INIBIC - Instituto de Investigación Biomédica A Coruña (Galicia)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16985

El Instituto de Investigación Biomédica de A Coruña (INIBIC) es un Instituto de Investigación Sanitaria (IIS) constituido por la Consellería de Sanidade, el Servicio Gallego de Salud (SERGAS), la Universidad de A Coruña (UDC) y la Fundación Profesor Novoa Santos. Fue creado el 31 de enero de 2008 mediante la firma de un convenio de colaboración entre las entidades firmantes. El Complejo Hospitalario Universitario de A Coruña (CHUAC) constituye el núcleo básico del INIBIC. El INIBIC promueve y estrecha las relaciones de intercambio de conocimiento entre todos los investigadores y grupos de investigación que pertenecen a los distintos centros -Gerencia de Gestión Integrada de A Coruña y UDC- y promover la colaboración con otras instituciones y entidades públicas y privadas priorizando la realización de actividades para potenciar las alianzas para llevar a cabo una investigación traslacional con repercusión en la actividad clínica. 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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Regulation of anti-phage defense mechanisms by using cinnamaldehyde as a quorum sensing inhibitor
(Frontiers Media, 2024) Barrio-Pujante, Antonio; Bleriot, Inés; Blasco, Lucía; Fernández-García, Laura; Pacios, Olga; Ortiz-Cartagena, Concha; Cuenca, Felipe Fernández; Oteo-Iglesias, Jesus; Tomás, María; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Xunta de Galicia (España)
Background: Multidrug-resistant bacteria and the shortage of new antibiotics constitute a serious health problem. This problem has led to increased interest in the use of bacteriophages, which have great potential as antimicrobial agents but also carry the risk of inducing resistance. The objective of the present study was to minimize the development of phage resistance in Klebsiella pneumoniae strains by inhibiting quorum sensing (QS) and thus demonstrate the role of QS in regulating defense mechanisms. Results: Cinnamaldehyde (CAD) was added to K. pneumoniae cultures to inhibit QS and thus demonstrate the role of the signaling system in regulating the anti-phage defense mechanism. The QS inhibitory activity of CAD in K. pneumoniae was confirmed by a reduction in the quantitative expression of the lsrB gene (AI-2 pathway) and by proteomic analysis. The infection assays showed that the phage was able to infect a previously resistant K. pneumoniae strain in the cultures to which CAD was added. The results were confirmed using proteomic analysis. Thus, anti-phage defense-related proteins from different systems, such as cyclic oligonucleotide-based bacterial anti-phage signaling systems (CBASS), restriction-modification (R-M) systems, clustered regularly interspaced short palindromic repeat-Cas (CRISPR-Cas) system, and bacteriophage control infection (BCI), were present in the cultures with phage but not in the cultures with phage and CAD. When the QS and anti-phage defense systems were inhibited by the combined treatment, proteins related to phage infection and proliferation, such as the tail fiber protein, the cell division protein DamX, and the outer membrane channel protein TolC, were detected. Conclusion: Inhibition of QS reduces phage resistance in K. pneumoniae, resulting in the infection of a previously resistant strain by phage, with a significant increase in phage proliferation and a significant reduction in bacterial growth. QS inhibitors could be considered for therapeutic application by including them in phage cocktails or in phage-antibiotic combinations to enhance synergistic effects and reduce the emergence of antimicrobial resistance.
Mitomycin C as an Anti-Persister Strategy against Klebsiella pneumoniae: Toxicity and Synergy Studies
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-08-28) Pacios, Olga; Herrera-Espejo, Soraya; Armán, Lucía; Ibarguren-Quiles, Clara; Blasco, Lucía; Bleriot, Inés; Fernández-García, Laura; Ortiz-Cartagena, Concha; Paniagua, María; Barrio-Pujante, Antonio; Aracil, Belen; Cisneros, José Miguel; Pachón-Ibáñez, María Eugenia; Tomás, María; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); RETICS-Investigación en Patología Infecciosa (REIPI-ISCIII) (España); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Xunta de Galicia (España); Fulbright Program (Estados Unidos); Plan Estatal de Investigación Científica y Técnica y de Innovación
The combination of several therapeutic strategies is often seen as a good way to decrease resistance rates, since bacteria can more easily overcome single-drug treatments than multi-drug ones. This strategy is especially attractive when several targets and subpopulations are affected, as it is the case of Klebsiella pneumoniae persister cells, a subpopulation of bacteria able to transiently survive antibiotic exposures. This work aims to evaluate the potential of a repurposed anticancer drug, mitomycin C, combined with the K. pneumoniae lytic phage vB_KpnM-VAC13 in vitro and its safety in an in vivo murine model against two clinical isolates of this pathogen, one of them exhibiting an imipenem-persister phenotype. At the same time, we verified the absence of toxicity of mitomycin C at the concentration using the human chondrocyte cell line T/C28a2. The viability of these human cells was checked using both cytotoxicity assays and flow cytometry.
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.
SEOM-GEICO clinical guidelines on endometrial cancer (2021)
(Springer, 2022-04) Barretina-Ginesta, Maria Pilar; Quindós, María; Alarcón Company, Jesús; Esteban, Carmen; Gaba Garcia, Lydia; Gomez, Cesar; Perez Fidalgo, Jose Alejandro; Romero, Ignacio; Santaballa, Ana; Rubio-Perez, Maria Jesús
Endometrial cancer (EC) is the second most common gynecological malignancy worldwide, the first in developed countries [Sung et al. in CA Cancer J Clin 71:209-249, 2021]. Although a majority is diagnosed at an early stage with a low risk of relapse, an important proportion of patients will relapse. Better knowledge of molecular abnormalities is crucial to identify high-risk groups in early stages as well as for recurrent or metastatic disease for whom adjuvant treatment must be personalized. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of EC, and to provide evidence-based recommendations for clinical practice.
Relationship between time from symptom's onset to diagnosis and prognosis in patients with symptomatic colorectal cancer
(BioMed Central (BMC), 2022-08-22) Esteva Cantó, Magdalena; Leiva, Alfonso; Ramos Monserrat, Maria; Espí, Alejandro; González-Luján, Luis; Macià, Francesc; Murta-Nascimento, Cristiane; Sanchez-Calavera, Maria Antonia; Magallón, Rosa; Balboa-Barreiro, Vanesa; Seoane-Pillado, Teresa; Pertega-Díaz, Sonia
Background: Controversy exists regarding the relationship of the outcome of patients with colorectal cancer (CRC) with the time from symptom onset to diagnosis. The aim of this study is to investigate this association, with the assumption that this relationship was nonlinear and with adjustment for multiple confounders, such as tumor grade, symptoms, or admission to an emergency department. Methods: This multicenter study with prospective follow-up was performed in five regions of Spain from 2010 to 2012. Symptomatic cases of incident CRC from a previous study were examined. At the time of diagnosis, each patient was interviewed, and the associated hospital and clinical records were reviewed. During follow-up, the clinical records were reviewed again to assess survival. Cox survival analysis with a restricted cubic spline was used to model overall and CRC-specific survival, with adjustment for variables related to the patient, health service, and tumor. Results: A total of 795 patients had symptomatic CRC and 769 of them had complete data on diagnostic delay and survival. Univariate analysis indicated a lower HR for death in patients who had diagnostic intervals less than 4.2 months. However, after adjustment for variables related to the patient, tumor, and utilized health service, there was no relationship of the diagnostic delay with survival of patients with colon and rectal cancer, colon cancer alone, or rectal cancer alone. Cubic spline analysis indicated an inverse association of the diagnostic delay with 5-year survival. However, this association was not statistically significant. Conclusions: Our results indicated that the duration of diagnostic delay had no significant effect on the outcome of patients with CRC. We suggest that the most important determinant of the duration of diagnostic delay is the biological profile of the tumor. However, it remains the responsibility of community health centers and authorities to minimize diagnostic delays in patients with CRC and to implement initiatives that improve early diagnosis and provide better outcomes.
Cost-Effectiveness of Next-Generation Sequencing Versus Single-Gene Testing for the Molecular Diagnosis of Patients With Metastatic Non-Small-Cell Lung Cancer From the Perspective of Spanish Reference Centers
(Lippincott Williams & Wilkins (LWW), 2023-03) Arriola, Edurne; Bernabé, Reyes; Campelo, Rosario García; Biscuola, Michele; Enguita, Ana Belén; López-Ríos, Fernando; Martínez, Rafael; Mezquita, Laura; Palanca, Sarai; Pareja, María Jesús; Zugazagoitia, Jon; Arrabal, Natalia; García, J Francisco; Carcedo, David; de Álava, Enrique; Roche
PURPOSE: The aim of this study was to assess the cost-effectiveness of using next-generation sequencing (NGS) versus single-gene testing (SgT) for the detection of genetic molecular subtypes and oncogenic markers in patients with advanced non-small-cell lung cancer (NSCLC) in the setting of Spanish reference centers. METHODS: A joint model combining decision tree with partitioned survival models was developed. A two-round consensus panel was performed to describe clinical practice of Spanish reference centers, providing data on testing rate, prevalence of alterations, turnaround times, and treatment pathways. Treatment efficacy data and utility values were obtained from the literature. Only direct costs (euros, 2022), obtained from Spanish databases, were included. A lifetime horizon was considered, so a 3% discount rate for future costs and outcomes was considered. Both deterministic and probabilistic sensitivity analyses were performed to assess uncertainty. RESULTS: A target population of 9,734 patients with advanced NSCLC was estimated. If NGS was used instead of SgT, 1,873 more alterations would be detected and 82 more patients could potentially be enrolled in clinical trials. In the long term, using NGS would provide 1,188 additional quality-adjusted life-years (QALYs) in the target population compared with SgT. On the other hand, the incremental cost of NGS versus SgT in the target population was ﾀ21,048,580 euros for a lifetime horizon (ﾀ1,333,288 for diagnosis phase only). The obtained incremental cost-utility ratios were ﾀ25,895 per QALY gained, below the standard cost-effectiveness thresholds. CONCLUSION: Using NGS in Spanish reference centers for the molecular diagnosis of patients with metastatic NSCLC would be a cost-effective strategy over SgT.
Temperate Bacteriophages (Prophages) inPseudomonas aeruginosaIsolates Belonging to the International Cystic Fibrosis Clone (CC274)
(Frontiers Media, 2020-09-25) Ambroa, Antón; Blasco, Lucia; López-Causapé, Carla; Trastoy, Rocío; Fernández-García, Laura; Bleriot, Ines; Ponce-Alonso, Manuel; Pacios, Olga; Lopez, Maria; Canton, Rafael; Kidd, Timothy J; Bou, Germán; Oliver, Antonio; Tomas, Maria
Bacteriophages are important in bacterial ecology and evolution.Pseudomonas aeruginosais the most prevalent bacterial pathogen in chronic bronchopulmonary infection in cystic fibrosis (CF). In this study, we used bioinformatics, microbiological and microscopy techniques to analyze the bacteriophages present in 24P. aeruginosaisolates belonging to the international CF clone (ST274-CC274). Interestingly, we detected the presence of five members of theInoviridaefamily of prophages (Pf1, Pf4, Pf5, Pf6, Pf7), which have previously been observed inP. aeruginosa. In addition, we identified a new filamentous prophage, designated Pf8, in theP. aeruginosaAUS411.500 isolate belonging to the international CF clone. We detected only one prophage, never previously described, from the familySiphoviridiae(with 66 proteins and displaying homology with PHAGE_Pseudo_phi297_NC_016762). This prophage was isolated from theP. aeruginosaAUS531 isolate carrying a new gene which is implicated in the phage infection ability, named Bacteriophage Control Infection (bci). We characterized the role of the Bci protein in bacteriophage infection and in regulating the host Quorum Sensing (QS) system, motility and biofilm and pyocyanin production in theP. aeruginosaisogenic mutant AUS531 Delta bciisolate. The findings may be relevant for the identification of targets in the development of new strategies to controlP. aeruginosainfections, particularly in CF patients.
Phenotypic characterisation of early COPD: a prospective case-control study
(European Respiratory Society (ERS), 2020-10-01) García-Cosío, Borja; Pascual-Guardia, Sergi; Borras-Santos, Alicia; Peces-Barba, German; Santos, Salud; Vigil, Laura; Soler-Cataluna, Juan Jose; Martinez-Gonzalez, Cristina; Casanova, Ciro; Marcos, Pedro J; Alvarez, Carlos J; Lopez-Campos, Jose Luis; Gea, Joaquim; Garcia-Aymerich, Judith; Molina, Jesus; Roman-Rodriguez, Miguel; Moises, Jorge; Szabo, Viktoria; Reagan, Elizabeth A; Estepar, Raul San Jose; Washko, George; Agusti, Alvar; Faner, Rosa; EARLY COPD Study group
The phenotypic characteristics of chronic obstructive pulmonary disease (COPD) in individuals younger than 50 years of age (early COPD) are not well defined. This prospective, multi-centre, case-control study sought to describe these characteristics and compare them with those of smokers (>= 10 pack-years) of similar age with normal spirometry (controls). We studied 92 cases (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7) and 197 controls. Results were contrasted with participants with similar inclusion criteria recruited into the ECLIPSE and COPDGene cohorts. Cases had moderate airflow limitation (FEV1 71.3 +/- 20.8%) but were often symptomatic, used healthcare resources frequently, had air trapping (residual volume 150.6 +/- 55.5% ref.), had reduced diffusing capacity (84.2 +/- 20.7% ref.) and had frequent evidence of computed tomography (CT) emphysema (61%). Of note, less than half of cases (46%) had been previously diagnosed with COPD. Interestingly, they also often reported a family history of respiratory diseases and had been hospitalised because of respiratory problems before the age of 5 years more frequently than controls (12% versus 3%, p=0.009). By and large, these observations were reproduced when available in the ECLIPSE and COPDGene cohorts. These results show that early COPD is associated with substantial health impact and significant structural and functional abnormalities, albeit it is often not diagnosed (hence, treated). The fact that a sizeable proportion of patients with early COPD report a family history of respiratory diseases and/or early-life events (including hospitalisations before the age of 5 years) renders further support to the possibility of early-life origin of COPD.
Negative screening of Fabry disease in patients with conduction disorders requiring a pacemaker
(BioMed Central (BMC), 2019-07-08) Lopez-Sainz, Angela; Climent, Vicente; Ripoll-Vera, Tomás; Angeles Espinosa, Maria; Barriales-Villa, Roberto; Navarro, Marina; Limeres, Javier; Domingo, Diana; Kasper, David C; Garcia-Pavia, Pablo
Identification of Fabry disease (FD) in cardiac patients has been restricted so far to patients with left ventricular hypertrophy. Conduction problems are frequent in FD and could precede other manifestations, offering a possible earlier diagnosis.We studied the prevalence of FD in 188 patients <70years with conduction problems requiring pacemaker implantation. Although classical manifestations of FD were not rare, no patient with FD was identified. Screening efforts should not be conducted in this population.
Emergency presentation of colorectal patients in Spain
(Public Library of Science (PLOS), 2018-10-01) Esteva, Magdalena; Ruiz-Diaz, Mercedes; Antonia Sanchez, M; Pertega, Sonia; Pita-Fernandez, Salvador; Macia, Francesc; Posso, Margarita; Gonzalez-Lujan, Luis; Bosca-Wats, Marta M; Leiva Rus, Alfonso; Ripoll Amengual, Joana; DECCIRE GRP
Background Colorectal cancer (CRC) is the leading cause of cancer deaths in Europe. Survival is poorer in patients admitted to hospitals through the emergency department than in electively admitted patients. Knowledge of factors associated with a cancer diagnosis through presentation at an emergency department may reduce the likelihood of an emergency diagnosis. This study evaluated factors influencing the diagnosis of CRC in the emergency department. Methods and findings This is a cross-sectional study in 5 Spanish regions; subjects were incident cases of CRC diagnosed in 9 public hospitals, between 2006 and 2008. Data were obtained from patient interviews and primary care and hospital clinical records. We found that approximately 40% of CRC patients first contacted a hospital for CRC through an emergency service. Women were more likely than men to be emergency presenters. The type of symptom associated with emergency presentation differed between patients with colon cancer and those with rectal cancer, in that the frequency of alarm symptoms was significantly lower in colon than in rectal cancer patients who initially presented to emergency services. Soon after symptom onset, some patients went to a hospital emergency service, whereas others contacted their GP. Lack of contact with a GP for CRC-related symptoms was consistently related to emergency presentation. Among patients who contacted a GP, a higher number of consultations for CRC symptoms and any referral to outpatient consultations reduced the likelihood of emergency presentation. All diagnostic time intervals were shorter in emergency presenters than in elective patients. Conclusions Emergency presenters are not a uniform category and can be divided into categories according to their symptoms, help seeking behavior trajectory and interaction with their GPs. Time constraints for testing and delays in obtaining outpatient appointments led patients to visit a hospital service either on their own or after referral by their GP.
Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy
(Elsevier, 2018-11-13) Pablo Ochoa, Juan; Sabater-Molina, Maria; Manuel Garcia-Pinilla, Jose; Mogensen, Jens; Restrepo-Cordoba, Alejandra; Palomino-Doza, Julian; Villacorta, Eduardo; Martinez-Moreno, Marina; Ramos-Maqueda, Javier; Zorio, Esther; Pena-Pena, Maria L; García-Granja, Pablo Elpidio; Rodriguez-Palomares, Jose F; Cardenas-Reyes, Ivonne J; de la Torre-Carpente, Maria M; Bautista-Paves, Alicia; Akhtar, Mohammed M; Cicerchia, Marcos N; Bilbao-Quesada, Raquel; Victoria Mogollon-Jimenez, Maria; Salazar-Mendiguchia, Joel; Mesa Latorre, Jose M; Arnaez, Blanca; Olavarri-Miguel, Ivan; Fuentes-Canamero, Maria E; Lamounier, Arsonval, Jr; Perez Ruiz, Jose Maria; Climent-Paya, Vicente; Perez-Sanchez, Inmaculada; Trujillo-Quintero, Juan P; Lopes, Luis R; Reparaz-Andrade, Alfredo; Marin-Iglesias, Rosario; Rodriguez-Vilela, Alejandro; Sandin-Fuentes, Maria; Garrote, Jose A; Cortel-Fuster, Alejandro; Lopez-Garrido, Miguel; Fontalba-Romero, Ana; Ripoll-Vera, Tomás; Llano-Rivas, Isabel; Fernandez-Fernandez, Xusto; Isidoro-Garcia, Maria; Garcia-Giustiniani, Diego; Barriales-Villa, Roberto; Ortiz-Genga, Martin; Garcia-Pavia, Pablo; Elliott, Perry M; Gimeno, Juan R; Monserrat, Lorenzo
BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 +/- 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 +/- 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.
Direct oral anticoagulants in patients with hypertrophic cardiomyopathy and atrial fibrillation
(Elsevier, 2017-12-01) Dominguez, Fernando; Climent, Vicente; Zorio, Esther; Ripoll-Vera, Tomás; Salazar-Mendiguchia, Joel; Manuel Garcia-Pinilla, Jose; Angel Urbano-Moral, Jose; Fernandez-Fernandez, Xusto; Lopez-Cuenca, David; Ajo-Ferrer, Raquel; Sanz-Sanchez, Jorge; Gomez-Perez, Yolanda; Lopez-Garrido, Miguel A; Barriales-Villa, Roberto; Ramon Gimeno, Juan; Garcia-Pavia, Pablo
Background: Chronic anticoagulation with vitamin K antagonists (VKAs) is recommended in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF). Direct oral anticoagulants (NOACs) are an alternative to VKAs but there are limited data to support their use in HCM. We sought to describe the pattern of use, thromboembolic events, bleeding and quality of life in patients with HCM and AF treated with NOACs. Methods: Data from patients treated with NOACs (n = 99) and VKA (n = 433) at 9 inherited cardiac diseases units were retrospectively collected. Annual rates of embolic events, serious bleeding and death were analysed and compared. Quality of life and treatment satisfaction were evaluated with SF-36 and SAFUCA questionnaires in 80 NOAC-treated and 57 VKA-treated patients. Results: After median follow-up of 63 months (IQR: 26-109), thromboembolic events (TIA/stroke and peripheral embolism) occurred in 10% of patients on oral anticoagulation. Major/clinically relevant bleeding occurred in 3.8% and the global mortality rate was 23.3%. Thromboembolic event rate was 0.62 per 100 patient-years in the NOAC group vs. 1.59 in the VKA group [subhazard ratio (SHR) 0.32;95% CI: 0.04-2.45; p = 0.27]. Major/clinically relevant bleeding occurred in 0.62 per 100 person-years in the NOAC group vs. 0.60 in the VKA group (SHR 1.28;95% CI 0.18-9.30; p = 0.85). Quality of life scores were similar in both groups; however, NOAC-treated patients achieved higher scores in the SAFUCA. Conclusions: HCM patients with AF on NOACs showed similar embolic and bleeding rates to those on VKA. Although quality of life was similar in both groups, the NOAC group reported higher treatment satisfaction.
Activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double β-lactamases under high and low permeability conditions
(Elsevier, 2024-05) Blanco-Martín, Tania; Alonso-García, Isaac; González-Pinto, Lucía; Outeda-García, Michelle; Guijarro-Sánchez, Paula; López-Hernández, Inmaculada; Perez-Vazquez, Maria; Aracil, Belen; López-Cerero, Lorena; Fraile-Ribot, Pablo; Oliver, Antonio; Vázquez-Ucha, Juan Carlos; Beceiro, Alejandro; Bou, Germán; Arca-Suárez, Jorge; GEMARA/SEIMC-CIBERINFEC Study Group on the activity and resistance mechanisms to new β-lactams and β-lactamase inhibitors (PROTECT); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Merck, Sharp & Dohme; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); RETICS-Investigación en Patología Infecciosa (REIPI-ISCIII) (España); Plan Nacional de I+D+i (España); Xunta de Galicia (España); Ministerio de Ciencia e Innovación (España)
Objectives: To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains. Methods: We constructed 82 E. coli laboratory transformants expressing the main β-lactamases circulating in Enterobacterales (70 expressing single β-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution. Results: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of β-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present. Conclusions: Our findings highlight the promising activity that cefiderocol and new β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.
Pseudomonas aeruginosa antimicrobial susceptibility profiles, resistance mechanisms and international clonal lineages: update from ESGARS-ESCMID/ISARPAE Group
(Elsevier, 2024-04) Oliver, Antonio; Rojo-Molinero, Estrella; Arca-Suárez, Jorge; Beşli, Yeşim; Bogaerts, Pierre; Cantón, Rafael; Cimen, Cansu; Croughs, Peter D; Denis, Olivier; Giske, Christian G; Graells, Tíscar; Daniel Huang, Te-Din; Iorga, Bogdan I; Karatuna, Onur; Kocsis, Béla; Kronenberg, Andreas; López-Causapé, Carla; Malhotra-Kumar, Surbhi; Martínez, Luis Martínez; Mazzariol, Annarita; Meyer, Sylvain; Naas, Thierry; Notermans, Daan W; Oteo-Iglesias, Jesus; Pedersen, Torunn; Pirš, Mateja; Poeta, Patricia; Poirel, Laurent; Pournaras, Spyros; Sundsfjord, Arnfinn; Szabó, Dora; Tambić-Andrašević, Arjana; Vatcheva-Dobrevska, Rossitza; Vitkauskienė, Astra; Jeannot, Katy; ESGARS-ISARPAE members; European Society of Clinical Microbiology and Infectious Diseases
Scope: Pseudomonas aeruginosa, a ubiquitous opportunistic pathogen considered one of the paradigms of antimicrobial resistance, is among the main causes of hospital-acquired and chronic infections associated with significant morbidity and mortality. This growing threat results from the extraordinary capacity of P. aeruginosa to develop antimicrobial resistance through chromosomal mutations, the increasing prevalence of transferable resistance determinants (such as the carbapenemases and the extended-spectrum β-lactamases), and the global expansion of epidemic lineages. The general objective of this initiative is to provide a comprehensive update of P. aeruginosa resistance mechanisms, especially for the extensively drug-resistant (XDR)/difficult-to-treat resistance (DTR) international high-risk epidemic lineages, and how the recently approved β-lactams and β-lactam/β-lactamase inhibitor combinations may affect resistance mechanisms and the definition of susceptibility profiles. Methods: To address this challenge, the European Study Group for Antimicrobial Resistance Surveillance (ESGARS) from the European Society of Clinical Microbiology and Infectious Diseases launched the 'Improving Surveillance of Antibiotic-Resistant Pseudomonas aeruginosa in Europe (ISARPAE)' initiative in 2022, supported by the Joint programming initiative on antimicrobial resistance network call and included a panel of over 40 researchers from 18 European Countries. Thus, a ESGARS-ISARPAE position paper was designed and the final version agreed after four rounds of revision and discussion by all panel members. Questions addressed in the position paper: To provide an update on (a) the emerging resistance mechanisms to classical and novel anti-pseudomonal agents, with a particular focus on β-lactams, (b) the susceptibility profiles associated with the most relevant β-lactam resistance mechanisms, (c) the impact of the novel agents and resistance mechanisms on the definitions of resistance profiles, and (d) the globally expanding XDR/DTR high-risk lineages and their association with transferable resistance mechanisms. Implication: The evidence presented herein can be used for coordinated epidemiological surveillance and decision making at the European and global level.
Beneficial Effects of Essential Oils from the Mediterranean Diet on Gut Microbiota and Their Metabolites in Ischemic Heart Disease and Type-2 Diabetes Mellitus.
(2022-11-03) Sánchez-Quintero, María José; Delgado, Josué; Medina-Vera, Dina; Becerra-Muñoz, Víctor M; Queipo-Ortuño, María Isabel; Estévez, Mario; Plaza-Andrades, Isaac; Rodríguez-Capitán, Jorge; Crespo-Leiro, Maria G; Jiménez-Navarro, Manuel F; Pavón-Morón, Francisco Javier
Ischemic heart disease (IHD) and type-2 diabetes mellitus (T2DM) remain major health problems worldwide and commonly coexist in individuals. Gut microbial metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), have been linked to cardiovascular and metabolic diseases. Previous studies have reported dysbiosis in the gut microbiota of these patients and the prebiotic effects of some components of the Mediterranean diet. Essential oil emulsions of savory (Satureja hortensis), parsley (Petroselinum crispum) and rosemary (Rosmarinus officinalis) were assessed as nutraceuticals and prebiotics in IHD and T2DM. Humanized mice harboring gut microbiota derived from that of patients with IHD and T2DM were supplemented with L-carnitine and orally treated with essential oil emulsions for 40 days. We assessed the effects on gut microbiota composition and abundance, microbial metabolites and plasma markers of cardiovascular disease, inflammation and oxidative stress. Our results showed that essential oil emulsions in mice supplemented with L-carnitine have prebiotic effects on beneficial commensal bacteria, mainly Lactobacillus genus. There was a decrease in plasma TMAO and an increase in fecal SCFAs levels in mice treated with parsley and rosemary essential oils. Thrombomodulin levels were increased in mice treated with savory and parsley essential oils. While mice treated with parsley and rosemary essential oils showed a decrease in plasma cytokines (INFɣ, TNFα, IL-12p70 and IL-22); savory essential oil was associated with increased levels of chemokines (CXCL1, CCL2 and CCL11). Finally, there was a decrease in protein carbonyls and pentosidine according to the essential oil emulsion. These results suggest that changes in the gut microbiota induced by essential oils of parsley, savory and rosemary as prebiotics could differentially regulate cardiovascular and metabolic factors, which highlights the potential of these nutraceuticals for reducing IHD risk in patients affected by T2DM.
The implications of the foot health status in Parkinson patients: A case-control study.
(2022-05-17) Jiménez-Cebrián, Ana María; López-López, Luis; Losa-Iglesias, Marta Elena; Becerro-de-Bengoa-Vallejo, Ricardo; Romero-Morales, Carlos; López-López, Daniel; Montiel-Luque, Alonso; Navarro-Flores, Emmanuel; de Labra, Carmen
Parkinson's disease (PD) is a neurodegenerative disorder that affects both health of the feet, as to gait patterns. This study aimed to find out about foot problems and their impact on self-perceived quality of life and related to foot health in Parkinson's patients compared to a group of healthy subjects and to measure it with Spanish Podiatry Health Questionnaire (PHQ-S). It is about a case-control study in a sample of Parkinson's patients n = 62, healthy controls n = 62. The PHQ-S was reported, it describes perception the subject has in each of podiatric 6 dimensions consulted, assessing appreciation of health status of interviewee's feet and a self-rated the foot health score on the visual analog scale (VAS). There were statistically significant differences (P < 0.05) in the dimensions that assessed problems with walking and moving, nail trimming, concern feet state, and affectation of quality of life related foot health. Regarding the self-perception of state of their feet, Parkinson's patients perceive a worse state of health of their feet than healthy subjects. The mean value was 4.8 (SD 2.2) for Parkinson's patients and 3.8 (SD 2.3) for healthy subjects. In conclusion, patients with PD have problems in walking or moving, foot pain, difficulties in foot hygiene and in cutting for their nails, as well as the concern they suffer from deterioration in state of their feet affect them and decrease their quality of life. Podiatric problems in Parkinson's patients have a great impact in reducing quality of life related to foot health.
Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator
(2022) Protonotarios, Alexandros; Bariani, Riccardo; Cappelletto, Chiara; Pavlou, Menelaos; García-García, Alba; Cipriani, Alberto; Protonotarios, Ioannis; Rivas, Adrian; Wittenberg, Regitze; Graziosi, Maddalena; Xylouri, Zafeirenia; Larrañaga-Moreira, José M; de Luca, Antonio; Celeghin, Rudy; Pilichou, Kalliopi; Bakalakos, Athanasios; Lopes, Luis Rocha; Savvatis, Konstantinos; Stolfo, Davide; Dal Ferro, Matteo; Merlo, Marco; Basso, Cristina; Freire, Javier Limeres; Rodriguez-Palomares, Jose F; Kubo, Toru; Ripoll-Vera, Tomas; Barriales-Villa, Roberto; Antoniades, Loizos; Mogensen, Jens; Garcia-Pavia, Pablo; Wahbi, Karim; Biagini, Elena; Anastasakis, Aris; Tsatsopoulou, Adalena; Zorio, Esther; Gimeno, Juan R; Garcia-Pinilla, Jose Manuel; Syrris, Petros; Sinagra, Gianfranco; Bauce, Barbara; Elliott, Perry M
Aims: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods and results: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. Conclusion: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.
Determinants of maximal oxygen uptake in patients with heart failure.
(2021-03-27) Roibal Pravio, Javier; Barge Caballero, Eduardo; Barbeito Caamaño, Cayetana; Paniagua Martin, Maria Jesus; Barge Caballero, Gonzalo; Couto Mallon, David; Pardo Martinez, Patricia; Grille Cancela, Zulaika; Blanco Canosa, Paula; García Pinilla, Jose Manuel; Vázquez Rodríguez, Jose Manuel; Crespo Leiro, Maria Generosa
Maximum oxygen uptake (VO2max ) is an essential parameter to assess functional capacity of patients with heart failure (HF). We aimed to identify clinical factors that determine its value, as they have not been well characterized yet. We conducted a retrospective, observational, single-centre study of 362 consecutive patients with HF who underwent cardiopulmonary exercise testing (CPET) as part of standard clinical assessment since 2009-2019. CPET was performed on treadmill, according to Bruce's protocol (n = 360) or Naughton's protocol (n = 2). We performed multivariable linear regression analyses in order to identify independent clinical predictors associated with peak VO2max . Mean age of study patients was 57.3 ± 10.9 years, mean left ventricular ejection fraction was 32.8 ± 14.2%, and mean VO2max was 19.8 ± 5.2 mL/kg/min. Eighty-nine (24.6%) patients were women, and 114 (31.5%) had ischaemic heart disease. Multivariable linear regression analysis identified six independent clinical predictors of VO2max , including NYHA class (B coefficient = -2.585; P The severity of HF (NYHA class, NT-proBNP) as well as age, body composition and haemoglobin levels influence significantly exercise capacity. In patients with HF, the right ventricular systolic function is of greater importance for the physical capacity than the left ventricular systolic function.
Osimertinib in advanced EGFR-T790M mutation-positive non-small cell lung cancer patients treated within the Special Use Medication Program in Spain: OSIREX-Spanish Lung Cancer Group.
(2021-03-06) Provencio, Mariano; Terrasa, Josefa; Garrido, Pilar; Campelo, Rosario García; Aparisi, Francisco; Diz, Pilar; Aguiar, David; García-Giron, Carlos; Hidalgo, Julia; Aguado, Carlos; González, Jorge García; Esteban, Emilio; Gómez-Aldavarí, Lorenzo; Moran, Teresa; Juan, Oscar; Chara, Luís Enrique; Marti, Juan L; Castro, Rafael López; Ortega, Ana Laura; Moreno, Elia Martínez; Coves, Juan; Sánchez Peña, Ana M; Bosch-Barrera, Joaquim; Gastaldo, Amparo Sánchez; Núñez, Natalia Fernández; Del Barco, Edel; Cobo, Manuel; Isla, Dolores; Majem, Margarita; Navarro, Fátima; Calvo, Virginia
AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain. Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016-December 2018) from 30 sites. progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources. 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted. This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Clinical trial registration number: NCT03790397 .
Incidence, Treatment, and Outcome Trends of Necrotizing Enterocolitis in Preterm Infants: A Multicenter Cohort Study.
(2020-05-13) Zozaya, Carlos; García González, Inés; Avila-Alvarez, Alejandro; Oikonomopoulou, Niki; Sánchez Tamayo, Tomás; Salguero, Enrique; Saenz de Pipaón, Miguel; García-Muñoz Rodrigo, Fermín; Couce, María L
Background: Data regarding the incidence and mortality of necrotizing enterocolitis trends are scarce in the literature. Recently, some preventive strategies have been confirmed (probiotics) or increased (breastfeeding rate). This study aims to describe the trends of necrotizing enterocolitis incidence, treatment, and mortality over the last decade in Spain. Methods: Multicenter cohort study with data from the Spanish Neonatal Network-SEN1500 database. The study period comprised from January 2005 to December 2017. Preterm infants

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