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Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

URI permanent per a aquesta col·leccióhttps://hdl.handle.net/2445/107206

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    Trends in revascularization therapies for patients with acute stroke with large infarcts: A population-based study
    (BMJ Publishing Group, 2025-10-01) Doncel Moriano, Antonio; Rodríguez Vázquez, Alejandro; Rosa, Irene; Rudilosso, Salvatore; Serrano Clerencia, Mònica; Renú, Arturo; Cabero Arnold, Andrea; Blasco, Jordi; Amaro, Sergio; Llull, Laura; Molina, Carlos A.; Cardona Portela, Pere; Camps Renom, Pol; Millán, Mónica; Figueras Aguirre, Georgina; Rodríguez Campello, Ana; Silva, Yolanda; Purroy, Francisco; Salvat, Mercè; Vargas, Martha; Urra, Xabier; Chamorro Sánchez, Ángel
    Background Evidence from randomized clinical trials shows that mechanical thrombectomy (MT) enhances functional outcomes in patients with large core ischemic stroke. Objective To evaluate trends in the use of revascularization therapies, particularly MT, and their impact on functional outcomes in patients with large core ischemic stroke in routine clinical settings. Methods Observational data from the Stroke Code Registry of Catalonia (CICAT, 2016–2024) were analyzed. Patients with anterior circulation ischemic stroke and Alberta Stroke Program Early CT Score (ASPECTS) <6, whether treated with reperfusion therapies or not, were included. Statistical analyses included trend analysis and multivariable logistic regression to identify predictors of favorable outcomes (modified Rankin Scale score 0–3 at 90 days) and mortality. Results Among 599 patients, MT use increased significantly from 22% pre-2022 to 36% post-2022. This increase was associated with improved functional outcomes, with favorable outcomes rising from 29% to 43% post-2022. MT was a significant independent predictor of favorable outcomes (OR 3.4, 95% CI 2.1 to 5.5) and reduced mortality (OR 0.46, 95% CI 0.32 to 0.68). Intravenous thrombolysis also improved outcomes (OR 2.1, 95% CI 1.3 to 3.5). The benefit of MT was consistent across ASPECTS subgroups (0–2 and 3–5). Mediation analysis indicated that 88% of improvement could be attributed to increased MT use. Conclusions Increased MT use significantly improved outcomes for patients with large core ischemic stroke, particularly after 2022. Benefits were observed across subgroups, including those with very low ASPECTS. These findings support broadening MT access and suggest the need to update treatment guidelines to consider patients with large ischemic cores, aiming to optimize outcomes in routine clinical practice.
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    Exploring the genetics of lithium response in bipolar disorders.
    (Springer Open, 2024-06-12) Herrera-Rivero, Marisol; Adli, Mazda; Akiyama, Kazufumi; Akula, Nirmala ; Amare, Azmeraw T.; Ardau, Raffaella; Arias, Bárbara; Aubry, Jean-Michel; Backlund, Lena; Bellivier, Frank; Benabarre, Antonio; Bengesser, Susanne; Bhattacharjee, Abesh Kumar; Biernacka, Joanna M.; Birner, Armin ; Cearns, Micah; Cervantes, Pablo; Chen, Hsi-Chung; Chillotti, Caterina; Cichon, Sven; Clark, Scott R.; Colom, Francesc; Cruceanu, Cristiana; Czerski, Piotr M.; Dalkner, Nina; Degenhardt, Franziska; Zompo, Maria del; DePaulo, J. Raymond; Etain, Bruno; Falkai, Peter; Ferensztajn-Rochowiak, Ewa; Forstner, Andreas J.; Frank, Josef; Frisén, Louise; Frye, Mark A.; Fullerton, Janice M.; Gallo, Carla; Gard, Sébastien; Garnham, Julie S.; Goes, Fernando S.; Grigoroiu-Serbanescu, Maria; Gro, Paul; Hashimoto, Ryota; Hasler, Roland; Hauser, Joanna; Heilbronner, Urs; Herms, Stefan; Hoffmann, Per; Hou, Liping; Hsu, Yi-Hsiang; Jamain, Stephane; Jimenez, Esther; Kahn, Jean-Pierre; Kassem, Layla; Kato, Tadafumi; Kelsoe, John; Kittel-Schneider, Sarah; Kuo, Po-Hsiu; Kusumi, Ichiro; König, Barbara; Laje, Gonzalo; Landén, Mikael; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G.; Maj, Mario; Manchia, Mirko; Marie-Claire, Cynthia; Martinsson, Lina; McCarthy, Michael J.; McElroy, Susan L.; Millischer, Vincent; Mitjans Niubo, Marina; Mondimore, Francis M.; Monteleone, Palmiero; Nievergelt, Caroline M. ; Novák, Tomas; Nöthen, Markus M.; O'Donovan, Claire; Ozaki, Norio; Papiol, Sergi; Pfennig, Andrea; Pisanu, Claudia; Potash, James B.; Reif, Andreas; Reininghaus, Eva; Richard-Lepouriel, Hélène; Roberts, Gloria; Rouleau, Guy A.; Rybakowski, Janusz K.; Schalling, Martin; Schofield, Peter R.; Schubert, Klaus Oliver; Schulte, Eva C.; Schweizer, Barbara W.; Severino, Giovanni; Shekhtman, Tatyana; Shilling, Paul D.; Shimoda, Katzutaka; Simhandl, Christian; Slaney, Claire M.; Squassina, Alessio; Stamm, Thomas; Stopkova, Pavla; Streit, Fabian; Tekola-Ayele, Fasil; Thalamuthu, Anbupalam; Tortorella, Alfonso; Turecki, Gustavo; Veeh, Julia; Vieta Pascual, Eduard; Viswanath, Biju; Witt, Stephanie H.; Zandi, Peter P.; Alda, Martin; Bauer, Michael; McMahon, Francis J.; Mitchell, Philip B.; Rietschel, Marcella; Schulze, Thomas G.; Baune, Bernhard T.
    Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
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    Chemical Optimization of Cerebral Embolectomy 2 (CHOICE 2) trial: study protocol.
    (2025-12-03) Renú Jornet, Arturo; de la Riva P; Delgado-Mederos R; Dorado L; Fernandez-Couto MD; Herrera-Isasi M; López Hernández N; Morales A; Morales-Caba L; Camps-Renom P; Singla A; Terceño M; Vega P; Amaro S; Blasco J; Laredo C; Leira EC; Oleaga L; Serena J; Urra X; Werner M; Hernández Fernández F; Valls J; Arenillas Lara JF; Freijo MDM; Pérez de la Ossa N; San Roman L; Torres Benitez, Ferran; Castellanos M; Davalos A; Chamorro A
    The potential value of rescue intra-arterial thrombolysis in patients with large vessel occlusion (LVO) stroke treated with mechanical thrombectomy (MT) remains to be validated in randomised trials. The Chemical Optimization of Cerebral Embolectomy 2 (CHOICE 2) trial is designed to confirm whether adjunctive intra-arterial alteplase, administered after successful MT, improves clinical outcomes in patients with LVO stroke. A total of 440 patients (220 per group) randomised in a 1:1 ratio to receive intra-arterial thrombolysis or not intra-arterial thrombolysis provides 80% statistical power to detect a 14% absolute benefit in the primary endpoint (the proportion of patients achieving modified Rankin Scale (mRS) 0-1 at 90 days), assuming a rate of 40% in the control group, a 5% two-sided type I error. The sample size also provides >95% power for detecting an 18% absolute benefit in secondary imaging endpoints, assuming a 58% rate in the control group. Multicentre, randomised, open, blinded end-point assessment phase III trial. Eligible patients are adults (≥18 years) with symptomatic LVO who undergo MT with successful or complete reperfusion at end of the procedure. Patients in the intervention group will receive a 15 min intra-arterial infusion of alteplase (1.0 mg/mL, maximum dose 20 mg). The primary outcome is the proportion of patients achieving excellent functional outcome (mRS 0-1) at 90 days. Key secondary outcomes are the presence of hypoperfusion on brain CT perfusion at 36±24 hours post randomisation, infarct expansion, Barthel Index and quality of life. Mortality and symptomatic intracerebral haemorrhage will also be evaluated. This trial will provide evidence whether rescue intra-arterial thrombolysis improves clinical outcome in patients with LVO stroke who achieve successful or complete angiographic reperfusion following MT.
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    Photoactivated adenylyl cyclase in cortical astrocytes promotes synaptic potentiation and reveals alterations in Huntington’s Disease
    (Elsevier, 2025-09-24) Sitjà Roqueta, Laia; Ngum, Neville M.; Zherebstov, Evgenii; Küçükerden, Melike; Givehchi, Maryam; Bova, Valentina; Delicata, Francis; Anaya Cubero, Elena; Santamaria, Enrique; Fernández Irigoyen, Joaquín; Conde-Berriozabal, Sara; Castañé, Anna; Sokolovski, Sergei; Rafailov, Edik; Rodríguez Allué, Manuel José; Alberch i Vié, Jordi, 1959-; Dalkara, Deniz; Möglich, Andreas; Bykov,Alexander; Meglinski, Igor; Rheinallt Parri, Harri; Masana Nadal, Mercè
    Coordinated neuron-astrocyte interactions are crucial for synaptic plasticity and brain function. Cyclic adenosine monophosphate (cAMP) pathways have a key role in modulating plasticity and are disrupted in neurodegenerative diseases. Yet, the role of astrocytic cAMP remains unclear. We addressed this by expressing the photoactivatable adenylyl cyclase DdPAC in cortical astrocytes, enabling cAMP synthesis under red light stimulation. Using electrophysiological and comprehensive proteomic analyses, we determined its effects in wild-type mice. The modulation of astrocytic cAMP triggered long-term synaptic potentiation and rapidly induced the phosphorylation of proteins involved in synaptic transmission, including PKA. In Huntington's Disease (HD) models, DdPAC activation in cortical astrocytes differentially enhanced brain hemodynamics and induced motor learning, while specifically increasing grooming and impairing coordination in HD mice. Thus, we reveal a mechanism of astrocyte-driven plasticity mediated by cAMP elevation and underscore the alterations in astrocytic cAMP signaling associated with HD.
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    MITF regulates autophagy and extracellular vesicle cargo in gastrointestinal stromal tumors
    (Springer Nature, 2025-10-31) Proaño Pérez, Elizabeth; Serrano Candelas, Eva, 1982-; Guerrero, Mario; Gómez Peregrina, David; Llorens, Carlos; Soriano, Beatriz; Gámez Valero, Ana; Herrero Lorenzo, Marina; Martí, Eulalia; Serrano, César; Martín Andorrà, Margarita
    The role of Microphthalmia-associated Transcription Factor (MITF) in gastrointestinal stromal tumors (GISTs) remains unclear, although previous studies suggest it contributes to tumor growth regulation. Previously, we demonstrated that MITF depletion reduces GIST cell proliferation and viability, accompanied by decreased expression of BCL-2 and CDK2. To elucidate the mechanisms underlying MITF function in GISTs, we performed chromatin immunoprecipitation and sequencing (ChIP-seq) as well as RNA sequencing. Integrated analyses revealed that MITF directly regulates genes involved in lysosome biogenesis, vesicle trafficking, autophagy, and the mTOR signaling pathway. Transcriptomic profiling following MITF silencing further demonstrated enrichment of differentially expressed genes in PI3K/ mTOR signaling, with downstream effects on tumor growth and autophagy. We next examined the functional consequences of MITF loss on mTOR inhibition-induced autophagy and on extracellular vesicle (EV) content and secretion, given their known interplay in tumor progression. MITF depletion reduced LC3-II levels and impaired autophagy flux, confirming its role in regulating autophagy in GISTs. EV size and number remained unaffected; however, silencing MITF altered EV cargo and notably decreased KIT expression in both cells and EVs. As KIT-containing EVs have been implicated in GIST invasion, these findings suggest that MITF contributes to tumor progression through coordinated regulation of autophagy and EV-mediated signaling. Collectively, our results identify MITF as a key regulator of GIST biology, highlighting its potential as a therapeutic target to limit tumor growth and metastasis.
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    Obese Asthma Syndrome: Multiple Inflammatory Patterns and A Key Solution
    (Esmon Publicidad S.A., 2025-12-01) Bantulà, Marina; Picado Vallés, César; García, A.; Arismendi, Ebymar
    Obesity frequently complicates the pathobiology, diagnosis, and management of asthma. Traditionally, obese asthma patients have been classified as presenting either early-onset obese asthma, characterized by atopy and type 2 inflammation, or late-onset, noneosinophilic, obese asthma
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    Article
    Mind the gap: The impact of discrepancy between current cognitive function and premorbid intelligence on psychosocial functioning in older age bipolar disorder
    (Elsevier B.V., 2025-08-21) Montejo Egido, Laura; Mariegaard Schandorff, Johanna; Zarp, Jeff; Lie Kjærstad, Hanne; Elleby Jespersen, Andreas; Bort, Marta; Ruiz Muñoz, Andrea; Solé Cabezuelo, Brisa; Torrent Font, Carla; Martínez-Arán, Anabel, 1971-; Vieta i Pascual, Eduard, 1963-; Miskowiak, Kamilla W.
    Introduction: A discrepancy between current cognitive performance and premorbid IQ may indicate cognitive decline and relate to poorer psychosocial functioning in bipolar disorder, even when cognition appears unimpaired by standard norms. This study examined how objective cognition and IQ-cognition discrepancy relate to psychosocial functioning in older age bipolar disorder (OABD). Methods: OABD underwent neurocognitive assessment, intelligence quotient (IQ) estimation (using vocabulary subtest of WAIS-III), and psychosocial functioning assessment via the Functioning Assessment Short Test (FAST). IQ-cognition discrepancy scores were calculated as the difference between current cognitive performance and estimated premorbid IQ (range: -10 to +10; negative values indicating possible cognitive decline). Linear regressions examined associations between cognition, discrepancy score, and psychosocial functioning. Discriminant analyses evaluated the ability of these scores to predict functional impairment. Results: The sample included 165 participants (116 OABD and 49 healthy controls). Poorer cognitive performance was significantly associated with worse psychosocial functioning (β = -3.38, p = .002). Greater IQ-cognition discrepancy also predicted worse functioning (β = -0.92, p = .04), though cognitive performance showed a stronger association (β = -2.93, p = .017) and better discriminative ability for functional impairment (AUC = 0.75; cut-off = -0.4 SD; sensitivity = 0.69; specificity = 0.72) compared to discrepancy score (AUC = 0.64; sensitivity = 0.39; specificity = 0.87). Conclusions: IQ-cognition discrepancy may serve as a useful idiographic marker of functional impairment in OABD, particularly for individuals with high premorbid IQ. Its use could enhance clinical decision-making and broaden inclusion in pro-cognitive intervention trials.
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    Influence of Persistent Inflammation in Follow-Up Biopsies After Antibody-Mediated Rejection in Kidney Transplantation.
    (Frontiers Media, 2021-11-12) Piñeiro, Gastón Julio; Montagud Marrahi, Enrique; Ríos, José; Ventura Aguiar, Pedro; Cucchiari, David; Revuelta, Ignacio; Lozano, Miquel; Cid Vidal, Joan; Cofán Pujol, Frederico; Esforzado Armengol, Nuria; Palou Ribera, Eduard; Oppenheimer Salinas, Federico; Campistol Plana, Josep M.; Bayés Genís, Beatriu; Rovira Juárez, Jordi; Diekmann, Fritz
    Background: Despite recent advances in immunosuppression treatment, antibody-mediated rejection (ABMR) remains the leading cause of kidney graft loss. Information about prognostic markers and the efficacy of treatment is scarce. Methods: Retrospective study with kidney recipients diagnosed an active ABMR from January 1, 2004 to December 31, 2019 to explore the influence of persistent inflammation in follow-up biopsies on graft survival after ABMR treatment. Results: About 116 patients were included. Active ABMR were treated with a combination of plasma exchange (PE), intravenous immunoglobulin (IVIg), rituximab, and steroids. At 6 months of treatment, 63 (54.3%) patients presented a stabilization or improvement in kidney-graft function. The effectiveness varied depending on the timepoint of the presentation between transplantation and rejection, which is lower for those with late ABMR (63 vs. 21% for early vs. late ABMR, respectively). Ninety patients (77%) underwent a control biopsy after ABMR treatment, from which 46 (51%) responded to the treatment. Microvascular inflammation (MVI) persisted in 64 (71%) biopsies, whereas tubulitis persisted in 17 (19%) biopsies. Death-censored graft survival at 1 year was significantly lower in patients with persistent MVI (86% vs. 95% without persistent MVI, P = 0.002), or with persistent tubulitis (44% vs. 66% without tubulitis, P = 0.02). In the Cox Regression analysis, the persistence of MVI [hazard ratio (HR), 4.50 (95%CI, 1.35-14.96), P = 0.01] and tubulitis [HR 2.88 95%CI (1.24-6.69), P = 0.01) in follow-up biopsies significantly increased the risk of graft failure. Conclusion: Persistent inflammation in follow-up biopsies after ABMR treatment was associated with an increased risk of graft loss, even without meeting Banff rejection criteria. Study Registration: Agencia Española de Medicamentos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTRINM-2017-01
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    Experiences during Switching from Two-Stage to One-Stage Revision Arthroplasty for Chronic Total Knee Arthroplasty Infection
    (MDPI, 2021-11-24) Navarro, Guillem; Lozano, Luis; Sastre, Sergi; Bori, Rosa; Bosch Mestres, Jordi; Bori Tuneu, Guillem
    The objective of this study was to evaluate our preliminary results after changing our surgical strategy from 2-stage revision arthroplasty to 1-stage revision arthroplasty for patients with chronic knee periprosthetic joint infection. We conducted a prospective study of knee arthroplasty patients that had been diagnosed with chronic infection and treated using a 1-stage revision regardless of the traditional criteria applied for indication thereof. We evaluated two main variables: infection control and economic costs. The definitive diagnosis of infection of the revision was determined by using the criteria proposed by the Musculoskeletal Infection Society. The costs were calculated as average costs in USD, as described by Srivastava (2019), for 1-stage or 2-stage revisions. Eighteen patients were included in the study, and infection was controlled in 17 patients. The total economic savings for our hospital from these 18 patients amounted to USD 291,152. This clinical success has led to major changes in how our hospital approaches the treatment of chronically infected knee replacements, in addition to substantial economic advantages for the hospital.
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    Association of adiposity and its changes over time with COVID-19 risk in older adults with overweight/obesity and metabolic syndrome: a longitudinal evaluation in the PREDIMED-Plus cohort
    (BioMed Central, 2023-10-13) Matía-Martín, Pilar; Shyam, Sangeetha; García Gavilán, Jesús; Paz-Graniel, Indira; Gaforio, José J.; Martínez-González, Miguel Ángel, 1957-; Corella Piquer, Dolores; Martínez Hernández, José Alfredo; Alonso Gómez, Ángel M.; Wärnberg, Julia; Vioque, Jesús; Romaguera, Dora; López-Miranda, José; Estruch Riba, Ramon; Tinahones, Francisco José; Lapetra, José; Serra-Majem, J. Luis; Bueno-Cavanillas, Aurora; Tur, Josep Antoni; Martín-Sánchez, V.; Pintó Sala, Xavier; Vidal i Cortada, Josep; Vázquez, Clotilde; Daimiel, Lidia; Ros Rahola, Emilio; Fernández Aranda, Fernando; Nishi, Stephanie K; Garcia-Regata, Oscar; Toledo, Estefanía; Asensio, Eva M; Castañer Niño, Olga; Garcia-Rios, Antonio; Torres-Collado, Laura; Gómez Gracia, Enrique; Zulet, M. Angeles; Goñi Ruiz, Nuria; Casas Rodríguez, Rosa M.; Cano Ibáñez, Naomi; Tojal-Sierra, Lucas; Gómez-Perez, AM; Sorlí, José V; Cinza-Sanjurjo, Sergio; Martín-Peláez, Sandra; Peña-Orihuela, Patricia J; Oncina-Canovas, Alejandro; Perez-Araluce, Rafael; Zomeño, Maria Dolores; Chaplin, Alice; Delgado Rodriguez, Miguel; Babio, Nancy; Fitó Colomer, Montserrat; Salas-Salvadó, Jordi
    Background: Cross-sectionally, older age and obesity are associated with increased coronavirus disease-2019 (COVID-19) risk. We assessed the longitudinal associations of baseline and changes in adiposity parameters with COVID-19 incidence in older adults at high cardiovascular risk. Methods: This analysis included 6874 men and women (aged 55-75 years) with overweight/obesity and metabolic syndrome in the PREDIMED-Plus lifestyle intervention trial for cardiovascular risk reduction. Body weight, body-mass-index (BMI), waist circumference, waist-to-height ratio (WHtR), and a body shape index (ABSI) were measured at baseline and annual follow-up visits. COVID-19 was ascertained by an independent Event Committee until 31 December 2021. Cox regression models were fitted to evaluate the risk of COVID-19 incidence based on baseline adiposity parameters measured 5-6 years before the pandemic and their changes at the visit prior to censoring. Results: At the time of censoring, 653 incident COVID-19 cases occurred. Higher baseline body weight, BMI, waist circumference, and WHtR were associated with increased COVID-19 risk. During the follow-up, every unit increase in body weight (HRadj (95%CI): 1.01 (1.00, 1.03)) and BMI (HRadj: 1.04 (1.003, 1.08)) was associated with increased COVID-19 risk. Conclusions: In older adults with overweight/obesity, clinically significant weight loss may protect against COVID-19.
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    Clinical, imaging, and serum biomarker predictors of malignant cerebral infarction
    (MDPI, 2025-10-04) Rodríguez Vázquez, Alejandro; Rudilosso, Salvatore; Doncel Moriano, Antonio; Cabero Arnold, Andrea; Laredo, Carlos; Ramis, Darío; Moraleja, David; Serrano Clerencia, Mònica; Gonzalez Romero, Yolanda; Renú, Arturo; Bartolomé Arenas, Inés; Rosa Batlle, Irene; Dolz Alvarez de la Ballina, Guillem; Torné, Ramón; Vargas, Martha; Urra, Xabier; Chamorro, Ángel
    Malignant cerebral infarction (MCI) is rare but often fatal. Early identification helps guide monitoring and decompressive surgery. This study evaluated whether serum biomarkers add predictive value beyond clinical and imaging data in severe stroke patients with anterior circulation large vessel occlusion (LVO). In this prospective study, 73 acute severe LVO stroke patients underwent whole-brain CT perfusion (CTP) with rCBV-based core measurement at admission and follow-up MRI at 24 ± 12 h for infarct and edema volume assessment. Serum biomarkers (s100b, NSE, VEGF, ICAM1) were sampled a median of 20.5 h after baseline imaging. Logistic regression models predicted MCI using baseline variables (NIHSS, ASPECTS, rCBV < 30%), adding treatment data (rtPA, mTICI, NIHSS posttreatment), and adding serum biomarkers. Performance was assessed by AUC, accuracy, F1, and cross-validated R2. MCI occurred in 18/73 (24%) patients. Baseline models showed an AUC of 0.72; adding treatment improved the AUC to 0.88. Biomarkers slightly increased the AUC (0.90) but did not improve F1. Higher s100b was associated with more severe injury but did not enhance the prediction of MCI. Models with baseline imaging and treatment best explained infarct (R2 ≈ 0.27) and edema (R2 ≈ 0.58). In conclusion, admission severity, CTP, and early treatment response are the main predictors of MCI and aid early risk stratification of patients. Despite their pathophysiologic relevance, serum biomarkers do not add substantial predictive value.
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    Variability vs. phenotype: Multimodal analysis of Dravet syndrome brain organoids powered by deep learning
    (Elsevier, 2025-11-21) Lao, Oscar; Acosta, Sandra; Turpin, Isabel; Modrego, Adriana; Martí Sarrias, Andrea; Ortega Gascó, Alba; Haeb, Anna-Christina; García González, Laura; Soriano i Fradera, Jordi; Ruiz, Núria; Peñuelas Haro, Irene; Espinet, Elisa; Tornero, Daniel
    Dravet syndrome (DS) is a developmental epileptic encephalopathy (DEE) driven by pathogenic variants in the SCN1A gene. Brain organoids (BOs) have emerged as reliable models for neurodevelopmental genetic disorders, reproducing human brain developmental milestones and rising as a promising drug testing tool. Here, we determined the underlying molecular DS pathophysiology affecting neuronal connectivity, revealing an early onset excitatory-inhibitory imbalance in maturing DS organoid circuitry. However, neuronal circuitry modeling in BOs remains hampered by the notorious inter- and intra-organoid variability. Thus, leveraging deep learning (DL), we developed ImPheNet, a predictive tool grounded in BO live imaging datasets, to overcome the limitations of the intrinsic BOs variability. ImPheNet accurately classified healthy and DS phenotypes at early onset stages, revealing differences between genotypes and upon antiseizure drug exposure. Altogether, our DL-predictive live imaging strategy, ImPheNet, emerges as a powerful tool to accelerate DEEs research and advance toward treatment discovery in a time- and cost-efficient manner.
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    Clinical Variables Related to Functional Capacity and Exertional Desaturation in Patients with COVID-19
    (MDPI, 2023-07-20) Larrateguy, Santiago; Vinagre, Julian; Londero, Federico; Dabin, Johana; Ricciardi, Evangelina; Jeanpaul, Santiago; Torres Castro, Rodrigo; Núñez Cortés, Rodrigo; Sánchez Ramírez, Diana; Gimeno Santos, Elena, 1980-; Blanco Vich, Isabel
    Impaired functional capacity is one of the most commonly reported consequences among post-COVID-19 patients. This study aimed to analyse the clinical variables related to functional capacity and exertional desaturation in post-COVID-19 patients at the time of hospital discharge. A cross-sectional study was conducted on patients recovering from COVID-19 pneumonia. The main outcomes measures were functional capacity, assessed using the 1 min sit-to-stand test (1 min STST), and exertional desaturation, defined as a drop of ≥4% in the arterial oxygen saturation. Factors used to characterise the participant outcomes included the use of a high-flow nasal cannula (HFNC), prolonged hospitalisation, occurrence of pulmonary embolism during hospitalisation, and underlying comorbidities. A total of 381 participants (mean age = 53.7 ± 13.2 years, 65.6% men) were included. Participants completed a mean of 16.9 ± 6.2 repetitions in the 1 min STST. Exertional desaturation was observed in 51% of the patients. Higher odds of exertional desaturation were found in the participants who used a HFNC (OR = 3.6; 95%CI: 1.6 to 7.8), were admitted in the hospital >10 days (OR = 4.2; 95%CI: 2.6 to 6.8), and had a pulmonary embolism (OR = 3.5; 95%CI: 2.2. to 5.3). Use of a HFNC (β = -3.4; 95%CI: -5.3 to -1.44), a hospital stay >10 days (β = -2.2; 95%CI: -3.4 to -0.9), and a history of pulmonary embolism (β = -1.4; 95%CI: -2.6 to -0.2) were also negatively associated with the 1 min STST. Most post-COVID-19 patients exhibited reduced functional capacity at the time of hospital discharge, and approximately half had exertional desaturation after the 1 min STST. The use of a HFNC, prolonged hospitalisation and pulmonary embolism were the main clinical variables associated with worse a 1 min STST performance and a higher likelihood of exertional desaturation.
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    Effectiveness of inspiratory muscle training in patients with a chronic respiratory disease: an overview of systematic reviews
    (Frontiers Media, 2025-05-21) Torres Castro, Rodrigo; Caicedo Trujillo, Saul; Gimeno Santos, Elena, 1980-; Gutiérrez Arias, Ruvistay; Alsina Restoy, Xavier; Vasconcello Castillo, Laura; Seron, Pamela; Spruit, Martijn A.; Blanco Vich, Isabel; Vilaró, Jordi
    Introduction: There has been inconclusive findings regarding the effectiveness of inspiratory muscle training (IMT) in chronic respiratory diseases (CRDs). Our objective was to determine the effectiveness of IMT on exercise tolerance, maximum respiratory pressure, lung function, symptoms and quality of life in different CRDs. Methods: We conducted an overview of systematic reviews (SRs) in adults with CRDs who underwent IMT. We reviewed five databases in March 2025. We chose the most comprehensive SRs to report on the analysed outcomes. Results: Twenty-three SRs were included. In chronic obstructive pulmonary disease (COPD), IMT increased the six-minute walk distance (6MWD) by 35.7 m (95% CI 25.7, 45.7), maximum inspiratory pressure (MIP) by 10.9 cmH2O (95% CI 8.0, 13.9). In asthma, IMT increased the forced expiratory volume in the first second (FEV1) by 3.3%pred (95% CI 1.4, 5.1), forced vital capacity (FVC) by 4.1%pred (95% CI 1.0, 7.3), MIP by 21.9 cmH2O (95% CI 15.0, 28.8), and dyspnoea was reduced (standard mean difference -0.8, 95% CI -1.3,-0.2). In obstructive sleep apnoea (OSA), IMT increased MIP by 29.6 cmH2O (95% CI 6.0, 53.1). In pulmonary hypertension (PH), IMT increased 6MWD by 39.0 m (95% CI 20.7, 57.4), MIP in 21.2 cmH2O (95% CI 11.3, 31.1), maximum expiratory pressure by 14.4 cmH2O (95% CI 6.9, 21.9), and dyspnoea was reduced by 0.5 (95% CI 0.1, 0.9) in modified Medical Research Council scale. In lung resection (LR), IMT increased MIP by 8.1 cmH2O (95% CI 1.3, 14.9). In bronchiectasis, IMT increased MIP by 6.1 cmH2O (95% CI 1.4, 10.8). Overall, the most consistent effect of IMT across different CRDs was an increase in MIP. Conclusion: IMT improved several clinically relevant outcomes, including MIP, exercise capacity, and dyspnoea in different CRDs. However, the limited evidence for certain outcomes and populations highlights the need for further high-quality studies.
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    Mitochondrial methylcytosines as blood-based biomarkers for Alzheimer's disease dementia prognosis
    (Elsevier, 2025-08-21) Gascón-Bayarri, Jordi; Mosquera Mayo, José Luís; Blanch Lozano, Marta; Martí Benaiges, Pau; Fontal Aina, Beatriz; Trapero Candela, Carla; Rojo Fité, Nuria; Rico, Inma; Campdelacreu i Fumadó, Jaume; Fowler, Cristopher; Laws, Simon M.; Tort Merino, Adrià; Sánchez del Valle Díaz, Raquel; Bello, Joan; Fortea Ormaechea, Juan; Lleó Bisa, Alberto; Mehanian, Courosh; Swerdlow, Russell H.; Reñé Ramírez, Ramon; Barrachina, Marta
    Alzheimer's Disease Dementia (ADD) prognosis is an unmet medical need. Mitochondrial dysfunction is an early AD etiopathogenic factor. The present study analyzed mitochondrial DNA (mtDNA) methylation patterns in blood samples from patients with mild cognitive impairment (MCI) who progressed to ADD (P), MCI remained stable (NP), and Cognitively Normal (CN) individuals. Differentially methylated sites were identified in the D-loop region in both CN vs. NP and NP vs. P comparisons, even before β-amyloid positivity. A Random Forest model was developed using mtDNA methylation data combined with cognitive and risk factor features. Model's performance was assessed by cross-validation and tested on an independent set, achieving 84.4% accuracy in training and 83.2% (95% CI: 75.2%-89.4%) in testing. For identifying P patients, sensitivity and specificity were 95.1% and 70.7%, respectively. The AUC-ROC was 90.3%. The developed model demonstrates predictive capacity in distinguishing cognitive decline and stability in MCI individuals, independently of their β-amyloid status.
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    Ex vivo normothermic preservation of a kidney graft from uncontrolled donation after circulatory death over 73 hours
    (Frontiers Media, 2023-01-12) Montagud Marrahi, Enrique; Luque, Yosu; Rabadán Ros, Rubén; Ajami, Tarek; Estrella, Héctor; Arancibia, Andrés; Sánchez-Etayo, Gerard; Bohils-Valle, Marc; Marrero, Ramsés; Fundora, Yilian; Cuadrado Payán, Elena; Ramírez Bajo, María José; Bañón Maneus, Elisenda; Rovira, Jordi; Larque, Ana-Belén; Campistol Plana, Josep M.; Diekmann, Fritz; Musquera i Felip, Mireia
    The transplant community is focused on prolonging the ex vivo preservation time of kidney grafts to allow for long-distance kidney graft transportation, assess the viability of marginal grafts, and optimize a platform for the translation of innovative therapeutics to clinical practice, especially those focused on cell and vector delivery to organ conditioning and reprogramming. We describe the first case of feasible preservation of a kidney from a donor after uncontrolled circulatory death over a 73-h period using normothermic perfusion and analyze hemodynamic, biochemical, histological, and transcriptomic parameters for inflammation and kidney injury. The mean pressure and flow values were 71.24 ± 9.62 mmHg and 99.65 ± 18.54 mL/min, respectively. The temperature range was 36.7°C-37.2°C. The renal resistance index was 0.75 ± 0.15 mmHg/mL/min. The mean pH was 7.29 ± 0.15. The lactate concentration peak increased until 213 mg/dL at 6 h, reaching normal values after 34 h of perfusion (8.92 mg/dL). The total urine output at the end of perfusion was 1.185 mL. Histological analysis revealed no significant increase in acute tubular necrosis (ATN) severity as perfusion progressed. The expression of KIM-1, VEGF, and TGFβ decreased after 6-18 h of perfusion until 60 h in which the expression of these genes increased again together with the expression of β-catenin, Ki67, and TIMP1. We show that normothermic perfusion can maintain a kidney graft viable ex vivo for 3 days, thus allowing a rapid translation of pre-clinical therapeutics to clinical practice.
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    Gene-Specific Detection Rate of Adenomas and Advanced Adenomas in Lynch Syndrome
    (Elsevier, 2025-09-01) Sánchez Brualla, Alicia; Castillo Iturra, Joaquín; Balmaña, Judith; Brunet, Joan; Castells Sánchez, Alba; Capellá, G. (Gabriel); Ladabaum, Uri; Dekker, Evelien; Moreira, Luciana; Pellisé, M.; Balaguer Prunés, Francesc; López Fernández, Adrià; Salces, Inmaculada; Picó, María Dolores; Rivas, Laura; Bujanda, Luis; Garzon, Marta; Pizarro, Angeles; Martinez de Castro, Eva; Roos, V.H.; Dueñas, Nuria; Pineda Riu, Marta; Moreno Calle, Lorena; Rodríguez Alonso, Lorena; Ramon y Cajal, Teresa; Llort, Gemma; Piñol, Virginia; López Arias, María .Jesús; Poves, Carmen; Garau, Catalina; Rodríguez Alcalde, Daniel; Herraiz, Maite; Álvarez Urrutia, Cristina; Dacal, Andrés; Carrillo Palau, Marta; Cid, Lucía; Ponce, Marta; Barreiro Alonso, Eva; Saperas, Esteban; Aguirre, Elena; Bastiaansen, B.; Ocaña, Teresa; Carballal, Sabela; Rivero Sánchez, Liseth; Ortiz, Oswaldo; Daca Álvarez, María; Prat Galito, Ricard; Bessa, Xavier; Cubiella, Joaquin; Jover, Rodrigo; Rodríguez Moranta, Francisco
    Background & Aims Colonoscopy is expected to reduce colorectal cancer (CRC) incidence in Lynch syndrome (LS) by detecting and removing adenomas. The existence of gene-specific differences in adenoma detection has been proposed yet remains insufficiently explored. This study aims to elucidate gene-specific adenoma detection rates and their association with post-colonoscopy CRC (PCCRC), which stands as an important issue in LS surveillance. Methods In this multicenter study, we analyzed 1072 LS carriers without prior CRC undergoing surveillance colonoscopy, evaluating adenoma and advanced adenoma (AA) detection rates by gene. The primary outcome was to compare adenoma detection rates in individuals without prior CRC carrying pathogenic variants in MLH1/MSH2 vs MSH6/PMS2. Subgroup analysis was performed to assess the intermediate risk profile in MSH6 carriers relative to MLH1/MSH2 and PMS2 carriers. We compared overall adenoma detection rates, adenoma burden, age at first adenoma occurrence, and 10-year cumulative detection rates. Risk factors for AA and PCCRC were also identified. Multiple testing and multivariate analyses were performed. Results The adenoma detection rates were similar across the 4 genes. However, MLH1/MSH2 carriers had a higher overall AA detection rate compared with MSH6/PMS2 carriers (14.5% vs 11.9%; P = .04) and showed higher cumulative AA detection rates over 10 years (21.6% vs 19.7%; P = .04). Subgroup analysis indicated that MSH6 carriers had an intermediate AA detection rate positioned between MLH1/MSH2 carriers and PMS2 carriers. Multivariate analysis indicated that AAs (odds ratio, 2.12; 95% confidence interval, 1.08–4.17; P=.03) and repeated AA detection (odds ratio, 4.62; 95% confidence interval, 1.70–12.57; P < .01) were independent risk factors for PCCRC. Conclusions Carriers of MLH1/MSH2 pathogenic variants are at a higher risk of developing AAs compared with those with MSH6/PMS2 mutations, with MSH6 carriers exhibiting an intermediate risk profile. AAs are an independent risk factor for PCCRC. LS patients with AAs should be identified as high risk and undergo enhanced colonoscopy surveillance.
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    Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer
    (BioMed Central, 2023-05-12) Ortiz Barahona, Vanessa; Soler, Marta; Davalos, Veronica; García-Prieto, Carlos A.; Janin, Maxime; Setién, Fernando; Fernández-Rebollo, Irene; Bech-Serra, Joan J.; De La Torre, Carolina; Guil, Sonia; Villanueva Garatachea, Alberto; Zhang, Pei-Hong; Yang, Li; Guarnacci, Marco; Schumann, Ulrike; Preiss, Thomas; Balaseviciute, Ugne; Montal, Robert; Llovet i Bayer, Josep Maria; Esteller, Manel
    Background: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. Methods: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. Results: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. Conclusion: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.
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    The Mediterranean Diet in Pregnancy: Implications for Maternal Brain Morphometry in a Secondary Analysis of the IMPACT BCN Randomized Clinical Trial
    (MDPI, 2024-05-24) Nakaki, Ayako; Gomez, Yvan; Castro-Barquero, Sara; Conti, Allegra; Vellvé, Kilian; Casas, Irene; Genero, Mariona; Youssef, Lina; Segalés, Laura; Benitez, Leticia; Casas Rodríguez, Rosa M.; Vieta i Pascual, Eduard, 1963-; Bargalló Alabart, Núria; Toschi, Nicola; Estruch Riba, Ramon; Crispi Brillas, Fàtima; Gratacós Solsona, Eduard; Crovetto, Francesca
    Introduction: A Mediterranean diet has positive effects on the brain in mid-older adults; however, there is scarce information on pregnant individuals. We aimed to evaluate the effect of a structured Mediterranean diet intervention on the cortical structure of the maternal brain during pregnancy. Methods: This study was a secondary analysis of the IMPACT BCN, a randomized clinical trial with 1221 high-risk pregnant women randomly allocated into three groups at 19-23 weeks of gestation: Mediterranean diet intervention, a mindfulness-based stress reduction program, or usual care. Maternal brain magnetic resonance imaging was performed during the third trimester of pregnancy in a random subgroup of participants. For this study, data from the Mediterranean diet and usual groups were analyzed. Maternal dietary intake, adherence to the Mediterranean diet and metabolite biomarkers were evaluated using a food frequency questionnaire, a 17-item dietary screener and plasma/urine samples, respectively. Results: The cluster-wise analysis showed that the Mediterranean diet group participants (n = 34) had significantly larger surface areas in the right precuneus (90%CI: <0.0001-0.0004, p < 0.001) and left superior parietal (90%CI: 0.026-0.033, p = 0.03) lobules compared to the usual care group participants (n = 37). A larger right precuneus area was associated with high improvements in adherence to the Mediterranean diet, a high intake of walnuts and high concentrations of urinary hydroxytyrosol. A larger left superior parietal area was associated with a high intake of walnuts and high concentrations of urinary hydroxytyrosol. Conclusions: The promotion of a Mediterranean diet during pregnancy has a significant effect on maternal brain structure.
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    Circulating extracellular vesicles and neutrophil extracellular traps contribute to endothelial dysfunction in preeclampsia
    (Frontiers Media, 2024-12-13) Ramos, Alex; Youssef, Lina; Molina, Patricia; Torramade Moix, Sergi; Martínez Sánchez, Julia; Moreno Castaño, Ana Belen; Blasco, Miquel; Guillén Olmos, Elena; Moner Rafel, Blanca de; Pino, Marc; Tortajada, Marta; Camacho, Marta; Borrell, Maria; Crovetto, Francesca; Ramírez Bajo, María José; Ventura Aguiar, Pedro; Bañón Maneus, Elisenda; Rovira, Jordi; Escolar Albaladejo, Ginés; Carreras, Enric; Gratacós Solsona, Eduard; Diaz Ricart, M. Isabel; Crispi Brillas, Fàtima; Palomo, Marta
    Background: Preeclampsia (PE) is a pregnancy complication characterized by hypertension, proteinuria, endothelial dysfunction, and complement dysregulation. Placenta-derived extracellular vesicles (EVs), necessary in maternal-fetal communication, might contribute to PE pathogenesis. Moreover, neutrophil extracellular traps (NETs) play a pathogenic role in other complement-mediated pathologies, and their contribution in PE remains unexplored. Materials and methods: EVs were isolated from PE (peEVs) and normotensive pregnant women sera. NETs were obtained incubating donor-pre-activated neutrophils with PE or control sera. Microvascular (HMEC) endothelial cells (ECs) were incubated with PE or control sera with or without (depleted sera) EVs or NETs, to assess changes in VCAM-1, ICAM-1, VE-cadherin, eNOS, VWF, ROS, and C5b-9 deposits. Results were expressed as fold increase vs. control. Results: VWF, VCAM-1, and ROS expression was significantly higher in cells exposed to PE sera vs. control (12.3 ± 8.1, 3.6 ± 2.3, and 1.8 ± 0.2, respectively, p < 0.05), though significantly lower in cells exposed to depleted PE (dPE) sera (6.1 ± 2.7, 0.7 ± 0.6, and 1.2 ± 0.1, respectively, vs. control, p < 0.05). EC exposure to depleted control sera supplemented with peEVs (dC+peEVs) significantly increased VWF, VCAM-1, and ROS compared to non-supplemented sera (4.5 ± 0.3, 2.8 ± 2.0, and 1.4 ± 0.2, respectively, p < 0.05). ICAM-1, VE-cadherin, and C5b-9 did not differ among groups. ECs incubated with PE-NETs increased VWF and VCAM-1 and decreased VE-cadherin expression vs. control (4 ± 1.6, 5.9 ± 1.2, and 0.5 ± 0.1, respectively, p < 0.05), and notably increased C5b-9 deposit (7.5 ± 2.9, p < 0.05). ICAM-1 and ROS did not differ. Conclusions: Both circulating EVs and NETs from PE pregnant women exhibit a deleterious effect on ECs. Whereas EVs trigger a pro-oxidant and proinflammatory state, NETs potentiate the activation of the complement system, as already described in PE.