Flores, Carlos; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Banco Santander; Fundación La Caixa; Agencia Estatal de Investigación (España); Gobierno de Canarias (España); Fundación Canaria de Investigación Sanitaria; Xunta de Galicia (España); Fundación Amancio Ortega; Estrella de Levante; Colabora Mujer
The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations ( and ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.
Health-Related Quality of Life in Long-Term Colorectal Cancer Survivors
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-09-25) Marcos-Delgado, Alba; Martín-Sánchez, Vicente; Molina-Barceló, Ana; Alonso-Molero, Jéssica; Perez-Gomez, Beatriz; Pollán, Marina; Aragones, Nuria; Ederra-Sanz, María; Fernández-Tardón, Guillermo; Binefa, Gemma; Moreno, Victor; Barrios-Rodríguez, Rocío; Amiano, Pilar; Huerta, José María; Teso, Enrique Pastor; Alguacil, Juan; Castaño-Vinyals, Gemma; Kogevinas, Manolis; Molina de la Torre, Antonio José; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Junta de Castilla y León (España); Regional Government of Andalusia (España)
The aim of our study is to evaluate the relationship between sociodemographic and clinical characteristics of individuals with Colorectal Cancer (CRC), tumour-intrinsic characteristics and treatment received with health-related quality of life (HRQoL). Methods: Cross-sectional analysis of data from 805 survivors from the MCC study was conducted. HRQoL was assessed through a general and specific questionnaire, SF-12 and FCSI (Colorectal Symptom Index). Statistical analyses were performed with linear regression with adjustment for sociodemographic variables, stage at diagnosis and histological grade. Results: Participants had survived a median of 7.9 years from diagnosis (IQR 7.1-8.5 years). Age at diagnosis, sex and area showed a clear association with HRQoL in both physical and mental dimensions of the SF-12 questionnaire. A direct association between CRC recurrence was also found in the PCS-12 and MCS-12 dimensions and radical surgery in the PCS-12. Regarding the scores in FCSI questionnaire, statistically significant differences were observed by sex, age and area, with older women being the most impaired (p < 0.001). Conclusions: Age, sex and area was associated with lower scores of HRQoL among CRC survivors. Knowing the determinants related to HRQoL would allow us to lay the groundwork to develop strategies that help reduce morbidity and mortality, relapses and increase HRQoL.
Executive Summary of the Consensus Statement of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Tropical Medicine and International Health (SEMTSI), the Spanish Association of Surgeons (AEC), the Spanish Society of Pneumology and Thoracic Surgery (SEPAR), the Spanish Society of Thoracic Surgery (SECT), the Spanish Society of Vascular and Interventional Radiology (SERVEI), and the Spanish Society of Paediatric Infectious Diseases (SEIP), on the Management of Cystic Echinococcosis
(Elsevier, 2020) Belhassen-García, Moncef; Balboa Arregui, Óscar; Calabuig-Muñoz, Eva; Carmena, David; Esteban Velasco, Maria Del Carmen; Fuentes Gago, Marta; Fumado Pérez, Victoria; García Alonso, Jesús; García López Hortelano, Milagros; González Fernández, Luis Miguel; Herrero Martínez, Juan María; Iglesias Iglesias, Manuel José; Jiménez López, Marcelo; López-Vélez, Rogelio; Muñoz-Bellvis, Luis; Muro, Antonio; Pardo-Lledías, Javier; Peñaranda-Vera, Maria; Perteguer-Prieto, Maria Jesus; Picado, Albert; Quiñones Sampedro, Jose Edecio; Rodríguez-Guardado, Azucena; Royo Crespo, Íñigo; Salvador, Fernando; Sánchez-Montalvá, Adrián; Torrús-Tendero, Diego; Velasco Pelayo, Luis; Sociedad Española de Medicina Tropical y Salud Internacional
[EN] The Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Tropical Medicine and International Health (SEMTSI), the Spanish Association of Surgeons (AEC), the Spanish Society of Pneumology and Thoracic Surgery (SEPAR), the Spanish Society of Thoracic Surgery (SECT), the Spanish Society of Vascular and Interventional Radiology (SERVEI), and the Spanish Society of Paediatric Infectious Diseases (SEIP) considered it pertinent to issue a consensus statement on the management of cystic echinococcosis (CE) to guide healthcare professionals in the care of patients with CE. Specialists from several fields (clinicians, surgeons, radiologists, microbiologists, and parasitologists) identified the most clinically relevant questions and developed this Consensus Statement, evaluating the available evidence-based data to propose a series of recommendations on the management of this disease. This Consensus Statement is accompanied by the corresponding references on which these recommendations are based. Prior to publication, the manuscript was open for comments and suggestions from the members of the SEIMC and the scientific committees and boards of the various societies involved. [ES] La Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC), la Sociedad Española de Medicina Tropical y Salud Internacional (SEMTSI), la Asociación Española de Cirujanos (AEC), la Sociedad Española de Neumología y Cirugía Torácica (SEPAR), la Sociedad Española de Cirugía Torácica (SECT), la Sociedad Española de Radiología Vascular e Intervencionista (SERVEI) y la Sociedad Española de Infectología Pediátrica (SEIP) han considerado pertinente la elaboración de una declaración de consenso sobre el tratamiento de la equinococosis quística (EQ) que sirva de ayuda al personal sanitario en la atención de pacientes con EQ. Varios tipos de profesionales (médicos, cirujanos, radiólogos, microbiólogos y parasitólogos) han seleccionado las preguntas más clínicamente relevantes y han desarrollado esta Declaración de consenso, en la que evalúan los datos basados en la evidencia disponibles para proponer una serie de recomendaciones sobre el tratamiento de esta enfermedad. Esta Declaración de consenso se acompaña de la bibliografía correspondiente que fundamenta estas recomendaciones. Antes de su publicación, el manuscrito estuvo abierto a comentarios y sugerencias de los miembros de la SEIMC y de los comités científicos y juntas directivas de las diferentes sociedades implicadas.
Expression and Functionality Study of 9 Toll-Like Receptors in 33 Drug-Naïve Non-Affective First Episode Psychosis Individuals: A 3-Month Study
(2020-08-25) Juncal-Ruiz, Maria; Riesco-Davila, Laura; Vazquez-Bourgon, Javier; Ortiz-Garcia de la Foz, Victor; Mayoral-Van Son, Jacqueline; Ayesa-Arriola, Rosa; Setien-Suero, Esther; Leza, Juan Carlos; Lopez-Hoyos, Marcos; Crespo-Facorro, Benedicto
Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-naïve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1-9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1-9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-α) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory response.
The CARBA-MAP study: national mapping of carbapenemases in Spain (2014-2018)
(Frontiers Media, 2023) Gracia-Ahufinger, Irene; López-González, Laura; Vasallo, Francisco José; Galar, Alicia; Siller, María; Pitart, Cristina; Bloise, Iván; Torrecillas, Miriam; Gijón-Cordero, Desirée; Viñado, Belén; Castillo-García, Javier; Campo, Rainer; Mulet, Xavier; Madueño-Alonso, Ana; Chamizo-López, Francisco Javier; Arrastia-Erviti, Maitane; Galán-Sánchez, Fátima; Fernández-Quejo, Melisa; Rodríguez-Díaz, Juan Carlos; Gutiérrez-Zufiaurre, María Nieves; Rodríguez-Maresca, Manuel Angel; Ortega-Lafont, María Del Pilar; Yague-Guirao, Genoveva; Chaves-Blanco, Lucía; Colomina-Rodríguez, Javier; Vidal-Acuña, María Reyes; Portillo, María Eugenia; Franco-Álvarez de Luna, Francisco; Centelles-Serrano, María José; Azcona-Gutiérrez, José Manuel; Delgado-Iribarren García Campero, Alberto; Rey-Cao, Sonia; Muñoz, Patricia; Calvo-Montes, Jorge; Zboromyrska, Yuliya; Grandioso, David; Càmara, Jordi; Cantón, Rafael; Larrosa-Escartín, Nieves; Díaz-Regañón, Jazmín; Martínez-Martínez, Luis
Introduction: Infections caused by carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa, including isolates producing acquired carbapenemases, constitute a prevalent health problem worldwide. The primary objective of this study was to determine the distribution of the different carbapenemases among carbapenemase-producing Enterobacterales (CPE, specifically Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and Klebsiella aerogenes) and carbapenemase-producing P. aeruginosa (CPPA) in Spain from January 2014 to December 2018. Methods: A national, retrospective, cross-sectional multicenter study was performed. The study included the first isolate per patient and year obtained from clinical samples and obtained for diagnosis of infection in hospitalized patients. A structured questionnaire was completed by the participating centers using the REDCap platform, and results were analyzed using IBM SPSS Statistics 29.0.0. Results: A total of 2,704 carbapenemase-producing microorganisms were included, for which the type of carbapenemase was determined in 2692 cases: 2280 CPE (84.7%) and 412 CPPA (15.3%), most often using molecular methods and immunochromatographic assays. Globally, the most frequent types of carbapenemase in Enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among Enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). In Enterobacterales, KPC is mainly present in the South and South-East regions of Spain and OXA-48-like in the rest of the country. Regarding P. aeruginosa, VIM is widely distributed all over the country. Globally, an increasing percentage of OXA-48-like enzymes was observed from 2014 to 2017. KPC enzymes were more frequent in 2017-2018 compared to 2014-2016. Discussion: Data from this study help to understand the situation and evolution of the main species of CPE and CPPA in Spain, with practical implications for control and optimal treatment of infections caused by these multi-drug resistant organisms.
Early identification of local infections in central venous catheters for hemodialysis: A systematic review
(Elsevier, 2023-07) Cobo-Sánchez, José Luis; Blanco-Mavillard, Ian; Mancebo-Salas, Noelia; Moya-Mier, Susana; González-Menéndez, Faustino; Renedo-González, Cristina; Lázaro-Otero, Mercedes; Pelayo-Alonso, Raquel; Gancedo-González, Zulema; de Pedro-Gómez, Joan Ernest
Background: The use of central venous catheters (CVC) is associated with higher morbidity and mortality, related to infectious complications, contributing to poorer clinical outcomes and increased healthcare costs. According to the literature, the incidence of local infections related to CVC for hemodialysis is highly variable. This variability is related to differences in definitions of catheter-related infections. Objective: To identify signs and symptoms for determining local infections (exit site and tunnel tract infections) used in the literature in tunnelled and nontunnelled CVC for hemodialysis. Design: Systematic review METHODS: Structured electronic searches were conducted in five electronic databases, from 1 January 2000-31 August 2022, using key words and specific vocabulary, as well as manual searches in several journals. Additionally, vascular access clinical guidelines and infection control clinical guidelines were reviewed. Results: After validity analysis, we selected 40 studies and seven clinical guidelines. The definitions of exit site infection and tunnel infection used in the different studies were heterogeneous. Among the studies, seven (17,5 %) used the definitions of exit site and tunnel infection based on a clinical practice guideline. Three of the studies (7.5 %) used the Twardowski scale definition of exit site infection or a modification. The remaining 30 studies (75 %) used different combinations of signs and symptoms. Conclusions: Definitions of local CVC infections are highly heterogeneous in the revised literature. It is necessary to establish a consensus regarding the definitions of hemodialysis CVC exit site and tunnel infections.
Validity of a catheter exit site clinical assessment scale for the early detection of exit site infections in patients on haemodialysis with a central venous catheter: protocol for a multicentre validation study in Spain (EXITA Study)
(2022) Cobo-Sánchez, José Luis; Blanco-Mavillard, Ian; Pelayo-Alonso, Raquel; Mancebo-Salas, Noelia; Fernandez-Fernandez, Ismael; de Pedro-Gómez, Joan Ernest
Introduction: Haemodialysis patients with central venous catheter (HD-CVC) are at increased risk of exit site infections (ESIs) and catheter-related bloodstream infections, causing an increase of hospitalisation, morbidity and mortality rates. The main aim of the EXITA Study is to develop and validate an instrument for the early detection of HD-CVC ESIs. Methods and analysis: EXITA is a multicentre prospective cohort study to validate the proposed instrument with a sample of 457 HD-CVCs: 92 in the ESI group and 365 in the non-ESI group. Sample size was calculated using Epidat V.4.2 software, with 95% and 90% expected sensitivity and specificity, respectively, an ESI incidence around 20% and 5%-10% precision range. During each haemodialysis session, the absence or presence of each item will be assessed by nurses. If any item is present, a microbiological study of pericatheter skin smears and/or exit site exudate will be carried out. HD-CVC ESI will be diagnosed when the pericatheter skin smears and/or exit site exudate culture are positive (≥15 CFU/mL by semiquantitative Maki's technique or ≥1000 CFU/mL by Cleri's technique). To validate the scale, a logistic regression analysis will be performed: the β coefficients of each of the signs/symptoms of the scale to be validated will be estimated. We will use logit function and calculate ESI probability=elogit ESI/1+elogit ESI. Ethics and dissemination: The study has been approved by the Research Ethics Committee with Medical Products of Cantabria (approval code 2019.146). We will obtain informed consent from all participants before data collection. We will publish the study results in a peer-reviewed scientific journal.
Allogeneic Hematopoietic Stem Cell Transplantation in Transformed Follicular Lymphoma (tFL): Results of a Retrospective Multicenter Study from GELTAMO/GETH-TC Spanish Groups
(Multidisciplinary Digital Publishing Institute (MDPI), 2022-11-18) Rey-Bua, Beatriz; Cabrero, Mónica; Bento, Leyre; Montoro, Juan; Bastos-Oreiro, Mariana; Parody, Rocio; Yanez, Lucrecia; Lopez-Godino, Oriana; Zanabili, Joud; Herrera, Pilar; Gutierrez, Gonzalo; Perez, Ariadna; Piñana, Jose L; Novelli, Silvana; Cortés, María; Sureda, Ana Maria; Caballero, Dolores; García-Sancho, Alejandro Martín
Background: Transformation of follicular lymphoma into an aggressive lymphoma (tFL) worsens the prognosis and the standard treatment is not completely defined. Allogeneic hematopoietic stem cell transplantation (alloSCT) could be a potentially curative option for these patients, but it has not been widely explored. Methods: We designed a retrospective multicenter study to analyze the efficacy and toxicity of alloSCT in tFL patients and potential prognostic factors of survival. Results: A total of 43 patients diagnosed with tFL who underwent alloSCT in 14 Spanish centers between January 2000 and January 2019 were included. Median age was 44 (31-67) years. After a median follow-up of 58 months, estimated 5-year overall survival (OS) and progression-free survival (PFS) were both 35%. Estimated 100-day and 1-year non-relapse mortality (NRM) were 20% and 34%, respectively. The type of conditioning regimen (3-year OS of 52% vs. 20%, respectively, for reduced-intensity vs. myeloablative conditioning) and development of chronic graft versus host disease (cGVHD) (3-year OS of 75% vs. 40%) were the only factors significantly associated with OS. The only variable with an independent association with OS was cGVHD (HR, 3.4; 95% CI, 1.2-9.6). Conclusions: Our results indicate that alloSCT continues to be a potentially curative option for patients with tFL.
Management of Kidney Failure in Patients with Diabetes Mellitus: What Are the Best Options?
(Multidisciplinary Digital Publishing Institute (MDPI), 2021-07) Buades-Fuster, Juan Manuel; Craver, Lourdes; del Pino y Pino, Maria Dolores; Prieto-Velasco, Mario; Ruiz, Juan C; Salgueira, Mercedes; de Sequera Ortiz, Patricia; Vega, Nicanor
Diabetic kidney disease (DKD) is the most frequent cause of kidney failure (KF). There are large variations in the incidence rates of kidney replacement therapy (KRT). Late referral to nephrology services has been associated with an increased risk of adverse outcomes. In many countries, when patients reach severely reduced glomerular filtration rate (GFR), they are managed by multidisciplinary teams led by nephrologists. In these clinics, efforts will continue to halt chronic kidney disease (CKD) progression and to prevent cardiovascular mortality and morbidity. In patients with diabetes and severely reduced GFR and KF, treating hyperglycemia is a challenge, since some drugs are contraindicated and most of them require dose adjustments. Even more, a decision-making process will help in deciding whether the patient would prefer comprehensive conservative care or KRT. On many occasions, this decision will be conditioned by diabetes mellitus itself. Effective education should cover the necessary information for the patient and family to answer these questions: 1. Should I go for KRT or not? 2. If the answer is KRT, dialysis and/or transplantation? 3. Dialysis at home or in center? 4. If dialysis at home, peritoneal dialysis or home hemodialysis? 5. If transplantation is desired, discuss the options of whether the donation would be from a living or deceased donor. This review addresses the determinant factors with an impact on DKD, aiming to shed light on the specific needs that arise in the management and recommendations on how to achieve a comprehensive approach to the diabetic patient with chronic kidney disease.
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
(Nature Publishing Group, 2023-05) Pairo-Castineira, Erola; Rawlik, Konrad; Bretherick, Andrew D; Qi, Ting; Wu, Yang; Nassiri, Isar; McConkey, Glenn A; Zechner, Marie; Klaric, Lucija; Griffiths, Fiona; Oosthuyzen, Wilna; Kousathanas, Athanasios; Richmond, Anne; Millar, Jonathan; Russell, Clark D; Malinauskas, Tomas; Thwaites, Ryan; Morrice, Kirstie; Keating, Sean; Maslove, David; Nichol, Alistair; Semple, Malcolm G; Knight, Julian; Shankar-Hari, Manu; Summers, Charlotte; Hinds, Charles; Horby, Peter; Ling, Lowell; McAuley, Danny; Montgomery, Hugh; Openshaw, Peter J M; Begg, Colin; Walsh, Timothy; Tenesa, Albert; Flores, Carlos; Riancho, José A; Rojas-Martinez, Augusto; Lapunzina, Pablo; Yang, Jian; Ponting, Chris P; Wilson, James F; Vitart, Veronique; Abedalthagafi, Malak; Luchessi, Andre D; Parra, Esteban J; Cruz, Raquel; Carracedo, Ángel; Fawkes, Angie; Murphy, Lee; Rowan, Kathy; Pereira, Alexandre C; Law, Andy; Fairfax, Benjamin; Hendry, Sara Clohisey; Baillie, J Kenneth; Sepsis Research (the Fiona Elizabeth Agnew Trust); Intensive Care Society; Wellcome Trust; UK Research and Innovation; Department of Health and Social Care (DHSC); BBSRC Institute Program Support Grant; Edinburgh Clinical Academic Track (ECAT) programm; Health Data Research UK; RCUK Innovation Fellowship from the National Productivity Investment Fund; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España); Fundacion Amancio Ortega; Fundación Canaria Instituto de Investigación Sanitaria de Canarias; Centro National de Genotipado (CEGEN); Centro de Supercomputacion de Galicia (CESGA); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)
Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation
(Nature Publishing Group, 2023-07) Ocio, Enrique M; Perrot, Aurore; Bories, Pierre; San-Miguel, Jesus F; Blau, Igor W; Karlin, Lionel; Martinez-Lopez, Joaquin; Wang, Song-Yau; Bringhen, Sara; Marcatti, Magda; Mateos, María-Victoria; Rodriguez-Otero, Paula; Oliva, Stefania; Nogai, Axel; Le Roux, Nadia; Dong, Liyan; Macé, Sandrine; Gassiot, Matthieu; Fitzmaurice, Thomas; Oprea, Corina; Moreau, Philippe; Sanofi
Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10-5 sensitivity). Grade ?3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).
Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin
(Nature Publishing Group, 2023-05-23) Capdevila, J; Hernando, J; Teule, A; Lopez, C; Garcia-Carbonero, R; Benavent, M; Custodio, A; Garcia-Alvarez, A; Cubillo, A; Alonso, V; Carmona-Bayonas, A; Alonso-Gordoa, T; Crespo, G; Jimenez-Fonseca, P; Blanco, M; Viudez, A; La Casta, A; Sevilla, I; Segura, A; Llanos, M; Landolfi, S; Nuciforo, P; Manzano, J L; García-Carbonero, Rocio; Grupo Espanol de Tumores Neuroendocrinos y Endocrinos (GETNE); AstraZeneca
Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.
Common and Differential Traits of the Membrane Lipidome of Colon Cancer Cell Lines and their Secreted Vesicles: Impact on Studies Using Cell Lines
(2020-05-20) Bestard-Escalas, Joan; Maimó-Barceló, Albert; Lopez, Daniel H; Reigada, Rebeca; Guardiola-Serrano, Francisca; Ramos-Vivas, José; Hornemann, Thorsten; Okazaki, Toshiro; Barceló-Coblijn, Gwendolyn
Colorectal cancer (CRC) is the fourth leading cause of cancer death in the world. Despite the screening programs, its incidence in the population below the 50s is increasing. Therefore, new stratification protocols based on multiparametric approaches are highly needed. In this scenario, the lipidome is emerging as a powerful tool to classify tumors, including CRC, wherein it has proven to be highly sensitive to cell malignization. Hence, the possibility to describe the lipidome at the level of lipid species has renewed the interest to investigate the role of specific lipid species in pathologic mechanisms, being commercial cell lines, a model still heavily used for this purpose. Herein, we characterize the membrane lipidome of five commercial colon cell lines and their extracellular vesicles (EVs). The results demonstrate that both cell and EVs lipidome was able to segregate cells according to their malignancy. Furthermore, all CRC lines shared a specific and strikingly homogenous impact on ether lipid species. Finally, this study also cautions about the need of being aware of the singularities of each cell line at the level of lipid species. Altogether, this study firmly lays the groundwork of using the lipidome as a solid source of tumor biomarkers.
Common and Differential Traits of the Membrane Lipidome of Colon Cancer Cell Lines and Their Secreted Vesicles: Impact on Studies Using Cell Lines
(Multidisciplinary Digital Publishing Institute (MDPI), 2020-05) Bestard-Escalas, Joan; Maimó-Barceló, Albert; Lopez, Daniel H; Reigada, Rebeca; Guardiola-Serrano, Francisca; Ramos-Vivas, Jose; Hornemann, Thorsten; Okazaki, Toshiro; Barcelo-Coblijn, Gwendolyn
Colorectal cancer (CRC) is the fourth leading cause of cancer death in the world. Despite the screening programs, its incidence in the population below the 50s is increasing. Therefore, new stratification protocols based on multiparametric approaches are highly needed. In this scenario, the lipidome is emerging as a powerful tool to classify tumors, including CRC, wherein it has proven to be highly sensitive to cell malignization. Hence, the possibility to describe the lipidome at the level of lipid species has renewed the interest to investigate the role of specific lipid species in pathologic mechanisms, being commercial cell lines, a model still heavily used for this purpose. Herein, we characterize the membrane lipidome of five commercial colon cell lines and their extracellular vesicles (EVs). The results demonstrate that both cell and EVs lipidome was able to segregate cells according to their malignancy. Furthermore, all CRC lines shared a specific and strikingly homogenous impact on ether lipid species. Finally, this study also cautions about the need of being aware of the singularities of each cell line at the level of lipid species. Altogether, this study firmly lays the groundwork of using the lipidome as a solid source of tumor biomarkers.
EpidemIBD: rationale and design of a large-scale epidemiological study of inflammatory bowel disease in Spain
(SAGE Publishing, 2019-05) Chaparro, Maria; Barreiro-de Acosta, Manuel; Benitez, Jose Manuel; Cabriada, Jose Luis; Casanova, Maria Jose; Ceballos, Daniel; Esteve, Maria; Fernandez, Hipolito; Ginard Vicens, Daniel; Gomollon, Fernando; Lorente, Rufo; Nos, Pilar; Riestra, Sabino; Rivero, Montserrat; Robledo, Pilar; Rodriguez, Cristina; Sicilia, Beatriz; Torrella, Emilio; Garre, Ana; Garcia-Esquinas, Esther; Rodríguez-Artalejo, Fernando; Gisbert, Javier P; EpidemIBD study group of GETECCU
Background: Inflammatory bowel disease (IBD) is associated with a considerable burden to the patient and society. However, current data on IBD incidence and burden are limited because of the paucity of nationwide epidemiological studies, heterogeneous designs, and a low number of participating centers and sample size. The EpidemIBD study is a large-scale investigation to provide an accurate assessment of the incidence of IBD in Spain, as well as treatment patterns and outcomes. Methods: This multicenter, population-based incidence cohort study included patients aged >18 years with IBD (Crohn's disease, ulcerative colitis, or unclassified IBD) diagnosed during 2017 in 108 hospitals in Spain, covering 50% of the Spanish population. Each participating patient will attend 10 clinic visits during 5 years of follow up. Demographic data, IBD characteristics and family history, complications, treatments, surgeries, and hospital admissions will be recorded. Results: The EpidemIBD study is the first large-scale nationwide study to investigate the incidence of IBD in Spain. Enrollment is now completed and 3627 patients are currently being followed up. Conclusions: The study has been designed to overcome many of the limitations of previous European studies into IBD incidence by prospectively recruiting a large number of patients from all regions of Spain. In addition to epidemiological information about the burden of IBD, the 5-year follow-up period will also provide information on treatment patterns, and the natural history and financial burden of IBD.
The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE epsilon 4 Non-carriers
(Frontiers Media, 2019-12-04) Sánchez-Juan, Pascual; Moreno, Sonia; de Rojas, Itziar; Hernandez, Isabel; Valero, Sergi; Alegret, Montse; Montrreal, Laura; Garcia Gonzalez, Pablo; Lage, Carmen; Lopez-Garcia, Sara; Rodriiguez-Rodriguez, Eloy; Orellana, Adelina; Tarraga, Lluis; Boada, Merce; Ruiz, Agustin; GR@ACE Study Group; DEGESCO Consortium
An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype (rs1800547) was associated with AD risk in a large population from the Dementia Genetics Spanish Consortium (DEGESCO) including 4435 cases and 6147 controls. The association was mainly driven by individuals that were non-carriers of the APOE epsilon 4 allele. Our aim was to replicate our previous findings in an independent sample of 4124 AD cases and 3290 controls from Spain (GR@ACE project) and to analyze the effect of the H1 sub-haplotype structure on the risk of AD. The H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0025). Stratification analysis showed that this association was mainly driven by the APOE epsilon 4 non-carriers (OR = 1.15; p = 0.0022). Pooled analysis of both Spanish datasets (n = 17,996) showed that the highest AD risk related to the MAPT H1/H2 haplotype was in those individuals that were the oldest [third tertile (>77 years)] and did not carry APOE epsilon 4 allele (p = 0.001). We did not find a significant association between H1 sub-haplotypes and AD. H1c was nominally associated but lost statistical significance after adjusting by population sub-structure. Our results are consistent with the hypothesis that genetic variants linked to the MAPT H1/H2 are tracking a genuine risk allele for AD. The fact that this association is stronger in APOE epsilon 4 non-carriers partially explains previous controversial results and might be related to a slower alternative causal pathway less dependent on brain amyloid load.
In-hospital care, complications, and 4-month mortality following a hip or proximal femur fracture: the Spanish registry of osteoporotic femur fractures prospective cohort study
(Springer, 2018-09-14) Prieto-Alhambra, Daniel; Reyes, Carlen; Sanz Sainz, Miguel; Gonzalez-Macias, Jesus; Gracia Delgado, Luis; Alonso Bouzon, Cristina; Mills Ganan, Sarah; Mifsut Miedes, Damian; Vaquero-Cervino, Eduardo; Bravo Bardaji, Manuel Francisco; Ezquerra Herrando, Laura; Branas Baztan, Fatima; Llado Ferrer, Bartolome; Perez-Coto, Ivan; Adrados Bueno, Gaspar; Mora-Fernandez, Jesus; Espallargas Donate, Teresa; Martinez-Iniguez Blasco, Jorge; Aguado-Maestro, Ignacio; Saez-Lopez, Pilar; Salomo Domenech, Monica; Climent-Peris, Vicente; Diez Rodriguez, Angel; Kessel Sardinas, Humberto; Tendero Gomez, Oscar; Teixidor Serra, Jordi; Ramon Caeiro-Rey, Jose; Andres Cano, Ignacio; Barres Carsi, Mariano; Etxebarria-Foronda, Inigo; Aviles Hernandez, Juan Dionisio; Rodriguez Solis, Juan; Torregrosa Suau, Oscar; Nogues, Xavier; Herrera, Antonio; Diez-Perez, Adolfo
We have characterised 997 hip fracture patients from a representative 45 Spanish hospitals, and followed them up prospectively for up to 4 months. Despite suboptimal surgical delays (average 59.1 hours), in-hospital mortality was lower than in Northern European cohorts. The secondary fracture prevention gap is unacceptably high at 85%. Purpose To characterise inpatient care, complications, and 4-month mortality following a hip or proximal femur fracture in Spain. Methods Design: prospective cohort study. Consecutive sample of patients >= 50 years old admitted in a representative 45 hospitals for a hip or proximal femur fragility fracture, from June 2014 to June 2016 and followed up for 4 months post-fracture. Patient characteristics, site of fracture, in-patient care (including secondary fracture prevention) and complications, and 4-month mortality are described. Results A total of 997 subjects (765 women) of mean (standard deviation) age 83.6 (8.4) years were included. Previous history of fracture/s (36.9%) and falls (43%) were common, and 10-year FRAX-estimated major and hip fracture risks were 15.2% (9.0%) and 8.5% (7.6%) respectively. Inter-trochanteric (44.6%) and displaced intra-capsular (28.0%) were the most common fracture sites, and fixation with short intramedullary nail (38.6%) with spinal anaesthesia (75.5%) the most common procedures. Surgery and rehabilitation were initiated within a mean 59.1 (56.7) and 61.9 (55.1) hours respectively, and average length of stay was 11.5 (9.3) days. Antithrombotic and antibiotic prophylaxis were given to 99.8% and 98.2% respectively, whilst only 12.4% received secondary fracture prevention at discharge. Common complications included delirium (36.1 %) and kidney failure (14.1%), with in-hospital and 4-month mortality of 2.1% and 11% respectively. Conclusions Despite suboptimal surgical delay, post-hip fracture mortality is low in Spanish hospitals. The secondary fracture prevention gap is unacceptably high at > 85%, in spite of virtually universal anti-thrombotic and antibiotic prophylaxis.
Geographical variation in therapy for bloodstream infections due to multidrug-resistant Enterobacteriaceae: a post-hoc analysis of the INCREMENT study
(Elsevier, 2017-11) Harris, Patrick NA; Pezzani, M. Diletta; Gutierrez-Gutierrez, Belen; Viale, Pierluigi; Hsueh, Po-Ren; Ruiz-Garbajosa, Patricia; Venditti, Mario; Tumbarello, Mario; Navarro-Francisco, Carolina; Calbo, Esther; Akova, Murat; Giamarellou, Helen; Oliver, Antonio; Almirante, Benito; Gasch, Oriol; Martinez-Martinez, Luis; Schwaber, Mitchell J; Daikos, George; Pitout, Johann; Pena, Carmen; Hernandez-Torres, Alicia; Doi, Yohei; Perez, Federico; Tuon, Felipe Francisco; Tacconelli, Evelina; Carmeli, Yehuda; Bonomo, Robert A; Pascual, Álvaro; Paterson, David L; Rodriguez-Bano, Jesus; ESGBIS Grp; REIPI Grp; INCREMENT Grp
We describe regional differences in therapy for bloodstream infection (BSI) caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) or carbapenemase-producing Enterobacteriaceae (CPE). Patients (n = 1482) in 12 countries from an observational study of BSI caused by ESBL-E or CPE were included. Multivariate logistic regression was used to calculate adjusted odds ratios (aORs) for the influence of country of recruitment on empirical use of beta-lactam/beta-lactamase inhibitors (BLBLIs) or carbapenems, targeted use of BLBLIs for ESBL-E and use of targeted combination therapy for CPE. Compared with Spain, BLBLI use for empirical therapy was least likely in sites from Israel (aOR 0.34, 95% CI 0.14-0.81), Greece (aOR 0.49, 95% CI 0.26-0.94) and Canada (aOR 0.31, 95% CI 0.11-0.88) but more likely in Italy (aOR 1.58, 95% CI 1.11-2.25) and Turkey (aOR 2.09, 95% CI 1.14-3.81). Empirical carbapenem use was more likely in sites from Taiwan (aOR 1.73, 95% CI 1.03-2.92) and USA (aOR 1.89, 95% CI 1.053.39) and less likely in Italy (aOR 0.44, 95% CI 0.28-0.69) and Canada (aOR 0.10, 95% CI 0.01-0.74). Targeted BLBLIs for ESBL-E was more likely in Italian sites. Treatment at sites within Israel, Taiwan, Turkey and Brazil was associated with less combination therapy for CPE. Although this study does not provide precise data on the relative prevalence of ESBL-E or CPE, significant variation in therapy exists across countries even after adjustment for patient factors. Better understanding of what influences therapeutic choices for these infections will aid antimicrobial stewardship efforts.

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