IIS BioBizkaia - Asociación Instituto de Investigación Sanitaria BioBizkaia (País Vasco)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16976

La Misión del Instituto BioBizkaia es potenciar la investigación traslacional y la innovación sanitaria, para crear valor y generar un impacto en salud para la sociedad: Fomentando la colaboración entre la investigación clínica y básica. Sirviendo de punto de encuentro entre el sistema de salud, la industria y el ecosistema de conocimiento científico y tecnológico. Garantizando la sostenibilidad de la investigación e innovación sanitaria. La potencia de BioBizkaia y sus avances se anclan en tres pilares fundamentales: sus profesionales, la red de alianzas con agentes biotecnológicos y empresas y el apoyo decidido de sus entidades societarias. BioBizkaia ha establecido una red de alianzas con los agentes biotecnológicos, destacándose los acuerdos con CIC bioGUNE, BCAM e Ikerbasque. 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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Epidemiological and clinical characterization of community, healthcare-associated and nosocomial colonization and infection due to carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in Spain
(Springer, 2024-12) Salamanca-Rivera, Elena; Palacios-Baena, Zaira R; Cañada-Garcia, Javier Enrique; Moure García, Zaira; Perez-Vazquez, Maria; Calvo-Montes, Jorge; Martínez-Martínez, Luis; Cantón, Rafael; Ruiz Carrascoso, Guillermo; Pitart, Cristina; Navarro, Ferran; Bou, Germán; Mulet, Xavier; González-López, Juan José; Sivianes, Fran; Delgado-Valverde, Mercedes; Pascual, Álvaro; Oteo-Iglesias, Jesus; Rodríguez-Baño, Jesús; GEMARA/GEIRAS-SEIMC/REIPI CARB-ES-19 Study Group; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Plan Nacional de I+D+i (España); Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: Community-acquired (CA) and healthcare-associated (HCA) infections caused by carbapenemase-producing Enterobacterales (CPE) are not well characterized. The objective was to provide detailed information about the clinical and molecular epidemiological features of nosocomial, HCA and CA infections caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp) and Escherichia coli (CP-Ec). Methods: A prospective cohort study was performed in 59 Spanish hospitals from February to March 2019, including the first 10 consecutive patients from whom CP-Kp or CP-Ec were isolated. Patients were stratified according to acquisition type. A multivariate analysis was performed to identify the impact of acquisition type in 30-day mortality. Results: Overall, 386 patients were included (363 [94%] with CP-Kp and 23 [6%] CP-Ec); in 296 patients (76.3%), the CPE was causing an infection. Acquisition was CA in 31 (8.0%) patients, HCA in 183 (47.4%) and nosocomial in 172 (48.3%). Among patients with a HCA acquisition, 100 (54.6%) had been previously admitted to hospital and 71 (38.8%) were nursing home residents. Urinary tract infections accounted for 19/23 (82.6%), 89/130 (68.5%) and 42/143 (29.4%) of CA, HCA and nosocomial infections, respectively. Overall, 68 infections (23%) were bacteremia (8.7%, 17.7% and 30.1% of CA, HCA and nosocomial, respectively). Mortality in infections was 28% (13%, 14.6% and 42.7% of CA, HCA and nosocomial, respectively). Nosocomial bloodstream infections were associated with increased odds for mortality (adjusted OR, 4.00; 95%CI 1.21-13.19). Conclusions: HCA and CA infections caused by CPE are frequent and clinically significant. This information may be useful for a better understanding of the epidemiology of CPE.
Novel risk loci for COVID-19 hospitalization among admixed American populations
(eLife Sciences Publications, 2024-10-03) Diz-de Almeida, Silvia; Cruz, Raquel; Luchessi, Andre D; Lorenzo-Salazar, José M; López de Heredia, Miguel; Quintela, Inés; González-Montelongo, Rafaela; Nogueira Silbiger, Vivian; Porras, Marta Sevilla; Tenorio Castaño, Jair Antonio; Nevado, Julián; Aguado, José María; Aguilar, Carlos; Aguilera-Albesa, Sergio; Almadana, Virginia; Almoguera, Berta; Alvarez, Nuria; Andreu-Bernabeu, Álvaro; Arana-Arri, Eunate; Arango, Celso; Arranz, María J; Artiga, Maria-Jesus; Baptista-Rosas, Raúl C; Barreda-Sánchez, María; Belhassen-García, Moncef; Bezerra, Joao F; Bezerra, Marcos A C; Boix-Palop, Lucía; Brion, María; Brugada, Ramón; Bustos, Matilde; Calderón, Enrique J; Carbonell, Cristina; Castano, Luis; Castelao, Jose E; Conde-Vicente, Rosa; Cordero-Lorenzana, M Lourdes; Cortes-Sanchez, Jose L; Corton, Marta; Darnaude, M Teresa; De Martino-Rodríguez, Alba; Del Campo-Pérez, Victor; Diaz de Bustamante, Aranzazu; Domínguez-Garrido, Elena; Eirós, Rocío; Fariñas, María Carmen; Fernandez-Nestosa, María J; Fernández-Robelo, Uxía; Fernandez-Rodriguez, Amanda; Fernández-Villa, Tania; Gago-Dominguez, Manuela; Gil-Fournier, Belén; Gómez-Arrue, Javier; González Álvarez, Beatriz; González Bernaldo de Quirós, Fernan; González-Neira, Anna; González-Peñas, Javier; Gutiérrez-Bautista, Juan F; Herrero, María José; Herrero-Gonzalez, Antonio; Jimenez-Sousa, Maria Angeles; Lattig, María Claudia; Liger Borja, Anabel; Lopez-Rodriguez, Rosario; Mancebo, Esther; Martín-López, Caridad; Martín, Vicente; Martinez-Nieto, Oscar; Martinez-Lopez, Iciar; Martinez-Resendez, Michel F; Martinez-Perez, Angel; Mazzeu, Juliana F; Merayo Macías, Eleuterio; Minguez, Pablo; Moreno Cuerda, Victor; Oliveira, Silviene F; Ortega-Paino, Eva; Pompa-Mera, Ericka N; Parellada, Mara; Paz-Artal, Estela; Santos, Ney PC; Pérez-Matute, Patricia; Perez, Patricia; Pérez-Tomás, M Elena; Perucho, Teresa; Pinsach-Abuin, Mel·lina; Pita, Guillermo; Porras-Hurtado, Gloria L; Pujol, Aurora; Ramiro León, Soraya; Resino, Salvador; Fernandes, Marianne R; Rodríguez-Ruiz, Emilio; Rodríguez-Artalejo, Fernando; Rodriguez-Garcia, José A; Ruiz-Cabello, Francisco; Ruiz-Hornillos, Javier; Ryan, Pablo; Soria, José Manuel; Souto, Juan Carlos; Tamayo, Eduardo; Tamayo-Velasco, Álvaro; Taracido-Fernandez, Juan Carlos; Teper, Alejandro; Torres-Tobar, Lilian; Urioste, Miguel; Valencia-Ramos, Juan; Yáñez, Zuleima; Zarate, Ruth; de Rojas, Itziar; Ruiz, Agustín; Sánchez, Pascual; Real, Luis Miguel; SCOURGE Cohort Group; Guillén-Navarro, Encarna; Ayuso, Carmen; Parra, Esteban; Riancho, José A; Rojas-Martinez, Augusto; Flores, Carlos; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Banco Santander; Fundación La Caixa; Agencia Estatal de Investigación (España); Gobierno de Canarias (España); Fundación Canaria de Investigación Sanitaria; Xunta de Galicia (España); Fundación Amancio Ortega; Estrella de Levante; Colabora Mujer
The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations ( and ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.
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).
Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial
(Elsevier, 2021-07-10) Borobia, Alberto M; Carcas, Antonio J; Perez-Olmeda, Mayte; Castaño, Luis; Bertrán, María Jesús; García-Pérez, Javier; Campins, Magdalena; Portolés, Antonio; Gonzalez-Perez, Maria; García Morales, María Teresa; Arana-Arri, Eunate; Aldea, Marta; Díez-Fuertes, Francisco; Fuentes, Inmaculada; Ascaso, Ana; Lora, David; Imaz-Ayo, Natale; Barón-Mira, Lourdes E; Agustí, Antonia; Pérez-Ingidua, Carla; Gómez de la Cámara, Agustín; Arribas, José Ramón; Ochando, Jordi; Alcamí, José; Belda-Iniesta, Cristobal; Frías, Jesús; CombiVacS Study Group; Portoles, Pilar; 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
[EN] Background: To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). Methods: We did a phase 2, open-label, randomised, controlled trial on adults aged 18-60 years, vaccinated with a single dose of ChAdOx1-S 8-12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing. Findings: Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 BAU/mL (7371·53-8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69-112·99) to 3684·87 BAU/mL (3429·87-3958·83). The interventional:control ratio was 77·69 (95% CI 59·57-101·32) for RBD protein and 36·41 (29·31-45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. No serious adverse events were reported. Interpretation: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile. [ES] Antecedentes: No hay datos de eficacia inmunológica procedentes de esquemas de vacunación heteróloga frente a SARS--CoV-2 en humanos. Este estudio evaluó la inmunogenicidad y la reactogenicidad de BNT162b2 (Comirnaty, BioNTech) administrado como segunda dosis en personas que habían recibido previamente una dosis de ChAdOx1-S (Vaxzevria, Astra Zeneca). Método: Realizamos un ensayo clínico de fase 2, abierto, aleatorizado y controlado en adultos de 18 a 59 años, vacunados con una dosis única de ChAdOx1-S entre 8 y 12 semanas antes del cribado, y sin antecedentes de infección por SARS-CoV-2 (EudraCT #2021-001978-37 y NCT04860739). Los participantes fueron asignados al azar (2:1) a un grupo que recibió BNT162b2 (0,3 mL, inyección intramuscular única) y a un grupo de control. Los objetivos principales fueron la reactogenicidad a los 7 días y la respuesta IgG anti-proteína spike a los 14 días, medida ésta a través de inmunoensayos que identificaban la proteína S trimérica del SARS-CoV-2 y el dominio de unión al receptor (RBD) de ésta. La funcionalidad de los anticuerpos y la respuesta inmunitaria celular se evaluaron mediante un ensayo de neutralización de pseudovirus y un inmunoensayo de IFN-gamma, respectivamente. Resultados: Entre el 24 y el 30 de abril de 2021, 676 individuos fueron asignados al azar (n=450 del grupo de intervención, n=226 del grupo de control) en 5 centros de España, y 663 (441 y 222, respectivamente) completaron el estudio al día 14 (edad media de 44 [SD 9], 56% [382] mujeres). En el grupo de intervención, la media geométrica de los títulos de anticuerpos antiRBD (GMT) aumentó de 71.46 BAU/mL (IC del 95%: 59.84-85.33) en el momento inicial a 7756.68 (7371.53; 8161.96) en el día 14 (p < 0-0001). La IgG contra la proteína S trimérica aumentó de 98.4 [85.69-112.99] a 3684.87 [3429.87-3958.83]). La relación respuesta/control fue de 77.69 (IC 95%: 59.57; 101.32) y 36.41 (29.31; 45.23) para la IgG contra la proteína de S trimérica y la RBD, respectivamente. Las reacciones fueron predominantemente leves (1.210; 68%) o moderadas (530; 30%), y la más frecuente consistió en dolor en el lugar de la inyección (395; 88%), induración (159; 35%), dolor de cabeza (199; 44%) y mialgia (194; 43%). No se notificaron acontecimientos adversos graves. Interpretación: El BNT162b2 administrado como segunda dosis en individuos vacunados con una primera dosis de ChAdOx1-S indujo una respuesta inmune robusta con un perfil de reactogenicidad aceptable y manejable.
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.
(2020-05-11) Gonzalez-Quereda, Lidia; Rodriguez, Maria Jose; Diaz-Manera, Jordi; Alonso-Perez, Jorge; Gallardo, Eduard; Nascimento, Andres; Ortez, Carlos; Natera-de Benito, Daniel; Olive, Montse; Gonzalez-Mera, Laura; Munain, Adolfo Lopez de; Zulaica, Miren; Poza, Juan Jose; Jerico, Ivonne; Torne, Laura; Riera, Pau; Milisenda, Jose; Sanchez, Aurora; Garrabou, Gloria; Llano, Isabel; Madruga-Garrido, Marcos; Gallano, Pia
The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients' clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.
Role of personal aptitudes as determinants of incident morbidity, lifestyles, quality of life, use of health services, and mortality (DESVELA cohort): quantitative study protocol for a prospective cohort study in a hybrid analysis
(Frontiers Media, 2023) Martí-Lluch, Ruth; Bolíbar, Bonaventura; Llobera Cànaves, Joan; Maderuelo-Fernández, José A; Magallón-Botaya, Rosa; Sánchez-Pérez, Álvaro; Fernández-Domínguez, Maria José; Motrico, Emma; Vicens-Pons, Enric; Notario-Pacheco, Blanca; Alves-Cabratosa, Lia; Ramos, Rafael
Introduction: The healthcare and well-being of the population depend on multiple factors and should adapt to societal changes. The opposite is also occurring; society has evolved concerning the individuals' approach to their care, which includes participation in decision-making processes. In this scenario, health promotion and prevention become crucial to provide an integrated perspective in the organization and management of the health systems.Health status and well-being depend on many aspects, determinants of health, which in turn may be modulated by individual behavior. Certain models and frameworks try to study the determinants of health and individual human behaviors, separately. However, the interrelation between these two aspects has not been examined in our population.Our main objective is to analyze whether personal aptitudes related to behaviors are independently associated with the incidence of morbidity. A secondary objective will enquire whether these personal aptitudes are independently associated with lower all-cause mortality, enhanced adoption of healthy lifestyles, higher quality of life, and lower utilization of health services during follow-up. Methods: This protocol addresses the quantitative branch of a multicenter project (10 teams) for the creation of a cohort of at least 3,083 persons aged 35 to 74 years from 9 Autonomous Communities (AACC). The personal variables to evaluate are self-efficacy, activation, health literacy, resilience, locus of control, and personality traits. Socio-demographic covariates and social capital will be recorded. A physical examination, blood analysis, and cognitive evaluation will be carried out.Several sets of six Cox models (one for each independent variable) will analyze the incidence of morbidity (objective 1); all-cause mortality and the rest of the dependent variables (objective 2). The models will be adjusted for the indicated covariates, and random effects will estimate Potential heterogeneity between AACC. Discussion: The analysis of the association of certain behavioral patterns and determinants of health is essential and will contribute to improving health promotion and prevention strategies. The description of the individual elements and interrelated aspects that modulate the onset and persistence of diseases will allow the evaluation of their role as prognostic factors and contribute to the development of patient-tailored preventive measures and healthcare.Clinical Trial Registration: ClinicalTrials.gov, NCT04386135. Registered on April 30, 2020.
Regulation of Cortico-Thalamic JNK1/2 and ERK1/2 MAPKs and Apoptosis-Related Signaling Pathways in PDYN Gene-Deficient Mice Following Acute and Chronic Mild Stress
(Multidisciplinary Digital Publishing Institute (MDPI), 2023-01-24) Yáñez-Gómez, Fernando; Ramos-Miguel, Alfredo; García-Sevilla, Jesús A; Manzanares, Jorge; Femenía, Teresa
The crosstalk between the opioidergic system and mitogen-activated protein kinases (MAPKs) has a critical role in mediating stress-induced behaviors related to the pathophysiology of anxiety. The present study evaluated the basal status and stress-induced alterations of cortico-thalamic MAPKs and other cell fate-related signaling pathways potentially underlying the anxiogenic endophenotype of PDYN gene-deficient mice. Compared to littermates, PDYN knockout (KO) mice had lower cortical and or thalamic amounts of the phospho-activated MAPKs c-Jun N-terminal kinase (JNK1/2) and extracellular signal-regulated kinase (ERK1/2). Similarly, PDYN-KO animals displayed reduced cortico-thalamic densities of total and phosphorylated (at Ser191) species of the cell fate regulator Fas-associated protein with death domain (FADD) without alterations in the Fas receptor. Exposure to acute restraint and chronic mild stress stimuli induced the robust stimulation of JNK1/2 and ERK1/2 MAPKs, FADD, and Akt-mTOR pathways, without apparent increases in apoptotic rates. Interestingly, PDYN deficiency prevented stress-induced JNK1/2 and FADD but not ERK1/2 or Akt-mTOR hyperactivations. These findings suggest that cortico-thalamic MAPK- and FADD-dependent neuroplasticity might be altered in PDYN-KO mice. In addition, the results also indicate that the PDYN gene (and hence dynorphin release) may be required to stimulate JNK1/2 and FADD (but not ERK1/2 or Akt/mTOR) pathways under environmental stress conditions.
La Red de Investigación en Actividades Preventivas y Promoción de la Salud (redIAPP): una red de referencia e impulsora de la investigación en atención primaria
(Elsevier, 2023-07-21) Bolibar Ribas, Bonaventura; Llobera Cànaves, Joan; García-Ortiz, Luis; Bellón, Juan-Ángel; Ramos, Rafel; García-Campayo, Javier; Sánchez-Pérez, Álvaro; Claveria, Ana; Martínez, Vicente; Vicens, Enric; Minué, César; Gil-Guillen, Vicente; Berenguera, Anna; Moleras-Serra, Anna
[ES] La Red de Investigación en Actividades Preventivas y Promoción de la Salud (redIAPP), una red de referencia e impulsora de la investigación en atención primaria fue creada en 2003 gracias al programa Redes Temáticas de Investigación Cooperativa en Salud (RETICS) del Instituto de Salud Carlos III (ISCIII). Su creación ha supuesto un cambio radical en la situación de la investigación en atención primaria. A lo largo de sus 19 años (2003-2021) han participado distintos grupos de investigación y comunidades autónomas, y se han desarrollado distintas líneas de investigación con numerosos proyectos y publicaciones. A pesar de las dificultades sufridas, ha creado una experiencia de investigación colaborativa entre distintas comunidades autónomas con gran vitalidad y con importantes resultados para la atención primaria. La redIAPP, por tanto, ha sido un gran referente para la investigación en atención primaria y para la profundización de su área de conocimiento. Se sugieren varias líneas de mejora para el futuro de la investigación en atención primaria. [EN] The Research Network on Preventive Activities and Health Promotion (redIAPP), a reference network and promoter of primary care research was created in 2003 thanks to the program Thematic Networks for Cooperative Research in Health (RETICS) of the Instituto de Salud Carlos III (ISCIII). Its creation has meant a radical change in the situation of research in primary care. Throughout its 19 years (2003-2021), different research groups and autonomous communities have participated, and different lines of research have been developed with numerous projects and publications. Despite the difficulties suffered, it has created a collaborative research experience between different autonomous communities with great vitality and with important results for primary care. The redIAPP, therefore, has been a great reference for research in primary care and for the deepening of its area of knowledge. Several lines of improvement are suggested for the future of primary care research.
A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype
(Frontiers Media, 2022) Cárcel-Márquez, Jara; Muiño, Elena; Gallego-Fabrega, Cristina; Cullell, Natalia; Lledós, Miquel; Llucià-Carol, Laia; Sobrino, Tomas; Campos, Francisco; Castillo, José; Freijo Guerrero, Maria del Mar; Arenillas, Juan Francisco; Obach, Victor; Álvarez-Sabín, José; Molina, Carlos A; Ribo, Marc; Jiménez-Conde, Jordi; Roquer, Jaume; Muñoz-Narbona, Lucia; Lopez-Cancio, Elena; Millán, Mònica; Diaz Navarro, Rosa; Vives-Bauza, Cristofol; Serrano-Heras, Gemma; Segura, Tomas; Ibañez, Laura; Heitsch, Laura; Delgado, Pilar; Dhar, Rajat; Krupinski, Jerzy; Delgado-Mederos, Raquel; Prats-Sánchez, Luis; Camps-Renom, Pol; Blay, Natalia; Sumoy, Lauro; de Cid, Rafael; Montaner, Joan; Cruchaga, Carlos; Lee, Jin-Moo; Martí-Fàbregas, Joan; Fernandez-Cadenas, Israel; Cárcel-Márquez, Jara; Muiño, Elena; Gallego-Fabrega, Cristina; Cullell, Natalia; Lledós, Miquel; Llucià-Carol, Laia; Sobrino, Tomas; Campos, Francisco; Castillo, José; Freijo Guerrero, Maria del Mar; Arenillas, Juan Francisco; Obach, Victor; Álvarez-Sabín, José; Molina, Carlos A; Ribo, Marc; Jiménez-Conde, Jordi; Roquer, Jaume; Muñoz-Narbona, Lucia; Lopez-Cancio, Elena; Millán, Mònica; Diaz Navarro, Rosa; Vives-Bauza, Cristofol; Serrano-Heras, Gemma; Segura, Tomas; Ibañez, Laura; Heitsch, Laura; Delgado, Pilar; Dhar, Rajat; Krupinski, Jerzy; Delgado-Mederos, Raquel; Prats-Sánchez, Luis; Camps-Renom, Pol; Blay, Natalia; Sumoy, Lauro; de Cid, Rafael; Montaner, Joan; Cruchaga, Carlos; Lee, Jin-Moo; Martí-Fàbregas, Joan; Fernandez-Cadenas, Israel
Background: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification. Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10-8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort. Results: We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension. Conclusion: The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.
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.
RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis
(Multidisciplinary Digital Publishing Institute (MDPI), 2021-07) Muiño, Elena; Carcel-Marquez, Jara; Carrera, Caty; Llucia-Carol, Laia; Gallego-Fabrega, Cristina; Cullell, Natalia; Lledos, Miquel; Castillo, Jose; Sobrino, Tomas; Campos, Francisco; Rodriguez-Castro, Emilio; Millan, Monica; Muñoz-Narbona, Lucia; Bustamante, Alejandro; Lopez-Cancio, Elena; Ribo, Marc; Alvarez-Sabin, Jose; Jimenez-Conde, Jordi; Roquer, Jaume; Giralt-Steinhauer, Eva; Soriano-Tarraga, Carolina; Vives-Bauza, Cristofol; Diaz Navarro, Rosa; Tur Campos, Silvia; Obach, Victor; Arenillas, Juan Francisco; Segura, Tomas; Serrano-Heras, Gemma; Marti-Fabregas, Joan; Delgado-Mederos, Raquel; Camps-Renom, Pol; Prats-Sanchez, Luis; Guisado, Daniel; Guasch, Marina; Marin, Rebeca; Martinez-Domeno, Alejandro; Freijo Guerrero, Maria del Mar; Moniche, Francisco; Cabezas, Juan Antonio; Castellanos, Mar; Krupinsky, Jerzy; Strbian, Daniel; Tatlisumak, Turgut; Thijs, Vincent; Lemmens, Robin; Slowik, Agnieszka; Pera, Joanna; Heitsch, Laura; Ibañez, Laura; Cruchaga, Carlos; Dhar, Rajat; Lee, Jin-Moo; Montaner, Joan; Fernandez-Cadenas, Israel; International Stroke Genetic Consortium; Spanish Stroke Genetic Consortium
Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 x 10(-8)) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 x 10(-8)) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-beta, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.
Evaluating the Implementation of a Multicomponent Intervention Consisting of Education and Feedback on Reducing Benzodiazepine Prescriptions by General Practitioners: BENZORED Hybrid Type I Cluster Randomized Controlled Trial
(Multidisciplinary Digital Publishing Institute (MDPI), 2021-08) Socias, Isabel; Leiva, Alfonso; Pombo-Ramos, Haizea; Bejarano, Ferran; Sempere-Verdu, Ermengol; Rodriguez-Rincon, Raquel Maria; Fiol, Francisca; Mengual, Marta; Ajenjo-Navarro, Asuncion; Do Pazo, Fernando; Mateu, Catalina; Folch, Silvia; Alegret, Santiago; Coll, Jose Maria; Martin-Rabadan, Maria; Vicens, Caterina
Background: General practitioners (GPs) in developed countries widely prescribe benzodiazepines (BZDs) for their anxiolytic, hypnotic, and muscle-relaxant effects. Treatment duration, however, is rarely limited, and this results in a significant number of chronic users. Long-term BZD use is associated with cognitive impairment, falls with hip fractures, traffic accidents, and increased mortality. The BENZORED IV trial was a hybrid type-1 trial conducted to evaluate the effectiveness and implementation of an intervention to reduce BZD prescription in primary care. The purpose of this qualitative study was to analyze the facilitators and barriers regarding the implementation of the intervention in primary care settings. Methods: A qualitative interview study with 40 GPs from three Spanish health districts. Focus group meetings with GPs from the intervention arm of the BENZORED IV trial were held at primary healthcare centers in the three districts. For sampling purposes, the GPs were classified as high or low implementers according to the success of the intervention measured at 12 months. The Consolidated Framework for Implementation Research (CFIR) was used to conduct the meetings and to code, rate, and analyze the data. Results: Three of the 41 CFIR constructs strongly distinguished between high and low implementers: the complexity of the intervention, the individual Stage of Change, and the key stakeholder's engagement. Seven constructs weakly discriminated between the two groups: adaptability in the intervention, external policy and incentives, implementation climate, relative priority, self-efficacy, compatibility, and engaging a formally appointed implementation leader. Fourteen constructs did not discriminate between the two groups, six had insufficient data for evaluation, and eleven had no data for evaluation. Conclusions: We identified constructs that could explain differences in the efficacy in implementation of the intervention. This information is relevant for the design of successful strategies for implementation of the intervention.
Effectiveness of a Multicomponent Intervention in Primary Care That Addresses Patients with Diabetes Mellitus with Two or More Unhealthy Habits, Such as Diet, Physical Activity or Smoking: Multicenter Randomized Cluster Trial (EIRA Study)
(Multidisciplinary Digital Publishing Institute (MDPI), 2021-06) Represas-Carrera, Francisco; Couso-Viana, Sabela; Mendez-Lopez, Fatima; Masluk, Barbara; Magallon-Botaya, Rosa; Recio-Rodriguez, Jose I; Pombo, Haizea; Leiva Rus, Alfonso; Gil-Girbau, Montserrat; Motrico, Emma; Marti-Lluch, Ruth; Gude, Francisco; Claveria, Ana
Introduction: We evaluated the effectiveness of an individual, group and community intervention to improve the glycemic control of patients with diabetes mellitus aged 45-75 years with two or three unhealthy life habits. As secondary endpoints, we evaluated the inverventions' effectiveness on adhering to Mediterranean diet, physical activity, sedentary lifestyle, smoking and quality of life. Method: A randomized clinical cluster (health centers) trial with two parallel groups in Spain from January 2016 to December 2019 was used. Patients with diabetes mellitus aged 45-75 years with two unhealthy life habits or more (smoking, not adhering to Mediterranean diet or little physical activity) participated. Centers were randomly assigned. The sample size was estimated to be 420 people for the main outcome variable. Educational intervention was done to improve adherence to Mediterranean diet, physical activity and smoking cessation by individual, group and community interventions for 12 months. Controls received the usual health care. The outcome variables were: HbA1c (main), the Mediterranean diet adherence score (MEDAS), the international diet quality index (DQI-I), the international physical activity questionnaire (IPAQ), sedentary lifestyle, smoking >= 1 cigarette/day and the EuroQuol questionnaire (EVA-EuroQol5D5L). Results: In total, 13 control centers (n = 356) and 12 intervention centers (n = 338) were included with similar baseline conditions. An analysis for intention-to-treat was done by applying multilevel mixed models fitted by basal values and the health center: the HbA1c adjusted mean difference = -0.09 (95% CI: -0.29-0.10), the DQI-I adjusted mean difference = 0.25 (95% CI: -0.32-0.82), the MEDAS adjusted mean difference = 0.45 (95% CI: 0.01-0.89), moderate/high physical activity OR = 1.09 (95% CI: 0.64-1.86), not living a sedentary lifestyle OR = 0.97 (95% CI: 0.55-1.73), no smoking OR = 0.61 (95% CI: 0.54-1.06), EVA adjusted mean difference = -1.26 (95% CI: -4.98-2.45). Conclusions: No statistically significant changes were found for either glycemic control or physical activity, sedentary lifestyle, smoking and quality of life. The multicomponent individual, group and community interventions only showed a statistically significant improvement in adhering to Mediterranean diet. Such innovative interventions need further research to demonstrate their effectiveness in patients with poor glycemic control.
Multiple health behaviour change primary care intervention for smoking cessation, physical activity and healthy diet in adults 45 to 75 years old (EIRA study): a hybrid effectiveness-implementation cluster randomised trial
(BioMed Central (BMC), 2021-12-04) Zabaleta-Del-Olmo, Edurne; Casajuana-Closas, Marc; Lopez-Jimenez, Tomas; Pombo, Haizea; Pons-Vigues, Mariona; Pujol-Ribera, Enriqueta; Cabezas-Peña, Carmen; Llobera Cànaves, Joan; Marti-Lluch, Ruth; Vicens, Caterina; Motrico, Emma; Gomez-Gomez, Irene; Maderuelo-Fernandez, Jose-Angel; Recio-Rodriguez, Jose, I; Masluk, Barbara; Contreras-Martos, Sara; Jacques-Aviño, Constanza; Aznar-Lou, Ignacio; Gil-Girbau, Montserrat; Claveria, Ana; Magallon-Botaya, Rosa; Bellon, Juan-Angel; Ramos, Rafael; Sánchez-Pérez, Álvaro; Moreno-Peral, Patricia; Leiva, Alfonso; Gonzalez-Formoso, Clara; Bolibar, Bonaventura
Background: This study aimed to evaluate the effectiveness of a) a Multiple Health Behaviour Change (MHBC) intervention on reducing smoking, increasing physical activity and adherence to a Mediterranean dietary pattern in people aged 45-75 years compared to usual care; and b) an implementation strategy. Methods: A cluster randomised effectiveness-implementation hybrid trial-type 2 with two parallel groups was conducted in 25 Spanish Primary Health Care (PHC) centres (3062 participants): 12 centres (1481 participants) were randomised to the intervention and 13 (1581 participants) to the control group (usual care). The intervention was based on the Transtheoretical Model and focused on all target behaviours using individual, group and community approaches. PHC professionals made it during routine care. The implementation strategy was based on the Consolidated Framework for Implementation Research (CFIR). Data were analysed using generalised linear mixed models, accounting for clustering. A mixed-methods data analysis was used to evaluate implementation outcomes (adoption, acceptability, appropriateness, feasibility and fidelity) and determinants of implementation success. Results: 14.5% of participants in the intervention group and 8.9% in the usual care group showed a positive change in two or all the target behaviours. Intervention was more effective in promoting dietary behaviour change (31.9% vs 21.4%). The overall adoption rate by professionals was 48.7%. Early and final appropriateness were perceived by professionals as moderate. Early acceptability was high, whereas final acceptability was only moderate. Initial and final acceptability as perceived by the participants was high, and appropriateness moderate. Consent and recruitment rates were 82.0% and 65.5%, respectively, intervention uptake was 89.5% and completion rate 74.7%. The global value of the percentage of approaches with fidelity >= 50% was 16.7%. Eight CFIR constructs distinguished between high and low implementation, five corresponding to the Inner Setting domain. Conclusions: Compared to usual care, the EIRA intervention was more effective in promoting MHBC and dietary behaviour change. Implementation outcomes were satisfactory except for the fidelity to the planned intervention, which was low. The organisational and structural contexts of the centres proved to be significant determinants of implementation effectiveness.
Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits
(Public Library of Science (PLOS), 2020-10) Vogelezang, Suzanne; Bradfield, Jonathan P; Ahluwalia, Tarunveer S; Curtin, John A; Lakka, Timo A; Grarup, Niels; Scholz, Markus; van der Most, Peter J; Monnereau, Claire; Stergiakouli, Evie; Heiskala, Anni; Horikoshi, Momoko; Fedko, Iryna O; Vilor-Tejedor, Natalia; Cousminer, Diana L; Standl, Marie; Wang, Carol A; Viikari, Jorma; Geller, Frank; iniguez, Carmen; Pitkanen, Niina; Chesi, Alessandra; Bacelis, Jonas; Yengo, Loic; Torrent Quetglas, Maties; Ntalla, Ioanna; Helgeland, Øyvind; Selzam, Saskia; Vonk, Judith M; Zafarmand, Mohammed H; Heude, Barbara; Farooqi, Ismaa Sadaf; Alyass, Akram; Beaumont, Robin N; Have, Christian T; Rzehak, Peter; Bilbao, Jose Ramon; Schnurr, Theresia M; Barroso, Ines; Bonnelykke, Klaus; Beilin, Lawrence J; Carstensen, Lisbeth; Charles, Marie-Aline; Chawes, Bo; Clement, Karine; Closa-Monasterolo, Ricardo; Custovic, Adnan; Eriksson, Johan G; Escribano, Joaquin; Groen-Blokhuis, Maria; Grote, Veit; Gruszfeld, Dariusz; Hakonarson, Hakon; Hansen, Torben; Hattersley, Andrew T; Hollensted, Mette; Hottenga, Jouke-Jan; Hyppönen, Elina; Johansson, Stefan; Joro, Raimo; Kähönen, Mika; Karhunen, Ville; Kiess, Wieland; Knight, Bridget A; Koletzko, Berthold; Küehnapfel, Andreas; Landgraf, Kathrin; Langhendries, Jean-Paul; Lehtimäki, Terho; Leinonen, Jaakko T; Li, Aihuali; Lindi, Virpi; Lowry, Estelle; Bustamante, Mariona; Medina-Gomez, Carolina; Melbye, Mads; Michaelsen, Kim F; Morgen, Camilla S; Mori, Trevor A; Nielsen, Tenna RH; Niinikoski, Harri; Oldehinkel, Albertine J; Pahkala, Katja; Panoutsopoulou, Kalliope; Pedersen, Oluf; Pennell, Craig E; Power, Christine; Reijneveld, Sijmen A; Rivadeneira, Fernando; Simpson, Angela; Sly, Peter D; Stokholm, Jakob; Teo, Kook K; Thiering, Elisabeth; Timpson, Nicholas J; Uitterlinden, Andre G; van Beijsterveldt, Catharina E. M; van Schaik, Barbera D. C; Vaudel, Marc; Verduci, Elvira; Vinding, Rebecca K; Vogel, Mandy; Zeggini, Eleftheria; Sebert, Sylvain; Lind, Mads V; Brown, Christopher D; Santa-Marina, Loreto; Reischl, Eva; Frithioff-Bøjsøe, Christine; Meyre, David; Wheeler, Eleanor; Ong, Ken; Nohr, Ellen A; Vrijkotte, Tanja G. M; Koppelman, Gerard H; Plomin, Robert; Njølstad, Pal R; Dedoussis, George D; Froguel, Philippe; Sorensen, Thorkild I. A; Jacobsson, Bo; Freathy, Rachel M; Zemel, Babette S; Raitakari, Olli; Vrijheid, Martine; Feenstra, Bjarke; Lyytikäinen, Leo-Pekka; Snieder, Harold; Kirsten, Holger; Holt, Patrick G; Heinrich, Joachim; Widen, Elisabeth; Sunyer, Jordi; Boomsma, Dorret I; Järvelin, Marjo-Riitta; Köerner, Antje; Davey Smith, George; Holm, Jens-Christian; Atalay, Mustafa; Murray, Clare; Bisgaard, Hans; McCarthy, Mark I; Early Growth Genetics Consortium; Jaddoe, Vincent WV; Grant, Struan FA; Felix, Janine F
The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood. Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. Our results suggest that the biological processes underlying childhood BMI largely overlap with those underlying adult BMI. However, the overlap is not complete. Additionally, the genetic backgrounds of childhood BMI and other cardio-metabolic phenotypes are overlapping. This may mean that the associations of childhood BMI and later cardio-metabolic outcomes are partially explained by shared genetics, but it could also be explained by the strong association of childhood BMI with adult BMI.
Early clinical trials in paediatric oncology in Spain: a nationwide perspective
(Elsevier, 2017-09) Bautista, Francisco; Gallego, Soledad; Canete, Adela; Mora, Jaume; Diaz de Heredia, Cristina; Cruz, Ofelia; Maria Fernandez, Jose; Rives, Susana; Berlanga, Pablo; Hladun, Raquel; Juan Ribelles, Antonio; Madero, Luis; Ramirez, Manuel; Fernandez Delgado, Rafael; Perez-Martinez, Antonio; Mata, Cristina; Llort, Anna; Martin Broto, Javier; Elena Cela, Maria; Ramirez, Gema; Sabado, Constantino; Acha, Tomas; Astigarraga, Itziar; Sastre, Ana; Munoz, Ascension; Guibelalde del Castillo, Mercedes; Sociedad Espanola Hematologia; New Drug Dev Grp Pediat Oncology
Introduction: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. Material and methods: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. Results: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. Conclusions: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
(Nature Publishing Group, 2024-02-19) Pérez-Jurado, Luis Alberto; Cáceres, Alejandro; Balagué-Dobón, Laura; Esko, Tonu; López de Heredia, Miguel; Quintela, Inés; Cruz, Raquel; Lapunzina, Pablo; Carracedo, Ángel; SCOURGE Cohort Group; González, Juan R; Meijome, Xose M; Brochado-Kith, Oscar; Ceballos, Francisco C; Fernandez-Rodriguez, Amanda; Jimenez-Sousa, Maria Angeles; Martin-Vicente, Maria; Resino, Salvador; Virseda-Berdices, Ana; Government of Catalonia (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Estonian Research Council; Instituto de Salud Carlos III; Amancio Ortega Foundation; Banco Santander
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.
Genomic Surveillance Uncovers a 10-Year Persistence of an OXA-24/40 Acinetobacter baumannii Clone in a Tertiary Hospital in Northern Spain
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-02-16) Aranzamendi, Maitane; Xanthopoulou, Kyriaki; Sánchez-Urtaza, Sandra; Burgwinkel, Tessa; Arazo Del Pino, Rocío; Lucaßen, Kai; Perez-Vazquez, Maria; Oteo-Iglesias, Jesus; Sota, Mercedes; Marimón, José María; Seifert, Harald; Higgins, Paul G; Gallego, Lucía; Basque Government (España); Biogipuzkoa Health Research Institute
Infections caused by carbapenem-resistant Acinetobacter baumannii are a global threat causing a high number of fatal infections. This microorganism can also easily acquire antibiotic resistance determinants, making the treatment of infections a big challenge, and has the ability to persist in the hospital environment under a wide range of conditions. The objective of this work was to study the molecular epidemiology and genetic characteristics of two blaOXA24/40Acinetobacter baumannii outbreaks (2009 and 2020-21) at a tertiary hospital in Northern Spain. Thirty-six isolates were investigated and genotypically screened by Whole Genome Sequencing to analyse the resistome and virulome. Isolates were resistant to carbapenems, aminoglycosides and fluoroquinolones. Multi-Locus Sequence Typing analysis identified that Outbreak 1 was mainly produced by isolates belonging to ST3Pas/ST106Oxf (IC3) containing blaOXA24/40, blaOXA71 and blaADC119. Outbreak 2 isolates were exclusively ST2Pas/ST801Oxf (IC2) blaOXA24/40, blaOXA66 and blaADC30, the same genotype seen in two isolates from 2009. Virulome analysis showed that IC2 isolates contained genes for capsular polysaccharide KL32 and lipooligosacharide OCL5. A 8.9 Kb plasmid encoding the blaOXA24/40 gene was common in all isolates. The persistance over time of a virulent IC2 clone highlights the need of active surveillance to control its spread.
A second update on mapping the human genetic architecture of COVID-19
(Nature Publishing Group, 2023-09) COVID-19 Host Genetics Initiative; Fernandez-Rodriguez, Amanda; Jimenez-Sousa, Maria Angeles; Ceballos, Francisco C; Resino, Salvador
Switching to Glycerol Phenylbutyrate in 48 Patients with Urea Cycle Disorders: Clinical Experience in Spain.
(2022-08-28) Martín-Hernández, Elena; Quijada-Fraile, Pilar; Correcher, Patricia; Meavilla, Silvia; Sánchez-Pintos, Paula; de Las Heras Montero, Javier; Blasco-Alonso, Javier; Dougherty, Lucy; Marquez, Ana; Peña-Quintana, Luis; Cañedo, Elvira; García-Jimenez, María Concepción; Moreno Lozano, Pedro Juan; Murray Hurtado, Mercedes; Camprodon Gómez, María; Barrio-Carreras, Delia; de Los Santos, Mariela; Del Toro, Mireia; Couce, María L; Vitoria Miñana, Isidro; Morales Conejo, Montserrat; Bellusci, Marcello
Background and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 μmol/L, p

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