Instituto de Investigación Biomédica de Málaga - Plataforma Bionand (IBIMA)
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Publication Cohort profile: the CORDELIA study (Collaborative cOhorts Reassembled Data to study mEchanisms and Longterm Incidence of chronic diseAses).(Kluwer Academic Publishers, 2025-05-12) Hernáez, Álvaro; Camps-Vilaró, Anna; Polo-Alonso, Sara; Subirana, Isaac; Ramos, Rafel; de Cid, Rafael; Rodríguez-Artalejo, Fernando; Elosua, Roberto; Chirlaque, M Dolores; Amiano, Pilar; Bermúdez-López, Marcelino; Guevara, Marcela; Cinza-Sanjurjo, Sergio; Sánchez, María José; de León, Antonio Cabrera; Laclaustra, Martín; Rojo-Martínez, Gemma; Guembe-Suescun, María J; Pérez-Gómez, Beatriz; Vega-Alonso, Tomás; Torán-Monserrat, Pere; Lora-Pablos, David; Huerta, José María; Valdivielso, José M; Dégano, Irene R; Félix-Redondo, Francisco J; Gandarillas, Ana María; Valdés, Sergio; Mundet-Tuduri, Xavier; Sánchez, Pedro L; Martín-Sánchez, Vicente; Rigo, Fernando; Alonso-Sampedro, Manuela; Moreno-Iribas, Conchi; Martín-Escudero, Juan Carlos; Delgado, Elías; Grau, Maria; Urrutia, Inés; Ovejero, Diana; Quintela, Inés; Martí-Lluch, Ruth; Blay, Natalia; Banegas, José R; Tizón-Marcos, Helena; Gómez, Jesús Humberto; Aizpurua, Amaia; Castro-Boqué, Eva; Delfrade, Josu; Prieto-Díaz, Miguel Ángel; Rodríguez-Barranco, Miguel; Almeida-González, Delia; Moreno-Franco, Belén; Oualla-Bachiri, Wasima; Sayón-Orea, Carmen; Plans-Beriso, Elena; Lozano, José Eugenio; López-Lifante, Víctor M; Cancelas-Navia, Pilar; Cabrera-Castro, Natalia; Cambray, Serafí; Zacarías-Pons, Lluís; Fernández-Bergés, Daniel; Donoso-Navarro, Encarnación; Maldonado-Araque, Cristina; Franch-Nadal, Josep; Dorado-Díaz, Pedro Ignacio; Villarín-Castro, Alejandro; Frontera-Juan, Guillem; Gude, Francisco; Andueza, Naroa; Téllez-Plaza, María; Ares-Blanco, Jessica; Cruz, Raquel; Ribas-Aulinas, Marc; Barretina, Jordi; Guallar-Castillón, Pilar; Caínzos-Achirica, Miguel; Colorado-Yohar, Sandra Milena; Llorente, Adrián; Diaz-Tocados, Juan Miguel; Ardanaz, Eva; Micó-Pérez, Rafael Manuel; Fernández-Martínez, Nicolás Francisco; Del Cristo Rodríguez-Pérez, María; Cenarro, Ana; Calle-Pascual, Alfonso L; Marrugat, Jaume; [Sanchez-Perez,MJ; Rodriguez-Barranco,M; Fernandez-Martinez,NF] CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.; [Sanchez-Perez,MJ; Rodriguez-Barranco,M; Fernandez-Martinez,NF] Escuela Andaluza de Salud Pública, Granada, Spain.; [Sanchez-Perez,MJ; Rodriguez-Barranco,M; Fernandez-Martinez,NF] Instituto de Investigación Biosanitaria Ibs.GRANADA, Granada, Spain.; Instituto de Salud Carlos III; European UnionThe CORDELIA Study (Collaborative Cohorts Reassembled Data to Study Mechanisms and Long-term Incidence of Chronic Diseases) combines 35 Spanish population cohorts to investigate the clinical, environmental, genetic, and omics determinants of cardiovascular disease in the Southern European population. It aims to conduct the largest genome-wide association study to date on cardiovascular disease in this population, improve predictions of cardiovascular incidence using genomic and clinical data, and identify subgroups that would benefit most from targeted pharmacological and lifestyle interventions. CORDELIA includes 196,632 individuals (ages 18-84, 54% female, 96% born in Spain, 20% with higher education, recruited from 1989 to 2020, with follow-up periods ranging from 5 to 30 years), with DNA samples available for 117,342 participants (60%). Of the participants, 24% were current smokers, 43% hypertensive, 11% diabetic, 15% medicated with lipid-lowering drugs, 44% overweight, and 27% obese. If not already available, genotyping is being performed using the Axiom™ Spain Biobank array (~ 750,000 variants, including 115,000 specific and 50,000 rare functional variants from the Spanish population). The cohort also includes incident events (coronary heart disease, stroke, heart failure, peripheral artery disease, hypertension, diabetes); date and cause of death; and harmonized data on risk factors (body mass index, waist circumference, lipid profile, blood pressure, glucose, creatinine), lifestyle (smoking, physical activity, diet, alcohol), and socioeconomic status. 99,019 participants (50%) also provide plasma samples. CORDELIA will significantly contribute to understanding the complex interplay of risk factors contributing to cardiovascular disease and advance the fields of precision medicine and public health in Southern European individuals.Publication Efficacy and safety of cosibelimab, an anti-PD-L1 antibody, in metastatic cutaneous squamous cell carcinoma(BMJ Group, 2023-10-17) Clingan, Philip; Ladwa, Rahul; Brungs, Daniel; Harris, Dean Laurence; McGrath, Margaret; Arnold, Susan; Coward, Jermaine; Fourie, Samuel; Kurochkin, Andriy; Malan, Daniel R.; Mant, Andrew; Sharma, Vinay; Shue, Hong; Tazbirkova, Andrea; Berciano-Guerrero, Miguel-Angel; Charoentum, Chaiyut; Dalle, Stephane; Dechaphunkul, Arunee; Dudnichenko, Oleksandr; Koralewski, Piotr; Lugowska, Iwona; Montaudie, Henri; Munoz-Couselo, Eva; Sriuranpong, Virote; Oliviero, James; Desai, Jayesh; Checkpoint TherapeuticsProgrammed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab.MethodsIn this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety.ResultsObjective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (>= 15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported.ConclusionsCosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile.Publication T-cell changes induced by desensitisation to BRAF inhibitors in two patients with DRESS.(Wiley-Blackwell Publishing, 2021-06-30) Salas, Maria; Berciano-Guerrero, Miguel-Angel; Palomares, Francisca; Rueda, Antonio; Fernandez, Tahia D; Mayorga, Cristobalina; Torres, Maria Jose; Andalusian Regional Ministry Health; Institute of Health “Carlos III” of the Ministry of Economy and CompetitivenessTo the Editor,Melanoma is an aggressive skin cancer, with low survival rates in pa-tients with advanced disease. Melanoma patients present mutationsin genes encoding kinases that participate in the mitogen-activatedprotein kinases (MAPK) cascade, such as RAF, encoded in BRAFgene and MEK.1 The commonest melanoma mutation is the V600E,which produces an abnormal protein that activates the MAPK cas-cade inducing cellular alterations. Besides surgical excision, there are different options according to clinical stage, like the use of drugcombinations as BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi),which inhibit the MAPK cascade activation. 2 This combination in-creases treatment effectiveness, decreases adverse effects andprevents drug resistance. 3 These drugs can induce severe cutane-ous allergic reactions (SCAR). 4 Generally, desensitisation in SCAR iscontraindicated. Moreover, in melanoma patients, desensitisationseems to be the only procedure that allows them to continue withtreatment. We have studied two melanoma patients (P1 and P2)who developed drug rash with eosinophilia and systemic symptoms(DRESS) after BRAFi administration and who tolerated this drugafter desensitisation. We have assessed T-cell involvement in skinbiopsies and peripheral blood samples at acute phase (T0), and im-munological response after desensitisation (T1). Additionally, prolif-erative response was assessed at two times.Publication Immune checkpoint inhibition in metastatic or non-resectable melanoma after failure of adjuvant anti-PD-1 treatment. A EUMelaReg real-world evidence study.(Elsevier, 2025-03-07) Weichenthal, Michael; Ellebaek, Eva; Mangana, Joanna; Asher, Nethanel; Gavrilova, Iva; Kandolf, Lidija; Ugurel, Selma; Hausschild, Axel; Meier, Friedegund; Leiter, Ulrike; Livingstone, Elisabeth; Gebhardt, Christoffer; Gutzmer, Ralf; Ruhlmann, Christina H; Mahncke-Guldbrandt, Louise; Haslund, Charlotte A; Kopec, Sylwia; Teterycz, Paweł; Bender, Marc; Poudroux, Wilfried; Muñoz-Couselo, Eva; Berciano-Guerrero, Miguel-Angel; Shalamanova, Gergana; DePalo, Danielle K; Brozic, Jasmina Maric; Chiarion-Sileni, Vanna; Arance, Anna; Ziogas, Dimitrios; Robert, Caroline; van-de-Velde, Anthonie Obik; Gassama, Awa Aminata; Shapira, Ronnie; BenBetzalel, Guy; Grynberg, Shirly; Ramelyte, Egle; Bertoldo, Fabio; DelPrete, Valerio; Gaudy-Marqueste, Caroline; Mohr, Peter; Dummer, Reinhard; Ascierto, Paolo A; Gogas, Helen; Espinosa, Enrique; Lebbe, Celeste; Rutkowski, Piotr; Haanen, John; Schadendorf, Dirk; Svane, Inge Marie; EUMelaReg Consortium MembersBackground: Adjuvant immune checkpoint inhibition (ICI) with anti-PD-1 antibodies in high-risk resected melanoma has been shown to improve recurrence-free survival. It is unclear whether prior adjuvant anti-PD-1 therapy is associated with altered response to subsequent ICI treatment in the metastatic setting. Methods: Using data from the European Melanoma Registry (EUMelaReg), we analyzed the efficiency of first-line (1L) ICI in non-resectable or metastatic melanoma after failure from prior adjuvant anti-PD-1 treatment. Both single-agent anti-PD-1 and combined anti-PD-1/CTLA-4 (Ipi/Nivo) 1L regimes were included in the analysis. We identified 389 patients receiving 1L ICI with prior adjuvant anti-PD-1 treatment. The control population was selected from a pool of 3390 PD-1-naive cases by 1:1 matching for the type of 1L ICI and various prognostic factors. As outcome measure, overall remission rates (ORR) were calculated and progression-free survival (PFS) was evaluated by Kaplan-Meier and Cox regression analysis. Results: Out of 389 patients, 303 (77.9 %) received Ipi/Nivo and 86 (22.1 %) anti-PD-1 in 1L. ORR was significantly lower in pre-treated patients (31.4 %) as compared to anti-PD-1 naive patients (48.8 %; p < 0.0001). Kaplan-Meier analysis showed significantly shorter median PFS for pre-treated patients. This applied to both anti-PD-1 and Ipi/Nivo treatment. Patients with early recurrence from adjuvant treatment (during or up to 12 weeks after end of treatment) showed lower ORR (28.5 %) and shorter PFS (3.1 months) than those who recurred later (37.7 % and 6.1 months, respectively). Conclusions: Patients with metastatic melanoma, previously exposed to anti-PD-1 ICI in the adjuvant setting showed significantly lower ORR and shorter PFS to 1L ICI with either Ipi/Nivo or single-agent anti-PD-1 retreatment.Publication Plan de Investigación, Desarrollo e innovación del Centro de Emergencias Sanitarias 061. Servicio Andaluz de Salud.(Centro de Emergencias Sanitarias, Junta de Andalucía, 2024-12-20) Luque-Hernández, María José; Romero-Olóriz, Carlos; Péculo-Carrasco, Juan Antonio; Castro-García. Susana de; Juan-Roldán, José-Ignacio; Gallego-España, Francisco-José; Parias-Ángel, María-Nieves; Roldán-Ortega, José-Manuel; Baena-Jiménez, Rosa-María; Sanjuán-Jiménez, Rocío; [Luque-Hernandez,MJ] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Romero-Olóriz,C] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Péculo-Carrasco,JA] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Castro-García.S] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Juan-Roldán,JI] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Gallego-España,FJ] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Parias-Ángel,MN] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Roldán-Ortega,JM] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Baena-Jiménez,RM] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.; [Sanjuán-Jiménez,R] Centro de Emergencias Sanitarias 061 Andalucía. Servicio Andaluz de Salud. Consejería de Salud y Consumo. Junta de Andalucía.El Centro de Emergencias Sanitarias 061 (CES061) reconoce la importancia de la investigación y la innovación para mejorar la calidad de la atención prehospitalaria, estableciendo directrices y objetivos para integrarlas en su operativa diaria. Estas actividades no solo permiten optimizar protocolos y tecnologías, sino también contribuir al avance del conocimiento en emergencias sanitarias, posicionando al centro como un referente en el sector. En este sentido, el CES061 reafirma su compromiso con la investigación y la innovación como pilares fundamentales para la mejora continua de los servicios prehospitalarios. El plan de I+D+i 2025-2030 establece una hoja de ruta centrada en la integración de nuevas tecnologías, la generación de conocimiento y la transferencia de resultados a la práctica asistencial, en alineación con los estándares europeos y nacionales en la materia. Con ello, el CES061 busca consolidarse como un referente nacional e internacional en la investigación e innovación en emergencias sanitarias y fortalecer su papel en la gestión eficiente de situaciones críticas. Este plan sigue los principios de gestión de la I+D+i de la Norma Española UNE 166002:2021, basada en la generación de conocimiento, la realización de valor, el liderazgo orientado al futuro, la dirección estratégica, la cultura innovadora, las ideas con propósito, la gestión de la incertidumbre, la adaptabilidad y el enfoque sistémico.Item The Nutritional Profile of Food Advertising for School-Aged Children via Television: A Longitudinal Approach.(2020-11-17) Campos, Daniel; Escudero-Marín, Mireia; Snitman, Camila M; Torres-Espínola, Francisco J; Azaryah, Hatim; Catena, Andrés; Campoy, CristinaThe prevalence of childhood obesity continues to increase. Screen time, one of the most documented reasons for the obesogenic environment, enhances childhood obesity, since advertisements for unhealthy food products are still broadcast on channels for children. This is presently one of the main challenges for the government in Spain, since the current laws and obligations are not updated. This study aims to analyze food advertising aimed at children on Spanish television in 2013 and 2018 on children's and general channels to test the effect of laws and obligations over time. In total, we viewed 512 h of the most viewed channels, two children's and two general channels, during the week and on weekends during specific periods of 2013 and 2018. Food advertising was categorized as core, non-core, and other food advertisement (CFA, NCFA, and OFA, respectively) according to the nutritional profile. A total of 2935 adverts were analyzed, 1263 in 2013 and 1672 in 2018. A higher proportion of NCFAs were broadcast on children's channels than in prior years, rising from 52.2% to 69.8% (p 2.5; pItem Contribution of a GATA4-Expressing Hematopoietic Progenitor Lineage to the Adult Mouse Endothelium.(MDPI AG, 2020-05-19) Carmona, Rita; Diaz del-Moral, Sandra ; Barrena, Silvia; Muñoz-Chapuli, Ramon; Spanish Ministry of Science, Innovation and Universities/FEDER, UE; Instituto de Salud Carlos III-TERCEL; Consejería de Salud and Consejería de Economía y Conocimiento, Junta de AndalucíaDifferent sources have been claimed for the embryonic origin of the coronary endothelium. Recently, the potential of circulating cells as progenitors of the cardiac endothelium has also been suggested. In a previous study we have shown that circulating progenitors are recruited by the embryonic endocardium and incorporated into the coronary vessels. These progenitors derive from a mesodermal lineage characterized by the expression of Gata4 under control of the enhancer G2. Herein, we aim to trace this specific lineage throughout postnatal stages. We have found that more than 50% of the adult cardiac endothelium derives from the G2-GATA4 lineage. This percentage increases from embryos to adults probably due to differential proliferation and postnatal recruitment of circulating endothelial progenitors. In fact, injection of fetal liver or placental cells in the blood stream of neonates leads to incorporation of G2-GATA4 lineage cells to the coronary endothelium. On the other hand, labeling of the hematopoietic lineage by the stage E7.5 also resulted in positive coronary endothelial cells from both, embryos and adults. Our results suggest that early hematopoietic progenitors recruited by the embryonic ventricular endocardium can become the predominant source of definitive endothelium during the vascularization of the heart.Item Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease(Mdpi, 2021-12-01) Barrios, Vicente; Chowen, Julie A.; Martin-Rivada, Alvaro; Guerra-Cantera, Santiago; Pozo, Jesus; Yakar, Shoshana; Rosenfeld, Ron G.; Perez-Jurado, Luis A.; Suarez, Juan; Argente, Jesus; [Barrios, Vicente] Hosp Infantil Univ Nino Jesus, Dept Pediat, Madrid 28009, Spain; [Chowen, Julie A.] Hosp Infantil Univ Nino Jesus, Dept Pediat, Madrid 28009, Spain; [Martin-Rivada, Alvaro] Hosp Infantil Univ Nino Jesus, Dept Pediat, Madrid 28009, Spain; [Guerra-Cantera, Santiago] Hosp Infantil Univ Nino Jesus, Dept Pediat, Madrid 28009, Spain; [Pozo, Jesus] Hosp Infantil Univ Nino Jesus, Dept Pediat, Madrid 28009, Spain; [Argente, Jesus] Hosp Infantil Univ Nino Jesus, Dept Pediat, Madrid 28009, Spain; [Barrios, Vicente] Hosp Infantil Univ Nino Jesus, Dept Pediat Endocrinol, Madrid 28009, Spain; [Chowen, Julie A.] Hosp Infantil Univ Nino Jesus, Dept Pediat Endocrinol, Madrid 28009, Spain; [Martin-Rivada, Alvaro] Hosp Infantil Univ Nino Jesus, Dept Pediat Endocrinol, Madrid 28009, Spain; [Guerra-Cantera, Santiago] Hosp Infantil Univ Nino Jesus, Dept Pediat Endocrinol, Madrid 28009, Spain; [Pozo, Jesus] Hosp Infantil Univ Nino Jesus, Dept Pediat Endocrinol, Madrid 28009, Spain; [Argente, Jesus] Hosp Infantil Univ Nino Jesus, Dept Pediat Endocrinol, Madrid 28009, Spain; [Barrios, Vicente] La Princesa Res Inst, Madrid 28009, Spain; [Chowen, Julie A.] La Princesa Res Inst, Madrid 28009, Spain; [Martin-Rivada, Alvaro] La Princesa Res Inst, Madrid 28009, Spain; [Pozo, Jesus] La Princesa Res Inst, Madrid 28009, Spain; [Argente, Jesus] La Princesa Res Inst, Madrid 28009, Spain; [Barrios, Vicente] Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Madrid 28029, Spain; [Chowen, Julie A.] Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Madrid 28029, Spain; [Argente, Jesus] Inst Salud Carlos III, Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, Madrid 28029, Spain; [Chowen, Julie A.] CEI UAM, IMDEA Food Inst, Madrid 28049, Spain; [Argente, Jesus] CEI UAM, IMDEA Food Inst, Madrid 28049, Spain; [Chowen, Julie A.] CSIC, Madrid 28049, Spain; [Argente, Jesus] CSIC, Madrid 28049, Spain; [Pozo, Jesus] Univ Autonoma Madrid, Dept Pediat, Madrid 28049, Spain; [Argente, Jesus] Univ Autonoma Madrid, Dept Pediat, Madrid 28049, Spain; [Yakar, Shoshana] NYU, Dept Mol Pathobiol, David B Kriser Dent Ctr, Coll Dent, New York, NY 10010 USA; [Rosenfeld, Ron G.] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97239 USA; [Perez-Jurado, Luis A.] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Genet Unit, Barcelona 08003, Spain; [Perez-Jurado, Luis A.] Hosp Mar, Serv Genet, Barcelona 08003, Spain; [Perez-Jurado, Luis A.] Hosp Mar Res Inst IMIM, Barcelona 08003, Spain; [Perez-Jurado, Luis A.] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona 08036, Spain; [Suarez, Juan] Univ Malaga, Dept Anat Humana Med Legal & Hist Ciencia, Malaga 29071, Spain; [Suarez, Juan] Inst Invest Biomed Malaga IBIMA, Malaga 29010, Spain; Spanish Ministry of Science and Innovation with the help of European FEDER; Ministerio de Economia y Competitividad; Network Center for Biomedical Research on Obesity and Nutrition (CIBEROBN) Instituto Carlos III; CIBEROBNThe growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.Item Impact of Glucocorticoid on a Cellular Model of Parkinson's Disease: Oxidative Stress and Mitochondrial Function.(2021-08-22) Claros, Silvia; Gil, Antonio; Martinelli, Mauro; Valverde, Nadia; Lara, Estrella; Boraldi, Federica; Pavia, Jose; Martín-Montañez, Elisa; Garcia-Fernandez, MaríaStress seems to contribute to the neuropathology of Parkinson's disease (PD), possibly by dysregulation of the hypothalamic-pituitary-adrenal axis. Oxidative distress and mitochondrial dysfunction are key factors involved in the pathophysiology of PD and neuronal glucocorticoid-induced toxicity. Animal PD models have been generated to study the effects of hormonal stress, but no in vitro model has yet been developed. Our aim was to examine the impact of corticosterone (CORT) administration on a dopaminergic neuronal cell model of PD induced by the neurotoxin MPP+, as a new combined PD model based on the marker of endocrine response to stress, CORT, and oxidative-mitochondrial damage. We determined the impact of CORT, MPP+ and their co-incubation on reactive oxygen species production (O2-•), oxidative stress cellular markers (advanced-oxidation protein products and total antioxidant status), mitochondrial function (mitochondrial membrane potential and mitochondrial oxygen consumption rate) and neurodegeneration (Fluoro-Jade staining). Accordingly, the administration of MPP+ or CORT individually led to cell damage compared to controls (pItem Patient and Public Involvement in Youth Mental Health Research: Protocol for a Systematic Review of Practices and Impact(Frontiers media sa, 2021-11-05) Sales, Celia M. D.; Martins, Filipa; Alves, Marisa M.; Carletto, Sara; Conejo-Ceron, Sonia; da Silva, Luis Costa; Cus, Anja; Edridge, Chloe; Ferreira, Nuno; Hancheva, Camellia; Lima, Esperanca M. A.; Liverpool, Shaun; Midgley, Nick; Moltrecht, Bettina; Moreno-Peral, Patricia; Morgan, Nicholas; Mortimer, Rose; Mota, Catarina Pinheiro; Pietrabissa, Giada; Sousa, Sonia; Ulberg, Randi; Edbrooke-Childs, Julian; [Sales, Celia M. D.] Univ Porto, Fac Psychol & Educ Sci, Porto, Portugal; [Martins, Filipa] Univ Porto, Fac Psychol & Educ Sci, Porto, Portugal; [Alves, Marisa M.] Univ Porto, Fac Psychol & Educ Sci, Porto, Portugal; [Lima, Esperanca M. A.] Univ Porto, Fac Psychol & Educ Sci, Porto, Portugal; [Sales, Celia M. D.] Univ Porto CPUP, Ctr Psychol, Porto, Portugal; [Carletto, Sara] Univ Torino, Dept Neurosci Rita Levi Montalcini, Turin, Italy; [Conejo-Ceron, Sonia] Biomed Res Inst Malaga IBIMA, Malaga, Spain; [Moreno-Peral, Patricia] Biomed Res Inst Malaga IBIMA, Malaga, Spain; [da Silva, Luis Costa] UCL, Evidence Based Practice Unit, London, England; [Edridge, Chloe] UCL, Evidence Based Practice Unit, London, England; [Liverpool, Shaun] UCL, Evidence Based Practice Unit, London, England; [Midgley, Nick] UCL, Evidence Based Practice Unit, London, England; [Moltrecht, Bettina] UCL, Evidence Based Practice Unit, London, England; [Mortimer, Rose] UCL, Evidence Based Practice Unit, London, England; [Mota, Catarina Pinheiro] UCL, Evidence Based Practice Unit, London, England; [Edbrooke-Childs, Julian] UCL, Evidence Based Practice Unit, London, England; [da Silva, Luis Costa] Anna Freud Natl Ctr Children & Families, Clin Educ & Hlth Psychol, London, England; [Edridge, Chloe] Anna Freud Natl Ctr Children & Families, Clin Educ & Hlth Psychol, London, England; [Liverpool, Shaun] Anna Freud Natl Ctr Children & Families, Clin Educ & Hlth Psychol, London, England; [Midgley, Nick] Anna Freud Natl Ctr Children & Families, Clin Educ & Hlth Psychol, London, England; [Moltrecht, Bettina] Anna Freud Natl Ctr Children & Families, Clin Educ & Hlth Psychol, London, England; [Mortimer, Rose] Anna Freud Natl Ctr Children & Families, Clin Educ & Hlth Psychol, London, England; [Mota, Catarina Pinheiro] Anna Freud Natl Ctr Children & Families, Clin Educ & Hlth Psychol, London, England; [Edbrooke-Childs, Julian] Anna Freud Natl Ctr Children & Families, Clin Educ & Hlth Psychol, London, England; [da Silva, Luis Costa] Anna Freud Natl Ctr Children & Families, Child Outcomes Res Consortium, London, England; [Edridge, Chloe] Anna Freud Natl Ctr Children & Families, Child Outcomes Res Consortium, London, England; [Morgan, Nicholas] Anna Freud Natl Ctr Children & Families, Child Outcomes Res Consortium, London, England; [Edbrooke-Childs, Julian] Anna Freud Natl Ctr Children & Families, Child Outcomes Res Consortium, London, England; [Cus, Anja] Med Univ Vienna, Dept Child & Adolescent Psychiat, Vienna, Austria; [Ferreira, Nuno] Univ Nicosia, Dept Social Sci, Nicosia, Cyprus; [Hancheva, Camellia] Sofia Univ St Kliment Ohridski, Sofia, Bulgaria; [Liverpool, Shaun] Edge Hill Univ, Fac Hlth Social Care & Med, Ormskirk, England; [Mota, Catarina Pinheiro] Univ Tras Os Montes & Alto Dour, Clin Educ & Hlth Psychol, Vila Real, Portugal; [Pietrabissa, Giada] Cathol Univ Milan, Dept Psychol, Milan, Italy; [Pietrabissa, Giada] Ist Auxol Italiano IRCCS, Psychol Res Lab, Milan, Italy; [Sousa, Sonia] Tallinn Univ, Sch Digital Technol, Tallinn, Estonia; [Ulberg, Randi] Univ Oslo, Inst Clin Med, Div Mental Hlth & Addict, Oslo, Norway; [Edbrooke-Childs, Julian] Diakonhjemmet Hosp, Dept Psychiat, Oslo, Norway; COST Action; COST (European Cooperation in Science and Technology)Various health settings have advocated for involving patients and members of the public (PPI) in research as a means to increase quality and relevance of the produced knowledge. However, youth PPI has been an understudied area. This protocol paper describes a new project that aims to summarize what is known about PPI with young people in mental health research. In line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses Statement guidelines we will identify and appraise suitable articles and extract and synthesize relevant information including at least two reviewers at each stage of the process. Results will be presented in two systematic reviews that will describe (a) how youth PPI has been conducted (Review1) and (b) what impact youth PPI had on the subsequent research and on stakeholders (Review2). To our knowledge, this is the first set of reviews that uses a critical appraisal tool, which is co-developed with children and young people. Findings from this project will provide valuable insights and set out the key steps to adopting adequate PPI methods when involving children and young people in mental health research.Item Sandwich-Type Electrochemical Paper-Based Immunosensor for Claudin 7 and CD81 Dual Determination on Extracellular Vesicles from Breast Cancer Patients.(2020-12-10) Ortega, Francisco G; Regiart, Matías D; Rodríguez-Martínez, Alba; de Miguel-Pérez, Diego; Serrano, María J; Lorente, José A; Tortella, Gonzalo; Rubilar, Olga; Sapag, Karim; Bertotti, Mauro; Fernández-Baldo, Martín AThis study is focused on identifying novel epithelial markers in circulating extracellular vesicles (EVs) through the development of a dual sandwich-type electrochemical paper-based immunosensor for Claudin 7 and CD81 determination, as well as its validation in breast cancer (BC) patients. This immunosensor allows for rapid, sensitive, and label-free detection of these two relevant BC biomarkers. Under optimum conditions, the limit of detection for Claudin 7 was 0.4 pg mL-1, with a wide linear range of 2 to 1000 pg mL-1, while for CD81, the limit of detection was 3 pg mL-1, with a wide linear range of 0.01 to 10 ng mL-1. Finally, we validated Claudin 7 and CD81 determination in EVs from 60 BC patients and 20 healthy volunteers, reporting higher diagnostic accuracy than the one observed with classical diagnostic markers. This analysis provides a low-cost, specific, versatile, and user-friendly strategy as a robust and reliable tool for early BC diagnosis.Item Mediators and Theories of Change in Psychotherapy for Young People With Personality Disorders: A Systematic Review Protocol.(2021-09-20) Volkert, Jana; Taubner, Svenja; Barkauskiene, Rasa; Mestre, Jose M; Sales, Célia M D; Thiele, Vanessa; Saliba, Andrea; Protić, Sonja; Adler, Asta; Conejo-Cerón, Sonia; Di Giacomo, Dina; Ioannou, Yianna; Moreno-Peral, Patricia; Vieira, Filipa Mucha; Mota, Catarina Pinheiro; Raleva, Marija; Rangel Santos Henriques, Margarida Isabel; Røssberg, Jan Ivar; Schmidt, Stefanie J; Perdih, Tjasa Stepisnik; Ulberg, Randi; Heinonen, ErkkiBackground: Personality disorders (PDs) are a severe health issue already prevalent among adolescents and young adults. Early detection and intervention offer the opportunity to reduce disease burden and chronicity of symptoms and to enhance long-term functional outcomes. While psychological treatments for PDs have been shown to be effective for young people, the mediators and specific change mechanisms of treatment are still unclear. Aim: As part of the "European Network of Individualized Psychotherapy Treatment of Young People with Mental Disorders" (TREATme), funded by the European Cooperation in Science and Technology (COST), we will conduct a systematic review to summarize the existing knowledge on mediators of treatment outcome and theories of change in psychotherapy for young people with personality disorders. In particular, we will evaluate whether mediators appear to be common or specific to particular age groups, treatment models, or outcome domains (e.g., psychosocial functioning, life quality, and adverse treatment effects). Method: We will follow the reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. Electronic databases (PubMed and PsycINFO) have been systematically searched for prospective, longitudinal, and case-control designs of psychological treatment studies, which examine mediators published in English. Participants will be young people between 10 and 30years of age who suffer from subclinical personality symptoms or have a personality disorder diagnosis and receive an intervention that aims at preventing, ameliorating, and/or treating psychological problems. Results: The results will be published in a peer-reviewed journal and at conference presentations and will be shared with relevant stakeholder groups. The data set will be made available to other research groups following recommendations of the open science initiative. Databases with the systematic search will be made openly available following open science initiatives. The review has been registered in PROSPERO (evaluation is pending, registration number ID 248959). Implications: This review will deliver a comprehensive overview on the empirical basis to contribute to the further development of psychological treatments for young people with personality disorders.Item Patients with Axial Spondyloarthritis Show an Altered Flexion/Relaxation Phenomenon(Mdpi, 2021-05-01) Aranda-Valera, I. Concepcion; Garrido-Castro, Juan Luis; Martinez-Galisteo, Alfonso; Pena-Amaro, Jose; Gonzalez-Navas, Cristina; Cuesta-Vargas, Antonio; Jimenez-Reina, Luis; Collantes-Estevez, Eduardo; Lopez-Medina, Clementina; [Aranda-Valera, I. Concepcion] Reina Sofia Univ Hosp, Rheumatol Dept, Cordoba 14004, Spain; [Collantes-Estevez, Eduardo] Reina Sofia Univ Hosp, Rheumatol Dept, Cordoba 14004, Spain; [Lopez-Medina, Clementina] Reina Sofia Univ Hosp, Rheumatol Dept, Cordoba 14004, Spain; [Aranda-Valera, I. Concepcion] Maimonides Inst Biomed Res Cordoba IMIBIC, G05 Grp, Cordoba 14004, Spain; [Garrido-Castro, Juan Luis] Maimonides Inst Biomed Res Cordoba IMIBIC, G05 Grp, Cordoba 14004, Spain; [Gonzalez-Navas, Cristina] Maimonides Inst Biomed Res Cordoba IMIBIC, G05 Grp, Cordoba 14004, Spain; [Collantes-Estevez, Eduardo] Maimonides Inst Biomed Res Cordoba IMIBIC, G05 Grp, Cordoba 14004, Spain; [Lopez-Medina, Clementina] Maimonides Inst Biomed Res Cordoba IMIBIC, G05 Grp, Cordoba 14004, Spain; [Aranda-Valera, I. Concepcion] Univ Cordoba, Cordoba 14004, Spain; [Garrido-Castro, Juan Luis] Univ Cordoba, Cordoba 14004, Spain; [Martinez-Galisteo, Alfonso] Univ Cordoba, Cordoba 14004, Spain; [Pena-Amaro, Jose] Univ Cordoba, Cordoba 14004, Spain; [Jimenez-Reina, Luis] Univ Cordoba, Cordoba 14004, Spain; [Collantes-Estevez, Eduardo] Univ Cordoba, Cordoba 14004, Spain; [Lopez-Medina, Clementina] Univ Cordoba, Cordoba 14004, Spain; [Cuesta-Vargas, Antonio] Univ Malaga, Malaga Inst Biomed Res IBIMA, Malaga 29016, Spain; Health Innovation Projects of Junta de Andalucia; University of CordobaAxial spondyloarthritis (axSpA) is a chronic rheumatic disease characterized by the presence of inflammatory back pain. In patients with chronic low back pain, the lumbar flexion relaxation phenomenon measured by surface electromyography (sEMG) differs from that in healthy individuals. However, sEMG activity in axSpA patients has not been studied. The purpose of this study was to analyze the flexion relaxation phenomenon in axSpA patients. A study evaluating 39 axSpA patients and 35 healthy controls was conducted. sEMG activity at the erector spinae muscles was measured during lumbar full flexion movements. sEMG activity was compared between axSpA patients and the controls, as well as between active (BASDAI >= 4) and non-active (BASDAI = 4) and non-active (BASDAI 0.8 for 1/FRR) and criterion validity. ROC analysis showed good discriminant validity for axSpA patients (AUC = 0.835) vs. the control group using 1/FRR. An abnormal flexion/relaxation phenomenon exists in axSpA patients compared with controls. sEMG could be an additional objective tool in the evaluation of patient function and disease activity status.Item Integrated Management of Multiple Sclerosis Spasticity and Associated Symptoms Using the Spasticity-Plus Syndrome Concept: Results of a Structured Specialists' Discussion Using the Workmat(R) Methodology(Frontiers media sa, 2021-09-27) Fernandez, Oscar; Costa-Frossard, Lucienne; Luisa Martinez-Gines, Maria; Montero, Paloma; Maria Prieto-Gonzalez, Jose; Ramio-Torrenta, Lluis; Spasticity-Plus Working Grp; [Fernandez, Oscar] Univ Malaga, Biomed Res Inst Malaga, Dept Pharmacol, Malaga, Spain; [Costa-Frossard, Lucienne] Hosp Univ Ramon y Cajal, Dept Neurol, Madrid, Spain; [Luisa Martinez-Gines, Maria] Hosp Gregorio Maranon, Dept Neurol, Madrid, Spain; [Montero, Paloma] Hosp Clin San Carlos, Dept Neurol, Madrid, Spain; [Maria Prieto-Gonzalez, Jose] Complejo Hosp Univ Santiago, Dept Neurol, Santiago De Compostela, Spain; [Ramio-Torrenta, Lluis] Hosp Univ Girona Doctor Josep Trueta, Dept Neurol, Girona, Spain; [Ramio-Torrenta, Lluis] Girona Biomed Res Inst IDIBGI, Neuroimmunol & Multiple Sclerosis Unit, Girona, Spain; [Ramio-Torrenta, Lluis] Univ Girona, Med Sci Dept, Girona, SpainBackground: Multiple sclerosis (MS) treatment has radically improved over the last years; however, MS symptom management is still challenging. The novel Spasticity-Plus syndrome was conceptualized to frame several spasticity-related symptoms that can be addressed together with broad-spectrum medication, such as certain cannabinoid-based drugs. The aim of this project was to gain insight into Spanish neurologists' clinical experience on MS spasticity and associated symptoms, and to assess the acknowledgment and applicability of the Spasticity-Plus syndrome concept in patients with MS.Methods: Ten online meetings were conducted using the Workmat(R) methodology to allow structured discussions. Fifty-five Spanish neurologists, experts in MS management, completed and discussed a set of predefined exercises comprising MS symptom assessment and its management in clinical practice, MS symptoms clustering in clinical practice, and their perception of the Spasticity-Plus syndrome concept. This document presents the quantitative and qualitative results of these discussions.Results: The specialists considered that polytherapy is a common concern in MS and that simplifying the management of MS spasticity and associated manifestations could be useful. They generally agreed that MS spasticity should be diagnosed before moderate or severe forms appear. According to the neurologists' clinical experience, symptoms commonly associated with MS spasticity included spasms/cramps (100% of the specialists), pain (85%), bladder dysfunction (62%), bowel dysfunction (42%), sleep disorders (42%), and sexual dysfunction (40%). The multiple correspondence analysis revealed two main symptom clusters: spasticity-spasms/cramps-pain, and ataxia-instability-vertigo. Twelve out of 16 symptoms (75%) were scored >7 in a 0-10 QoL impact scale by the specialists, representing a moderate-high impact. The MS specialists considered that pain, spasticity, spasms/cramps, bladder dysfunction, and depression should be a treatment priority given their frequency and chance of therapeutic success. The neurologists agreed on the usefulness of the new Spasticity-Plus syndrome concept to manage spasticity and associated symptoms together, and their experience with treatments targeting the cannabinoid system was satisfactory.Conclusions: The applicability of the new concept of Spasticity-Plus in MS clinical practice seems possible and may lead to an integrated management of several MS symptoms, thus reducing the treatment burden of disease symptoms.Item WadD, a New Brucella Lipopolysaccharide Core Glycosyltransferase Identified by Genomic Search and Phenotypic Characterization.(2018-09-27) Salvador-Bescós, Miriam; Gil-Ramírez, Yolanda; Zúñiga-Ripa, Amaia; Martínez-Gómez, Estrella; de Miguel, María J; Muñoz, Pilar M; Cloeckaert, Axel; Zygmunt, Michel S; Moriyón, Ignacio; Iriarte, Maite; Conde-Álvarez, RaquelBrucellosis, an infectious disease caused by Brucella, is one of the most extended bacterial zoonosis in the world and an important cause of economic losses and human suffering. The lipopolysaccharide (LPS) of Brucella plays a major role in virulence as it impairs normal recognition by the innate immune system and delays the immune response. The LPS core is a branched structure involved in resistance to complement and polycationic peptides, and mutants in glycosyltransferases required for the synthesis of the lateral branch not linked to the O-polysaccharide (O-PS) are attenuated and have been proposed as vaccine candidates. For this reason, the complete understanding of the genes involved in the synthesis of this LPS section is of particular interest. The chemical structure of the Brucella LPS core suggests that, in addition to the already identified WadB and WadC glycosyltransferases, others could be implicated in the synthesis of this lateral branch. To clarify this point, we identified and constructed mutants in 11 ORFs encoding putative glycosyltransferases in B. abortus. Four of these ORFs, regulated by the virulence regulator MucR (involved in LPS synthesis) or the BvrR/BvrS system (implicated in the synthesis of surface components), were not required for the synthesis of a complete LPS neither for virulence or interaction with polycationic peptides and/or complement. Among the other seven ORFs, six seemed not to be required for the synthesis of the core LPS since the corresponding mutants kept the O-PS and reacted as the wild type with polyclonal sera. Interestingly, mutant in ORF BAB1_0953 (renamed wadD) lost reactivity against antibodies that recognize the core section while kept the O-PS. This suggests that WadD is a new glycosyltransferase adding one or more sugars to the core lateral branch. WadD mutants were more sensitive than the parental strain to components of the innate immune system and played a role in chronic stages of infection. These results corroborate and extend previous work indicating that the Brucella LPS core is a branched structure that constitutes a steric impairment preventing the elements of the innate immune system to fight against Brucella.Item Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials.(2020-09-11) Hontecillas-Prieto, Lourdes; Flores-Campos, Rocío; Silver, Andrew; de Álava, Enrique; Hajji, Nabil; García-Domínguez, Daniel JChemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies.Item Systematic Review of Prevalence Studies and Familial Aggregation in Vestibular Migraine.(2020-08-31) Paz-Tamayo, Ana; Perez-Carpena, Patricia; Lopez-Escamez, Jose ABackground: Vestibular migraine (VM) is complex disorder consisting of episodes of migraine and vertigo with an estimated prevalence of 1-3%. As migraine, it is considered that VM has genetic predisposition; however, evidence to support a genetic contribution has not been critically appraised. Objective: The aim of this systematic review is to assess available evidence in scientific publications to determine the role of inheritance in VM. Methods: After performing the quality assessment of the retrieved records, 31 studies were included (24 epidemiological reports and 7 genetic association studies in families or case-control in candidate genes). We gathered data about prevalence of VM in different populations and in families, and also about the genetic findings reported. In addition, other variables were considered to assess the heritability of VM, such as the ancestry, the age of onset or the familial history of vertigo and migraine. Results: The estimated prevalence of VM was different between black (3.13%), white (2.64%) and Asian (1.07%) ethnicities. The reported prevalence of VM in migraine patients is higher in European countries (21%) than in Asian countries (10%). Moreover, the prevalence of the migraine-vertigo association in families is 4-10 times higher than the prevalence reported in the general population (sibling recurrence risk ratio λs = 4.31-10.42). We also found that the age of onset is lower in patients with simultaneous onset of symptoms and in those who have familial history for migraine and/or vertigo, suggesting anticipation. Although some genetic studies have reported few allelic variants associated to MV, replication studies are needed to validate these results. Conclusions: The available evidence to support heritability in VM is limited. Variability in prevalence depending on ethnicity and geographic location suggests a combined genetic and environmental contribution to VM. However, the familial aggregation observed in VM support genetic and shared familial environmental effects that remarks the necessity of twins and adoptees-based epidemiological studies to estimate its heritability.Item High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis(Frontiers media sa, 2020-08-21) Cismaru, Anca Liliana; Grimm, Livia; Rudin, Deborah; Ibanez, Luisa; Liakoni, Evangelia; Bonadies, Nicolas; Kreutz, Reinhold; Hallberg, Par; Wadelius, Mia; Haschke, Manuel; Largiader, Carlo R.; Amstutz, Ursula; EuDAC Collaborators; [Cismaru, Anca Liliana] Univ Bern, Bern Univ Hosp, Dept Clin Chem, Inselspital, Bern, Switzerland; [Grimm, Livia] Univ Bern, Bern Univ Hosp, Dept Clin Chem, Inselspital, Bern, Switzerland; [Largiader, Carlo R.] Univ Bern, Bern Univ Hosp, Dept Clin Chem, Inselspital, Bern, Switzerland; [Amstutz, Ursula] Univ Bern, Bern Univ Hosp, Dept Clin Chem, Inselspital, Bern, Switzerland; [Cismaru, Anca Liliana] Univ Bern, Grad Sch Cellular & Biomed Sci, Bern, Switzerland; [Rudin, Deborah] Univ Hosp Basel, Div Clin Pharmacol & Toxicol, Basel, Switzerland; [Rudin, Deborah] Univ Basel, Dept Biomed, Basel, Switzerland; [Ibanez, Luisa] Autonomous Univ Barcelona, Fdn Inst Catala Farmacol, Hosp Univ Vall dHebron, Dept Pharmacol Therapeut & Toxicol,Clin Pharmacol, Barcelona, Spain; [Liakoni, Evangelia] Univ Bern, Bern Univ Hosp, Dept Gen Internal Med, Clin Pharmacol & Toxicol,Inselspital, Bern, Switzerland; [Haschke, Manuel] Univ Bern, Bern Univ Hosp, Dept Gen Internal Med, Clin Pharmacol & Toxicol,Inselspital, Bern, Switzerland; [Liakoni, Evangelia] Univ Bern, Inst Pharmacol, Bern, Switzerland; [Haschke, Manuel] Univ Bern, Inst Pharmacol, Bern, Switzerland; [Bonadies, Nicolas] Univ Bern, Bern Univ Hosp, Dept Hematol, Inselspital, Bern, Switzerland; [Bonadies, Nicolas] Univ Bern, Bern Univ Hosp, Cent Hematol Lab, Inselspital, Bern, Switzerland; [Kreutz, Reinhold] Charite Univ Med Berlin, Berlin, Germany; [Kreutz, Reinhold] Free Univ Berlin, Berlin, Germany; [Kreutz, Reinhold] Humboldt Univ, Berlin, Germany; [Kreutz, Reinhold] Berlin Inst Hlth, Inst Klin Pharmakol & Toxikol, Berlin, Germany; [Hallberg, Par] Uppsala Univ, Dept Med Sci, Clin Pharmacol & Sci Life Lab, Uppsala, Sweden; [Wadelius, Mia] Uppsala Univ, Dept Med Sci, Clin Pharmacol & Sci Life Lab, Uppsala, Sweden; Swiss National Science Foundation (SNF); Carlos III Spanish Health Institute; European Regional Development Fund FEDER; Swedish Research Council; Swedish Heart and Lung Foundation; Federal Institute for Drugs and Medical Devices (Bonn, Germany); EC 5th Framework program; Serious Adverse Events Consortium, SAEC; National Institute for Health Research Biomedical Research Center at Guy's and St Thomas' National Health Service Foundation Trust and King's College London; Vinnova; Swiss National Science Foundation (SNF); Swedish Research CouncilBackground and Objective:Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. While the mechanism underlying this adverse drug reaction is not well understood, involvement of the immune system has been suggested. In addition, associations between genetic variants in the Human Leukocyte Antigen (HLA) region and agranulocytosis induced by other drugs have been reported. The aim of the present study was to assess whether genetic variants in classical HLA genes are associated with the susceptibility to metamizole-induced agranulocytosis (MIA) in a European population by targeted resequencing of eight HLA genes. Design:A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure (n= 53), metamizole-tolerant (n= 39) and unexposed controls (n= 161) was recruited for this study. A high-throughput resequencing (HTS) and high-resolution typing method was used to sequence and analyze eight HLA loci in a discovery subset of this cohort (n= 31 cases,n= 38 controls). Identified candidate alleles were investigated in the full Swiss cohort as well as in two independent cohorts from Germany and Spain using HLA imputation from genome-wide SNP array data. In addition, variant calling based on HTS data was performed in the discovery subset for the class I genesHLA-A, -B, and -Cusing the HLA-specific mapperhla-mapper. Results:Eight candidate alleles (pItem Patients with alcohol use disorder: initial results from a prospective multicenter registry in the Spanish Network on Addiction Disorders. CohRTA Study.(2018-01-12) Sanvisens, Arantza; Zuluaga, Paola; Rivas, Inmaculada; Rubio, Gabriel; Gual, Antoni; Torrens, Marta; Short, Antoni; Álvarez, Francisco Javier; Tor, Jordi; Farré, Magí; Rodríguez de Fonseca, Fernando; Muga, RobertoThe Alcohol Program of the Spanish Network on Addictive Disorders-RTA requires a longitudinal study to address different research questions related to alcoholism. The cohort study (CohRTA) focuses on patients seeking treatment for alcohol use disorder, as a multicentre, collaborative research project aimed to improve secondary prevention and early diagnosis of pathological processes associated with the disorder. Methods: multicentre cohort study in adults (>18 years) seeking their first treatment of the disorder. Patients sign an informed consent and data is collected in an online platform specifically designed for the study; patients are also requested to provide biological samples that are stored in a biobank. Baseline and prospective, socio-demographic, epidemiological, clinical and treatment data are collected. Currently there are 10 participating centres that expect to recruit more than 1,000 patients. Results: As of December 2015, 344 patients (77% men) were included. Median age at admission was 50 years (IQR: 43-55 years). Median age at the start of alcohol consumption was 15 years (IQR: 14-18 years) and 61% of cases reported antecedents of alcohol use disorder in the family. During the 30 days prior to admission, alcohol consumption amounted to 12.5 SDU/day (IQR: 7.1-20 SDU/day), 72% of the patients were tobacco smokers and 30% currently used cocaine. Organising an open cohort of patients with alcohol use disorder may be crucial to better understand the clinical consequences of alcoholism in Spain. This cohort may potentiate quantitative and qualitative research within the Spanish Network on Addictive Disorders-RTA/RETICS. Having a well-established, representative cohort of patients will increase translational research on consequences of alcoholism in our country.Item Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod: The Spanish GILENYA registry(Public library science, 2021-10-13) Meca-Lallana, J. E.; Oreja-Guevara, C.; Munoz, D.; Olascoaga, J.; Pato, A.; Ramio-Torrenta, L.; Meca-Lallana, V.; Hernandez, M. A.; Marzo, M. E.; Alvarez- Cermeno, J. C.; Rodriguez-Antigueedad, A.; Montalban, X.; Fernandez, O.; Spanish Gilenya Registry Investi; [Meca-Lallana, J. E.] Hosp Clin Univ Virgen Arrixaca, Neurol Dept, Murcia, Spain; [Oreja-Guevara, C.] Hosp Clin San Carlos, Neurol Dept, Madrid, Spain; [Munoz, D.] Hosp Xeral Vigo, Neurol Dept, Vigo, Spain; [Olascoaga, J.] Hosp Univ Donostia, Neurol Dept, San Sebastian, Spain; [Pato, A.] Hosp Povisa, Neurol Dept, Vigo, Spain; [Ramio-Torrenta, L.] Univ Girona, Hosp Univ Girona Dr Josep Trueta, IDIBGI, Neurol Dept, Girona, Spain; [Ramio-Torrenta, L.] Univ Girona, Med Sci Dept, Girona, Spain; [Meca-Lallana, V.] Hosp Univ La Princesa, Neurol Dept, Madrid, Spain; [Hernandez, M. A.] Hosp Univ Nuestra Senora Candelaria, Neurol Dept, Santa Cruz De Tenerife, Spain; [Marzo, M. E.] Hosp San Pedro, Logrono, Spain; [Alvarez- Cermeno, J. C.] Hosp Univ Ramon y Cajal, IRYCIS, Neurol Dept, Madrid, Spain; [Rodriguez-Antigueedad, A.] Hosp Univ Cruces, Neurol Dept, Baracaldo, Spain; [Montalban, X.] Hosp Univ Vall dHebron, Neurol Dept, Barcelona, Spain; [Fernandez, O.] Univ Malaga, Fac Med, Dept Pharmacol, Malaga, Spain; [Fernandez, O.] Inst Invest Biomed Malaga IBIMA, Malaga, Spain; Spanish Gilenya Registry InvestiTo describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p<0.001). This significant reduction in the ARR continued to be observed in all subgroups. After 4 years, the EDSS showed a minimal deterioration, with the EDSS scores from year 1 to year 4 remaining mostly stable. The percentage of patients without T1 Gd+ lesions progressively increased from 45.6% during the year prior to fingolimod initiation to 88.2% at year 4. The proportion of patients free from new/enlarged T2 lesions after 4 years of fingolimod treatment was 80.3%. This trend in both radiological measures was also observed in the subgroups. Adverse events (AEs) were experienced by up to 41.6% of patients (most commonly: lymphopenia [12.5%] and urinary tract infection [3.7%]). Most AEs were mild in severity, 3.6% of patients had serious AEs. The patient profile was similar to other observational studies. The results obtained from the long-term use of fingolimod showed that it was effective, regardless of prior DMT, and it had adequate safety results, with a positive benefit-risk balance.