i+12 - Instituto de Investigación Hospital 12 de Octubre (Madrid)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16938

El Instituto de Investigación Sanitaria Hospital 12 de Octubre (Instituto i+12) se creó el 15 de diciembre de 2009 por convenio firmado entre el Servicio Madrileño de Salud, la Universidad Complutense de Madrid, la Universidad Autónoma de Madrid, la Fundación para la Investigación Biomédica del Hospital 12 de Octubre y la Agencia de Formación, Investigación y Estudios Sanitarios de la Comunidad de Madrid “Pedro Laín Entralgo”. Posteriormente, en 2015 se incorporaron el Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) y la Universidad Europea. El Instituto i+12 se concibe como una estructura funcional de investigación biomédica multidisciplinar y traslacional orientada a la investigación básica, clínica, epidemiológica y en servicios de salud. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2011, 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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Longitudinal Immunoprofiling of the CD8 T-Cell Response in SARS-CoV-2 mRNA Vaccinees and COVID-19 Patients
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-05-22) Brunetti, Jesús Emanuel; Escudero-Pérez, Beatriz; Lasala, Fátima; Rivas, Gonzalo; Mancheño-Losa, Mikel; Rial-Crestelo, David; Lora-Tamayo, Jaime; Cadar, Dániel; Carroll, Miles; Delgado, Rafael; Muñoz-Fontela, César; Rodríguez-Burgos, Estefanía; Alexander von Humboldt Foundation; Unión Europea. Comisión Europea. H2020; Unión Europea. Comisión Europea. Horizonte Europa; German Heart Research Foundation (Alemania); French National Agency of Research (Francia); Comunidad de Madrid (España)
Background: SARS-CoV-2 was the causing agent of the COVID-19 pandemic, which resulted in millions of deaths worldwide and massive economic losses. Although there are already several vaccines licensed, as novel variants develop, understanding the immune response induced by vaccination and natural infection is key for the development of future vaccines. Methods: In this study, we have used flow cytometry and next-generation sequencing to assess the longitudinal CD8+ T-cell response against natural infection and vaccination in convalescent and vaccinated individuals, from early activation to immune memory establishment. Moreover, we have characterized the T-cell receptor clonality and diversity at different stages post-infection and post-vaccination. Results: We have found no significant differences in CD8+ T-cell activation during the first three weeks post-infection compared to the first three weeks after first vaccination. Conversely, natural infection resulted in sustained high levels of T-cell activation at four weeks post-infection, a point in which we observed a decline in T-cell activation post-vaccination despite boosting with a second vaccination shot. Moreover, additional vaccination did not result in enhanced T-cell activation. Of note, we have observed variations in the memory subset structure at every stage of disease and vaccination. Overall, both infection and immunization induced a highly diverse T-cell receptor repertoire, which was observed both between study groups and between patients inside a given group. Conclusions: These data contribute to expand our knowledge about the immune response to SARS-CoV-2 infection and vaccination and call for additional strategies to enhance T-cell responses by booster immunization.
Newer generations of multi-target CAR and STAb-T immunotherapeutics: NEXT CART Consortium as a cooperative effort to overcome current limitations
(Frontiers Media, 2024) Martín-Antonio, Beatriz; Blanco, Belén; González-Murillo, África; Hidalgo, Laura; Minguillón, Jordi; Pérez-Chacón, Gema; Next Generation CART MAD Consortium; Rodriguez-Milla, Miguel A; García-Rodriguez, Patricia; Somovilla-Crespo, Beatriz; Garcia-Castro, Javier; Comunidad de Madrid (España); Instituto de Salud Carlos III
Adoptive T cellular immunotherapies have emerged as relevant approaches for treating cancer patients who have relapsed or become refractory (R/R) to traditional cancer treatments. Chimeric antigen receptor (CAR) T-cell therapy has improved survival in various hematological malignancies. However, significant limitations still impede the widespread adoption of these therapies in most cancers. To advance in this field, six research groups have created the "NEXT Generation CART MAD Consortium" (NEXT CART) in Madrid's Community, which aims to develop novel cell-based immunotherapies for R/R and poor prognosis cancers. At NEXT CART, various basic and translational research groups and hospitals in Madrid concur to share and synergize their basic expertise in immunotherapy, gene therapy, and immunological synapse, and clinical expertise in pediatric and adult oncology. NEXT CART goal is to develop new cell engineering approaches and treatments for R/R adult and pediatric neoplasms to evaluate in multicenter clinical trials. Here, we discuss the current limitations of T cell-based therapies and introduce our perspective on future developments. Advancement opportunities include developing allogeneic products, optimizing CAR signaling domains, combining cellular immunotherapies, multi-targeting strategies, and improving tumor-infiltrating lymphocytes (TILs)/T cell receptor (TCR) therapy. Furthermore, basic studies aim to identify novel tumor targets, tumor molecules in the tumor microenvironment that impact CAR efficacy, and strategies to enhance the efficiency of the immunological synapse between immune and tumor cells. Our perspective of current cellular immunotherapy underscores the potential of these treatments while acknowledging the existing hurdles that demand innovative solutions to develop their potential for cancer treatment fully.
The Association of HIV-1 Neutralization in Aviremic Children and Adults with Time to ART Initiation and CD4+/CD8+ Ratios
(Multidisciplinary Digital Publishing Institute (MDPI), 2024) Sanchez-Merino, Victor; Martin-Serrano, Miguel; Beltran, Manuela; Lazaro-Martin, Beatriz; Cervantes, Eloísa; Oltra, Manuel; Sainz, Talia; García, Felipe; Navarro, Maria Luisa; Yuste, Eloisa; Instituto de Salud Carlos III; RETICS-Sida (RIS-ISCIII) (España); Plan Nacional de I+D+i (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia e Innovación (España); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Fundación Banco Santander; Fundación Universidad Alfonso X el Sabio
Broadly neutralizing antibodies (bnAbs) bind and neutralize diverse HIV isolates and demonstrate protective effects in primate models and humans against specific isolates. To develop an effective HIV vaccine, it is widely believed that inducing these antibodies is crucial. However, the high somatic hypermutation in bnAbs and the limited affinity of HIV Env proteins for bnAb germline precursors suggest that extended antigen exposure is necessary for their production. Consequently, HIV vaccine research is exploring complex sequential vaccination strategies to guide the immune response through maturation stages. In this context, the exploration of the factors linked to the generation of these antibodies across diverse age groups becomes critical. In this study, we assessed the anti-HIV-1 neutralization potency and breadth in 108 aviremic adults and 109 aviremic children under 15 years of age who were receiving ART. We used a previously described minipanel of recombinant viruses and investigated the factors associated with neutralization in these individuals. We identified individuals in both groups who were capable of neutralizing viruses from three different subtypes, with greater cross-neutralization observed in the adult group (49.0% vs. 9.2%). In both groups, we observed an inverse association between neutralization breadth and the CD4+/CD8+ ratio, as well as a direct association with the time to ART initiation. However, we found no association with time post-infection, cumulative ART duration, or CD8+ cell levels. The present study demonstrates that children receiving antiretroviral therapy generate broadly neutralizing responses to HIV-1, albeit with lower magnitude compared to adults. We also observed that neutralization breadth is associated with CD4+/CD8+ levels and time to treatment initiation in both children and adults living with HIV-1. Our interpretation of these results is that a delay in ART initiation could have prolonged the antigenic stimulation associated with viral replication and thus facilitate the capacity to elicit long-lasting broadly neutralizing responses. These results corroborate prior findings that show that HIV-1-neutralizing responses can persist for years, even at low antigen levels, implying an HIV-1 vaccine may induce lasting neutralizing antibody response.
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.
Influenza vaccine outcomes: a meta-analysis revealing morbidity benefits amid low infection prevention.
(European Respiratory Society (ERS), 2025-01) Presa, Jesús; Arranz-Herrero, Javier; Alvarez-Losa, Laura; Rius-Rocabert, Sergio; Pozuelo, Maria Jose; Lalueza, Antonio; Ochando, Jordi; Eiros, José María; Sanz-Muñoz, Ivan; Nistal-Villan, Estanislao; Ministerio de Ciencia e Innovación (España); CEU San Pablo University; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Unión Europea. Fondo Social Europeo (ESF/FSE); Instituto de Salud Carlos III
Background: The morbidity and mortality associated with influenza viruses are a significant public health challenge. Annual vaccination against circulating influenza strains reduces hospitalisations and increases survival rates but requires a yearly redesign of vaccines against prevalent subtypes. The complex genetics of influenza viruses with high antigenic drift create an ongoing challenge in vaccine development to address dynamic influenza epidemiology. Understanding the evolution of influenza viruses and the vaccine's effectiveness against different types and subtypes is pivotal to designing public health measures against influenza. Methods: We conducted a systematic review and meta-analysis of 192 705 patients, collecting information on the incidence and severity of the disease. The results of this meta-analysis were further validated using data from 6 594 765 patients from TriNetX. We analysed the prevalence of the most common influenza A virus (IAV) subtypes (H1N1 and H3N2) and influenza B virus (IBV), as well as vaccination effectiveness against them in three age groups, given that age is associated with influenza disease severity. Results: Our analysis reflects that overall vaccination against H1N1 IAV and IBV is effective in reducing infection and influenza-related complications in children aged <5 years old, individuals between 5 and 65 years old and older adults aged >65 years old. By contrast, while vaccination against H3N2 IAV is effective in protecting against infection in infants <5 years old, it provides reduced protection against infection in older individuals. Conclusions: Despite higher infection rates, vaccination against H3N2 remains as highly effective as vaccination against H1N1 and IBV in reducing influenza-related morbidity and mortality in all age groups. Detailing vaccine effectiveness in terms of infection protection and disease burden across different age groups is necessary for understanding vaccine impacts in terms of other outcomes, e.g. hospitalisations, mortality and disease severity; for improving vaccine formulations and public awareness; and for enhancing vaccination campaigns to improve coverage and public acceptance.
Immunogenicity of a third dose with mRNA-vaccines in the ChAdOx1-S/BNT162b2 vaccination regimen against SARS-CoV-2 variants
(Elsevier, 2024-09-20) García-Pérez, Javier; Borobia, Alberto M; Perez-Olmeda, Mayte; Portolés, Antonio; Castaño, Luis; Campins-Artí, Magdalena; Bertrán, María Jesús; Bermejo, Mercedes; Arribas, José Ramón; López, Andrea; Ascaso-Del-Rio, Ana; Arana-Arri, Eunate; Fuentes Camps, Inmaculada; Vilella, Anna; Cascajero Díaz, Almudena; García-Morales, María Teresa; Castillo de la Osa, María; Pérez Ingidua, Carla; Lora, David; Jiménez Santana, Paloma; Pino-Rosa, Silvia del; Gómez de la Cámara, Agustín; de la Torre-Tarazona, Humberto Erick; Calonge, Esther; Cruces Fernández, Raquel; Belda-Iniesta, Cristobal; Alcamí, José; Frías, Jesús; Carcas, Antonio J; Díez-Fuertes, Francisco; CombiVacS Study Group; Instituto de Salud Carlos III; Plan Nacional de I+D+i (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Unión Europea. Comisión Europea. H2020
CombiVacS study has demonstrated a strong immune response of the heterologous ChAdOx1-S/BNT162b2 vaccine combination. The primary outcomes of the study were to assess the humoral immune response against SARS-CoV-2, 28 days after a third dose of a mRNA vaccine, in subjects that received a previous prime-boost scheme with ChAdOx1-S/BNT162b2. Secondary outcomes extended the study to 3 and 6 months. The third vaccine dose of mRNA-1273 in naive participants previously vaccinated with ChAdOx1-S/BNT162b2 regimen reached higher neutralizing antibodies titers against the variants of concern Delta and BA.1 lineage of Omicron compared with those receiving a third dose of BNT162b2 at day 28. These differences between BNT162b2 and mRNA-1273 arms were observed against the ancestral variant G614 at day 90. Suboptimal neutralizing response was observed against BQ.1.1, XBB.1.5/XBB.1.9, and JN.1 in a relevant proportion of individuals 180 days after the third dose, even after asymptomatic Omicron breakthrough infections. EudraCT (2021-001978-37); ClinicalTrials.gov (NCT04860739).
Olfactory Receptor OR2K2 Expression in Human Choroid Plexus as a Potential Marker in Early Sporadic Alzheimer's Disease
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-03-21) Alves, Victoria Cunha; Figueiro-Silva, Joana; Trullas, Ramon; Ferrer, Isidre; Carro, Eva; Instituto de Salud Carlos III; Comunidad de Madrid (España); Centro de Investigación Biomédica en Red - CIBERNED (Enfermedades Neurodegenerativas)
Epithelial cells comprising the choroid plexus (CP) form a crucial barrier between the blood and the cerebrospinal fluid, thereby assuming a central position in brain homeostasis and signaling. Mounting evidence suggests that the impairment of CP function may be a significant contributor to Alzheimer's disease (AD) pathogenesis. CP function relies on the expression of specific receptors, and the potential involvement of olfactory receptors (ORs) and taste receptors (TASRs) in chemical surveillance within the CP is being investigated. Previous studies have implicated ORs and TASRs in neurodegenerative disorders like AD, although the direct evidence of their expression in the human CP remains to be established. In this study, we conducted a transcriptomic analysis encompassing eleven and in the CP, comparing samples from healthy age-matched controls to those from patients with AD spanning Braak stages I to VI. Among these receptors, a striking finding emerged- exhibited robust expression, with a statistically significant upregulation noted at Braak stage I. Surprisingly, at the protein level, OR2K2 showed a significant decrease in both Braak stage I and VI. Additionally, we identified CP epithelial cells as the source of OR2K2 expression, where it colocalized with autophagy markers LC3 and p62. We postulate that OR2K2 could be subjected to degradation by autophagy in the early stages of AD, triggering a compensatory mechanism that leads to increased mRNA transcription. This study uncovers a potential role for OR2K2 in AD pathogenesis, offering a novel perspective on the intricate dynamics at play in this neurodegenerative disorder.
EGFR amplification and EGFRvIII predict and participate in TAT-Cx43266-283 antitumor response in preclinical glioblastoma models
(Oxford University Press, 2024-07-05) Álvarez-Vázquez, Andrea; San-Segundo, Laura; Cerveró-García, Pilar; Flores-Hernández, Raquel; Ollauri-Ibáñez, Claudia; Segura-Collar, Berta; Hubert, Christopher G; Morrison, Gillian; Pollard, Steven M; Lathia, Justin D; Sánchez-Gómez, Pilar; Tabernero, Arantxa; Álvarez-Vázquez, Andrea; San-Segundo, Laura; Cerveró-García, Pilar; Flores-Hernández, Raquel; Ollauri-Ibáñez, Claudia; Segura-Collar, Berta; Hubert, Christopher G; Morrison, Gillian; Pollard, Steven M; Lathia, Justin D; Tabernero, Arantxa; Junta de Castilla y León (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Agencia Estatal de Investigación (España); Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Instituto de Salud Carlos III; Cleveland Clinic Lerner Research Institute; Cancer Research UK (Reino Unido); European Molecular Biology Organization
Background: Glioblastoma (GBM) commonly displays epidermal growth factor receptor (EGFR) alterations (mainly amplification and EGFRvIII) and TAT-Cx43266-283 is a Src-inhibitory peptide with antitumor properties in preclinical GBM models. Given the link between EGFR and Src, the aim of this study was to explore the role of EGFR in the antitumor effects of TAT-Cx43266-283. Methods: The effect of TAT-Cx43266-283, temozolomide (TMZ), and erlotinib (EGFR inhibitor) was studied in patient-derived GBM stem cells (GSCs) and murine neural stem cells (NSCs) with and without EGFR alterations, in vitro and in vivo. EGFR alterations were analyzed by western blot and fluorescence in situ hybridization in these cells, and compared with Src activity and survival in GBM samples from The Cancer Genome Atlas. Results: The effect of TAT-Cx43266-283 correlated with EGFR alterations in a set of patient-derived GSCs and was stronger than that exerted by TMZ and erlotinib. In fact, TAT-Cx43266-283 only affected NSCs with EGFR alterations, but not healthy NSCs. EGFR alterations correlated with Src activity and poor survival in GBM patients. Finally, tumors generated from NSCs with EGFR alterations showed a decrease in growth, invasiveness, and vascularization after treatment with TAT-Cx43266-283, which enhanced the survival of immunocompetent mice. Conclusions: Clinically relevant EGFR alterations are predictors of TAT-Cx43266-283 response and part of its mechanism of action, even in TMZ- and erlotinib-resistant GSCs. TAT-Cx43266-283 targets NSCs with GBM-driver mutations, including EGFR alterations, in an immunocompetent GBM model in vivo, suggesting a promising effect on GBM recurrence. Together, this study represents an important step toward the clinical application of TAT-Cx43266-283.
Experience of the national cohort of pregnant women with HIV and their children in Spain: temporal trends in vertical transmission of HIV and associated infections
(Elsevier, 2024-10) Illán Ramos, Marta; Berzosa Sánchez, Arantxa; Carrasco García, Itziar; Diaz Franco, Asuncion; Jarrin Vera, Inmaculada; Prieto Tato, Luis; Polo Rodríguez, Rosa; Navarro Gómez, María Luisa; Ramos Amador, José Tomás; Grupo de Trabajo de la Cohorte Nacional de mujeres embarazadas que viven con VIH y sus hijos en España; Ministerio de Sanidad (España)
Introduction: The vertical transmission rate (VTR) of HIV has decreased to less than 2% in high-income countries, in spite of which perinatal infections continue to occur. We present data from the national cohort of pregnant women living with HIV and their children in Spain. The objectives were to describe the characteristics of this population, evaluate the VTR of HIV, the safety of antiretroviral therapy (ART) and the prevalence of coinfection. Patients and methods: Multicentre prospective, observational and descriptive study with participation of 62 hospitals. The sample included pegnant women living with HIV whose children were born between January 2020 and December 2022. We collected prospective data on the characteristics of mothers and children using an online questionnaire (REDCap web application). Results: The study included 414 mother-child dyads. Most mothers were immigrants (227/349; 65.1%). The main route of HIV infection was heterosexual transmission (160/402; 39.8%), followed by vertical transmission (44/402; 10.9%). The diagnosis was made before conception in 313/389 women (80.4%), 394/402 (98%) received ART during pregnancy and 356/402 (89.3%) had an undetectable viral load at the time of delivery. The delivery was vaginal in 230/388 children (59.3%). The proportion of preterm birth was 11.1%. The most frequent neonatal prophylaxis approach was monotherapy with zidovudine (358/414; 86.5%). There were 3 cases of vertical transmission of HIV (95% CI, 0%-1.54%). Only one newborn was breastfed. Conclusions: At present, most women living with HIV in Spain receive the diagnosis before conception, are of foreign ancestry and achieve good control of the infection. Although the VTR is very low in Spain, there are still infections that could be prevented with early diagnosis and treatment.
Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
(Wiley, 2024-07) López-Ayllón, Blanca D; Marin, Silvia; Fariñas Fernández, Marco; García-García, Tránsito; Fernández-Rodríguez, Raúl; de Lucas-Rius, Ana; Redondo, Natalia; Mendoza-García, Laura; Foguet, Carles; Grigas, Juozas; Calvet, Alba; Villalba, José Manuel; Rodríguez, María Josefa; Megías, Diego; Mandracchia, Biagio; Luque, Daniel; Lozano, Juan José; Calvo, Cristina; Merino Herrán, Unai; Thomson, Timothy M; Garrido, Juan J; Cascante, Marta; Montoya, Maria; López-Ayllón, Blanca D; Marin, Silvia; Fariñas Fernández, Marco; García-García, Tránsito; Fernández-Rodríguez, Raúl; de Lucas-Rius, Ana; Redondo, Natalia; Mendoza-García, Laura; Foguet, Carles; Grigas, Juozas; Calvet, Alba; Villalba, José Manuel; Megías, Diego; Mandracchia, Biagio; Luque, Daniel; Lozano, Juan José; Calvo, Cristina; Merino Herrán, Unai; Thomson, Timothy M; Garrido, Juan J; Cascante, Marta; Montoya, María; Unión Europea. Comisión Europea. NextGenerationEU; Consejo Superior de Investigaciones Científicas (España); Regional Government of Andalusia (España); Ministerio de Ciencia (España); Agència de Gestió d´Ajuts Universitaris i de Recerca (AGAUR); Institució Catalana de Recerca i Estudis Avançats; Instituto de Salud Carlos III; Agencia Estatal de Investigación (España)
Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.
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.
Numb-like (NumbL) downregulation increases tumorigenicity, cancer stem cell-like properties and resistance to chemotherapy
(2016) García-Heredia, José M; Verdugo Sivianes, Eva M; Lucena-Cacace, Antonio; Molina-Pinelo, Sonia; Carnero, Amancio
NumbL, or Numb-like, is a close homologue of Numb, and is part of an evolutionary conserved protein family implicated in some important cellular processes. Numb is a protein involved in cell development, in cell adhesion and migration, in asymmetric cell division, and in targeting proteins for endocytosis and ubiquitination. NumbL exhibits some overlapping functions with Numb, but its role in tumorigenesis is not fully known. Here we showed that the downregulation of NumbL alone is sufficient to increase NICD nuclear translocation and induce Notch pathway activation. Furthermore, NumbL downregulation increases epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related gene transcripts and CSC-like phenotypes, including an increase in the CSC-like pool. These data suggest that NumbL can act independently as a tumor suppressor gene. Furthermore, an absence of NumbL induces chemoresistance in tumor cells. An analysis of human tumors indicates that NumbL is downregulated in a variable percentage of human tumors, with lower levels of this gene correlated with worse prognosis in colon, breast and lung tumors. Therefore, NumbL can act as an independent tumor suppressor inhibiting the Notch pathway and regulating the cancer stem cell pool.
NKG2C/ KLRC2 tumor cell expression enhances immunotherapeutic efficacy against glioblastoma
(BMJ Publishing Group, 2024-08-30) Dios Huerta, Olaya de; Ramírez-González, María A; Gómez-Soria, Irene; Segura-Collar, Berta; Manosalva, Juliana; Megías, Diego; de Andrea, Carlos E; Fernández-Rubio, Leticia; Hernández-Laín, Aurelio; Sepúlveda-Sánchez, Juan Manuel; Rodriguez-Ruiz, Maria E; Pérez-Núñez, Ángel; Wainwright, Derek A; Gargini, Ricardo; Sánchez-Gómez, Pilar; Ministerio de Ciencia, Innovación y Universidades (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; National Institutes of Health (Estados Unidos); Cancer Research UK (Reino Unido); American Cancer Society; Asociación Española Contra el Cáncer; Brain Tumor Association (ABTA)
Background: Activating and inhibitory receptors of natural killer (NK) cells such as NKp, NKG2, or CLEC are highly relevant to cold tumors including glioblastoma (GBM). Here, we aimed to characterize the expression of these receptors in GBM to gain insight into their potential role as modulators of the intratumoral microenvironment. Methods: We performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded by KLRC2, NKG2C, among bulk and single-cell RNA sequencing GBM data sets. We also evaluated the effects of KLRC2-overexpressing GL261 cells in mice treated with or without programmed cell death protein-1 (PD-1) monoclonal antibody (mAb). Finally, we analyzed samples from two clinical trials evaluating PD-1 mAb effects in patients with GBM to determine the potential of NKG2C to serve as a biomarker of response. Results: We observed significant expression of several inhibitory NK receptors on GBM-infiltrating NK and T cells, which contrasts with the strong expression of KLRC2 on tumor cells, mainly at the infiltrative margin. Neoplastic KLRC2 expression was associated with a reduction in the number of myeloid-derived suppressor cells and with a higher level of tumor-resident lymphocytes. A stronger antitumor activity after PD-1 mAb treatment was observed in NKG2Chigh-expressing tumors both in mouse models and patients with GBM whereas the expression of inhibitory NK receptors showed an inverse association. Conclusions: This study explored the role of neoplastic NKG2C/KLRC2 expression in shaping the immune profile of GBM and suggests that it is a predictive biomarker for positive responses to immune checkpoint inhibitor treatment in patients with GBM. Future studies could further validate this finding in prospective trials.
Secondary prevention therapies in real-world patients with myocardial infarction: eligibility based on randomized trials supporting European and American guidelines
(Elsevier, 2023-10-12) Mas-Lladó, Caterina; Rosselló, Xavier; González-Del-Hoyo, Maribel; Pocock, Stuart; de Werf, Frans Van; Chin, Chee Tang; Danchin, Nicolas; Lee, Stephen W-L; Medina, Jesús; Huo, Yong; Bueno, Héctor; Mas-Lladó, Caterina; Rosselló, Xavier; González-Del-Hoyo, Maribel; Pocock, Stuart; de Werf, Frans Van; Chin, Chee Tang; Danchin, Nicolas; Lee, Stephen W-L; Medina, Jesús; Huo, Yong; Bueno, Héctor
Objective: We aimed to evaluate the applicability of the eligibility criteria of randomized controlled trials (RCTs) cited in guideline recommendations in a real-world cohort of patients receiving secondary prevention after acute myocardial infarction from the EPICOR registries. Methods: Recommendations provided by American and European guidelines for acute myocardial infarction were classified into general (applying to all patients) and specific (applying to patients with left ventricular dysfunction or heart failure). Randomized controlled trials cited in these recommendations were selected, and their entry criteria were applied to our international cohort of 18,117 patients. Results: There were 91.5% patients eligible for beta blockers (84.6% for general, and 5.9% for specific recommendations), 97.7% eligible for renin-angiotensin system inhibitor (angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers [ACEI/ARB]) recommendations (69.9% for general, 27.9% for specific) and 4.1% eligible for mineralocorticoid receptor antagonists (only specific recommendations). The percentages of patients with eligibility criteria who were discharged with a prescription of the recommended therapies were 80%-85% for beta blockers, 70%-75% for ACEI/ARB, and 29% for mineralocorticoid receptor antagonists. There were large regional variations in the percentage of eligible patients and in those receiving the medications (eg, 95% in Northern Europe and 57% in Southeast Asia for beta blockers). Conclusion: Most real-world acute myocardial infarction patients are eligible for secondary prevention therapy in both general and specific guideline recommendations, and the percentage of those on beta blockers and ACEI/ARB at hospital discharge is high. There are large regional variations in the proportion of patients receiving recommended therapies. Local targeted interventions are needed for quality improvement.
Sex differences in the comorbidity of patients seeking a first treatment for Alcohol Use Disorder
(Springer, 2023) García-Marchena, Nuria; Sanvisens, Arantza; Abellí-Deulofeu, Enric; Blanes, Rafael; Torrens, Marta; Miquel, Laia; Rubio, Gabriel; Bolao, Ferran; Muga, Robert; Zuluaga, Paola; Fuster, Daniel; Hernández-Rubio, Anna; Farre, Magi; Papasseit, Esther; Pérez-Mañá, Clara; Poyatos, Lourdes; Moranta, Catalina; Sion, Ana; Ortega, Lluisa; Bruguera, Pol; Caballeria, Elsa; Messeguer, Ana; Fonseca, Francina; Mestre-Pinto, Joan-Ignasi; Alías, María; Dinamarca, Fernando; Rodríguez-Fonseca, Fernando; Pavón-Morón, Francisco Javier; Marcos, Miguel; Martín, Candelaria; Pérez-Hernández, Onán; Manzanares, Jorge; Navarrete, Francisco; Gasparyan, Ani
Background: The CohRTA multicenter study aims to characterize patients undergoing a first treatment for alcohol use disorder (AUD). The objective is to analyze sex-specific differences in the comorbidity of AUD when starting the first treatment for the disorder. Methods: A multicenter study was carried out between 2014 and 2021 in 6 public centers in Spain. Sociodemographic characteristics were collected, variables related to alcohol consumption, medical comorbidity according to Cumulative Illness Rating Scale-Substance Abuse (CIRS-SA), antecedent of psychiatric comorbidity, general blood test and screening for drugs in urine. Logistic regression models were used to establish associations. Results: A total of 896 patients (634 M, 262 W) were included. Median age at admission was 48 years [IQR:41ﾖ56 years]. Men reported beginning regular alcohol consumption at an earlier age and drank more alcohol. The most frequent medical comorbidities were hepatic, respiratory, vascular and neurological. The median number of affected systems was three, with no differences between men and women. However, depressive disorder was more frequent in women. In the multivariate analysis, women were up to 4 times more likely to have a major depressive disorder, elevated ESR and elevated total cholesterol than men. Men started alcohol consumption earlier, had a higher body mass index (BMI), a higher probability of using cocaine and a higher frequency of GGT and bilirubin alteration than women. Conclusion: Differences by sex were found among individuals beginning first treatment for AUD. These differences must be taken into account when designing specific therapeutic strategies for men and women.
The Response to Biologics is Better in Patients with Severe Asthma Than in Patients with Asthma-COPD Overlap Syndrome
(Dove Medical Press, 2022) Perez de Llano, Luis Alejandro; Dacal Rivas, David; Marina Malanda, Nuria; Plaza Moral, Vicente; Gullon Blanco, Jose Antonio; Muñoz-Esquerre, Mariana; Garcia-Moguel, Ismael; Diaz Campos, Rocio M; Martinez-Moragon, Eva; Harbenau Mena, Alicia; García-Cosío, Borja; Padilla Galo, Alicia; Cisneros Serrano, Carolina
Although biologics have demonstrated to be effective in T2-high asthma patients, there is little experience with these drugs in asthma-COPD overlap (ACO). The aim of this study was to compare the effectiveness of biologics in these two conditions. We included 318 patients (24 ACO and 297 asthma) treated with monoclonal antibodies and followed for at least 12 months. Omalizumab was the most frequently employed biologic agent both in patients with ACO and asthma. Asthma control test (ACT) scores after at least 12 months of biologic therapy were not significantly different between groups. The percentage of patients with ≥1 exacerbation and ≥1 corticosteroid burst was significantly higher in ACO patients (70.8 vs 27.3 and 83.3% vs 37.5%, respectively), whereas the percentage of "controlled" patients (with no exacerbations, no need for corticosteroids and ACT ≥ 20) was significantly lower (16.7% vs 39.7%). In conclusion, this report suggests that patients with ACO treated with biologics reach worse outcomes than asthma patients.
Development and validation of a nomogram to predict kidney survival at baseline in patients with C3 glomerulopathy
(2022) Caravaca-Fontán, Fernando; Rivero, Marta; Cavero, Teresa; Díaz-Encarnación, Montserrat; Cabello, Virginia; Ariceta, Gema; Quintana, Luis F; Marco, Helena; Barros, Xoana; Ramos, Natalia; Rodríguez-Mendiola, Nuria; Cruz, Sonia; Fernández-Juárez, Gema; Rodríguez, Adela; Pérez de José, Ana; Rabasco, Cristina; Rodado, Raquel; Fernández, Loreto; Pérez-Gómez, Vanessa; Ávila, Ana; Bravo, Luis; Espinosa, Natalia; Allende Burgos, Natalia; Sanchez de la Nieta, Maria Dolores; Rodríguez, Eva; Olea, Teresa; Melgosa, Marta; Huerta, Ana; Miquel, Rosa; Mon, Carmen; Fraga, Gloria; de Lorenzo, Alberto; Draibe, Juliana; González, Fayna; Shabaka, Amir; López-Rubio, Maria Esperanza; Fenollosa, María Ángeles; Martín-Penagos, Luis; Da Silva, Iara; Alonso Titos, Juana; Rodriguez de Cordoba, Santiago; Goicoechea de Jorge, Elena; Praga, Manuel
Background: C3 glomerulopathy is a rare and heterogeneous complement-driven disease. It is often challenging to accurately predict in clinical practice the individual kidney prognosis at baseline. We herein sought to develop and validate a prognostic nomogram to predict long-term kidney survival. Methods: We conducted a retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. The dataset was randomly divided into a training group (n = 87) and a validation group (n = 28). The least absolute shrinkage and selection operator (LASSO) regression was used to screen the main predictors of kidney outcome and to build the nomogram. The accuracy of the nomogram was assessed by discrimination and risk calibration in the training and validation sets. Results: The study group comprised 115 patients, of whom 46 (40%) reached kidney failure in a median follow-up of 49 months (range 24-112). No significant differences were observed in baseline estimated glomerular filtration rate (eGFR), proteinuria or total chronicity score of kidney biopsies, between patients in the training versus those in the validation set. The selected variables by LASSO were eGFR, proteinuria and total chronicity score. Based on a Cox model, a nomogram was developed for the prediction of kidney survival at 1, 2, 5 and 10 years from diagnosis. The C-index of the nomogram was 0.860 (95% confidence interval 0.834-0.887) and calibration plots showed optimal agreement between predicted and observed outcomes. Conclusions: We constructed and validated a practical nomogram with good discrimination and calibration to predict the risk of kidney failure in C3 glomerulopathy patients at 1, 2, 5 and 10 years.
Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial
(Oxford University Press, 2021-05-01) Pujol, Miquel; Miró, José María; Shaw, Evelyn; Aguado, José María; San-Juan, Rafael; Puig-Asensio, Mireia; Pigrau, Carles; Calbo, Esther; Montejo, Miguel; Rodriguez-Alvarez, Regino; Garcia-Pais, Maria-Jose; Pintado, Vicente; Escudero-Sanchez, Rosa; Lopez-Contreras, Joaquin; Morata, Laura; Montero, Milagros; Andres, Marta; Pasquau, Juan; Arenas, Maria-del-Mar; Padilla, Belen; Murillas, Javier; Jover-Saenz, Alfredo; Lopez-Cortes, Luis Eduardo; Garcia-Pardo, Graciano; Gasch, Oriol; Videla, Sebastian; Hereu, Pilar; Tebe, Cristian; Pallares, Natalia; Sanllorente, Mireia; Dominguez, Maria-Angeles; Camara, Jordi; Ferrer, Ana; Padulles, Ariadna; Cuervo, Guillermo; Carratalà, Jordi; MRSA Bacteremia (BACSARM) Trial Investigators
Background. We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. Methods. A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. Results. of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). Conclusions. Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.
Dexamethasone for the treatment of traumatic brain injured patients with brain contusions and pericontusional edema Study protocol for a prospective, randomized and double blind trial
(Lippincott Williams & Wilkins (LWW), 2021-01-22) Pérez-Bárcena, Jon; Castano-Leon, Ana Maria; Lagares Gomez-Abascal, Alfonso; Barea-Mendoza, Jesus Abelardo; Navarro Main, Blanca; Pomar Pons, Jaume; Periáñez Párraga, Leonor; Ibáñez Domínguez, Javier Angel; Chico-Fernandez, Mario; Llompart-Pou, Juan Antonio; Frontera-Juan, Guillem; DEXCON TBI Trial Collaborators
Background: Traumatic brain injury (TBI) constitutes a leading cause of death and disability. Patients with TBI and cerebral contusions developing pericontusional edema are occasionally given dexamethasone on the belief that this edema is similar to that of tumors, in which the beneficial effect of dexamethasone has been demonstrated. Methods: The DEXCON TBI trial is a multicenter, pragmatic, randomized, triple-blind, placebo controlled trial to quantify the effects of dexamethasone on the prognosis of TBI patients with brain contusions and pericontusional edema. Adult patients who fulfill the elegibility criteria will be randomized to dexamethasone/placebo in a short and descending course: 4 mg/6 h (2 days); 4 mg/8 hours (2 days); 2 mg/6 hours (2 days); 2 mg/8 hours (2 days); 1 mg/8 hours (2 days); 1 mg/12 hours (2 days). The primary outcome is the Glasgow Scale Outcome Extended (GOSE) performed 1 month and 6 months after TBI. Secondary outcomes are: number of episodes of neurological deterioration; symptoms associated with TBI; adverse events; volume of pericontusional edema before and after 12 days of treatment; results of the neuropsychological tests one month and 6 months after TBI. The main analysis will be on an intention-to-treat basis. Logistic regression will estimate the effect of dexamethasone/placebo on GOSE at one month and at 6 months, dichotomized in unfavorable outcome (GOSE 1-6) and favorable outcome (GOSE 7-8). Efficacy will also be analyzed using the 'sliding dichotomy'. An interim and safety analysis will be performed including patients recruited during the first year to calculate the conditional power. A study with 600 patients would have 80% power (2 sided alpha = 5%) to detect a 12% absolute increase (from 50% to 62%) in good recovery. Discussion: This is a confirmative trial to elucidate the therapeutic efficacy of dexamethasone in a very specific group of TBI patients: patients with brain contusions and pericontusional edema. This trial could become an important milestone for TBI patients as nowadays there is no effective treatment in this type of patients.
Long-Term Antithrombotic Therapy and Clinical Outcomes in Patients with Acute Coronary Syndrome and Renal Impairment: Insights from EPICOR and EPICOR Asia
(ADIS Int Ltd, 2021-02) Huo, Yong; Van de Werf, Frans; Han, Yaling; Rosselló, Xavier; Pocock, Stuart J; Chin, Chee Tang; Lee, Stephen W-L; Li, Yi; Jiang, Jie; Vega, Ana Maria; Medina, Jesus; Bueno, Hector
Background: Information is lacking on long-term management of patients with acute coronary syndrome (ACS) and chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m(2)). Objectives: Our objectives were to describe antithrombotic management patterns and outcomes in patients with ACS with varying renal function from the EPICOR (long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients; NCT01171404) and EPICOR Asia (NCT01361386) studies. Methods EPICOR and EPICOR Asia were prospective observational studies of patients who survived hospitalization for ACS and were enrolled at discharge in 28 countries across Europe, Latin America, and Asia. The studies were conducted from 2010 to 2013 and from 2011 to 2014, respectively. This analysis evaluated patient characteristics and oral antithrombotic management patterns and outcomes up to 2 years post-discharge according to admission eGFR: >= 90, 60-89, 30-59, or < 30 mL/min/1.73 m(2). Results: Among 22,380 patients with available data, eGFR < 60 mL/min/1.73 m(2) was observed in 16.7%. Patients with poorer renal function were older, were at greater cardiovascular risk, and had more prior cardiovascular disease and bleeding. Patients with CKD underwent fewer cardiovascular interventions and had more in-hospital cardiovascular and bleeding events. Dual antiplatelet therapy was less likely at discharge in patients with eGFR < 30 (82.3%) than in those with >= 90 (91.3%) mL/min/1.73 m(2) and declined more sharply during follow-up in patients with low eGFR (p < 0.0001). An adjusted proportional hazards model showed that patients with lower eGFR levels had a higher risk of cardiovascular events and bleeding. Conclusions: The presence of CKD in patients with ACS was associated with less aggressive cardiovascular management and an increased risk of cardiovascular events.

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