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

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Towards a point of care approach for intra-amniotic infection or early delivery using minimally invasive prediction models in women with preterm labor.
(Elsevier Inc., 2026-03-27) Cobo T; Boada D; Burgos-Artizzu XP; Goya M; Kacerovsky M; Ferrero S; Filella X; Sellarés A; González B; Mouriz N; Mohedano N; Ampurdanes Q; Roldán E; del Barco E; Murillo C; Hidalgo J; Garbí S; Musilova I; Fabregat A; Vergara A; Palacio M; Gratacós Solsona, Eduard
Among women with preterm labor and intact membranes, those with intra-amniotic infection or inflammation represent the highest risk group of spontaneous delivery and worse adverse outcome. Identification of this group requires amniocentesis, which is perceived as too invasive by both patients and physicians. This study aimed to develop a minimally invasive prediction model for intra-amniotic infection or early delivery, thereby better stratifying patients (low or high-risk) and rationalizing the use of amniocentesis limiting the indications to the highest-risk group of spontaneous preterm delivery. We performed external validation of 4 prediction models using data from 2022-2024 of women diagnosed with preterm labor below 34 weeks admitted to the Hospital Clinic, Hospital Sant Joan de Déu, and the Hospital Vall Hebron in Barcelona (Spain), and the Hradec Kralove University Hospital, in Kradec Kralove (Czech Republic), who underwent amniocentesis to rule in/out intra-amniotic infection or inflammation. Different prediction models, including ultrasound (US) transvaginal cervical length, serum C-reactive protein (CRP), vaginal IL-6, vaginal pH, vaginal lactic acid, and vaginal Lactobacillus genus, were validated in these patients. Diagnostic performance was done in 114 women with PTL below 34 weeks, 42 (36.8%) of whom had intra-amniotic infection or spontaneous delivery within 7 days. The areas under the curve (AUC) of the different models ranged from ranging from 84 (95% confidence interval (CI) 78.8-89.2%) to 89.9% (88.4-91.4%), sensitivities ranging from 78.6 (33/42) to 90.5% (38/42). and specificities from 70.8% (51/72) to 84.7% (61/72). The most feasible and efficient model was formed by combining US cervical length, serum CRP and vaginal IL-6, showing an AUC of 84% with a sensitivity of 78.6% (33/42), specificity of 84.7% (61/72), positive predictive value of 75% (33/44), and negative predictive value of 87.1% (61/70). We developed minimally invasive models to screen women at high risk of intra-amniotic infection or early delivery and guide the selective use of amniocentesis, thereby improving both antenatal counseling and the clinical management of high-risk patients.
Deficiency in Mice Enhances Regeneration in Healthy Liver but Drives Pathological Repair and Functional Decline in Fibrotic Liver
(MDPI, 2026-03-30) Ribera, Jordi; Cardona Simó, Anna; Portolés, Irene; Samper, Esther; Boix i Ferrero, Loreto; Fabregat Bolufer, Aleix B.; Fernández Galán, Esther; Rodríguez Garcia, María; Azkargorta, Mikel; Elortza, Felix; Celton-Morizur, Séverine; Desdouets, Chantal; Melgar Lesmes, Pedro; Jiménez Povedano, Wladimiro; Casals Mercadal, Gregori; Morales Ruiz, Manuel
MicroRNA-122 (miR-122) is the most abundant hepatic microRNA and a key regulator of hepatocyte proliferation, metabolism and differentiation. Although widely studied in hepatocellular carcinoma, its role in liver regeneration remains unexplored. This study investigated how miR-122 deficiency modulates liver regeneration under physiological conditions and during chronic liver injury. A miR-122-deficient mouse model (miR-122-/-) was generated using CRISPR/Cas9, and liver regeneration was assessed after two-thirds partial hepatectomy (PHx) in healthy and CCl4-induced fibrotic livers. In healthy liver, miR-122 expression was transiently downregulated within 24 h after PHx, suggesting a physiological role in cell cycle entry. After PHx in non-fibrotic livers, miR-122-/- mice showed increased basal proliferation and accelerated regeneration, associated with Cyclin D1 and RhoA overexpression, enhanced cytokinesis and a predominance of diploid hepatocytes. In contrast, miR-122 deficiency markedly exacerbated CCl4-induced fibrosis, leading to cirrhosis-like architecture, impaired hepatocyte function, and severe metabolic dysregulation. Despite increased proliferation after PHx, fibrotic miR-122-/- mice exhibited severely impaired regeneration and near-complete mortality. Proteomic analyses revealed metabolic failure, oxidative stress, and inflammatory activation, creating an unfavorable environment for tissue repair. In conclusion, miR-122 plays a dual role in liver regeneration. While its suppression enhances regeneration in healthy liver, loss of miR-122 under fibrotic conditions drives pathological repair, metabolic failure and lethality, highlighting its critical role in chronic liver disease.
Posttranscriptional reprogramming controls MASLD progression through chronic ER stress adaptation
(American Association for the Advancement of Science, 2026-04-03) Belloc Rocasalbas, Eulàlia; CALDERONE, VITTORIO; Naranjo-Suarez, S; Mateo Ramos, Lidia; MARTIN, J; MALIZIA, FLORENCIA; Sibilio, Annarita; Chanes Villar, Verónica; Ramirez-Pedraza, M; Delgado, ME; Drebber, U; Rheinwalt, KP; Klein, S; Brol, MJ; Schierwagen, R; Trebicka, J; Aloy Calaf, Patrick; Fernandez, M; Méndez De La Iglesia, Raúl
Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well characterized, the posttranscriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the posttranscriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that similar to 70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs, enriched in suboptimal codons and bearing short poly(A) tails under normal diet, becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3 ' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.
Treatment of bipolar depression: results from a comprehensive network meta-analysis and updated systematic review
(Elsevier B.V., 2026-07-01) Yalin, Nefize; Yildiz, Aysegul; Siafis, Spyridon; Vieta i Pascual, Eduard, 1963-; Leucht, Stefan
Depressive episodes present a treatment challenge in bipolar disorder (BD), and an urgent need exists for novel treatment options. This review sought to revisit the results from a recent network meta-analysis (NMA) that examined treatment options for bipolar depression and to update those findings with a complementary systematic review (PROSPERO-ID: CRD42020171726). The NMA was based on the qualitative synthesis of 145 studies and the quantitative analysis of 101 studies investigating acute depression in adults with bipolar depression from inception to April 2023. A complementary systematic review was conducted using MEDLINE, OVID, EMBASE, PsychINFO, CINAHL, LILACS, Cochrane, Web of Science Core Collaboration, and Google Scholar databases from April 2023 to November 2024 to identify the most recent randomized controlled trials on the treatment of bipolar depression. Studies identified via systematic review were subjected to narrative synthesis and quality assessment was completed using revised Cochrane risk of bias tool. The original NMA showed that olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were more efficacious than placebo in reducing depressive symptoms in BD with good confidence. Several other drugs might also be efficacious, but confidence in the evidence was very low to low. The complementary systematic review identified 24 clinical trials, seven of which had published results suitable for meta-analysis; the remaining 17 studies were either ongoing or completed with no available results. Collectively, the NMA and systematic review findings can inform evidence-based care and the development of international treatment guidelines for bipolar depression.
Seasonal longitudinal effects of winter birth on psychopathology, cognition, and functioning in schizophrenia-spectrum and affective disorders: Findings from the PsyCourse Study
(Elsevier B.V., 2026-09-01) Pérez Ramos, Anaid; Budde, Monika; Adorjan, Kristina; Amoretti Guadall, Silvia; Anghelescu, Ion-George; Arolt, Volker; Baune, Bernhard T.; Dannlowski, Udo; Dietrich, Detlef E.; Fallgatter, Andreas J.; Figge, Christian; Garriga, Marina; García Rizo, Clemente; Guasch Capella, Nora; Heilbronner, Maria; Lang, Fabian U.; Juckel, Georg; Kohshour, Mojtaba Oraki; Konrad, Carsten; Martínez-Arán, Anabel, 1971-; Mezquida Mateos, Gisela; Navarro Flores, Alba; Reich-Erkelenz, Daniela; Reimer, Jens; Reininghaus, Eva Z.; Senner, Fanny; Schmauß, Max; Schmitt, Andrea; Schulte, Eva C.; Spitzer, Carsten; Vieta i Pascual, Eduard, 1963-; Wiltfang, Jens; Falkai, Peter; Schulze, Thomas G.; Papiol, Sergi; Torrent Font, Carla; Heilbronner, Urs
Aims Winter birth (WB) is a replicated risk factor for mental health conditions, potentially due to third-trimester Vitamin D deficiency and maternal viral infections. Beyond diagnosis, WB is associated with psychopathology, cognition, and functionality as epiphenomena. We analysed these outcomes in psychosis and affective disorders, considering illness duration and sex-specific effects. Methods We included 535 individuals with schizophrenia-spectrum and 667 with affective disorders from the PsyCourse Study, evaluated at four time points over 18 months. Participants were stratified by the birth season: winter vs. other seasons and by duration of illness (</≥5 years). Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) for psychosis, Inventory of Depressive Symptomatology (IDS-C30) and Young Mania Rating Scale (YMRS) for affective disorders, functionality with the Global Assessment of Functioning Scale (GAF), and cognitive performance with Trail Making Tests A (TMT-A) and B (TMT-B), Verbal Digit Span, and Digit Symbol Test (DST). Linear mixed models adjusted for covariates were applied. Results No interaction effects between WB and diagnostic group or time remained significant after correction for multiple comparisons. In sex-stratified models, a significant WB × time interaction emerged for DST in females, with WB participants showing improvements over time in schizophrenia-spectrum disorders, and a crossover pattern in affective disorders. Conclusions WB has no robust effect on long-term outcomes on schizophrenia-spectrum or affective disorders. Subtle, sex-dependent effects on cognition were observed in females, with divergent longitudinal patterns between diagnostic groups, suggesting a possible early-life influence that attenuates over the course of illness.
Age-stratified associations between severe mental illness, dementia, and ischemic stroke: findings from the PADRIS-PRESTO cohort
(Elsevier B.V., 2026-04-20) De Prisco, Michele; Oliva, Vincenzo; Sánchez del Valle Díaz, Raquel; Parellada Rodón, Eduard; Junqué i Plaja, Carme, 1955-; Martí Domènech, Ma. Josep; Bortolozzi Biasoni, Analía; Alberch i Vié, Jordi, 1959-; Garrabou Tornos, Glòria; Sánchez-Vives, María Victoria; Giralt Torroella, Albert; Segura i Fàbregas, Bàrbara; Lladó Plarrumaní, Albert; Compta, Yaroslau; Radua, Joaquim; Vieta i Pascual, Eduard, 1963-; Hidalgo Mazzei, Diego; Anmella, Gerard
People with severe mental illnesses (SMIs), including schizophrenia spectrum disorders (SSD), major depressive disorder (MDD), and bipolar disorder (BD), experience elevated rates of physical comorbidity and premature mortality. Dementia and ischemic stroke contribute substantially to this burden, yet age-specific patterns of these associations remain poorly characterized. To bridge this gap, we conducted a population-based cross-sectional study using the PADRIS-PRESTO cohort, integrating primary and specialized care records from the Catalan public health system (Spain). Adults with a lifetime SMI diagnosis were compared with controls without any psychiatric condition. Weighted age-stratified prevalence was calculated and logistic regression models estimated age-specific odds ratios (ORs) with 95% confidence intervals (CIs), adjusting for socioeconomic status and medical comorbidity burden. Among 694,086 participants, 176,870 had an SMI diagnosis. Dementia prevalence was 3.49% (range, 0.33% at ages 20-29 to 39.51% at 90-99 years) in SMIs and 0.36% (0.02%-17.7%) in controls. Ischemic stroke prevalence was 5.3% (0.22%-16.4%) in SMIs and 2.75% (0.08%-14.67%) in controls. The ORs between SMI and dementia were significant across all age groups, with the strongest association observed at younger ages (OR = 23.21, 95% CIs = 13.74-39.19 at 30-39 years). Elevated ORs for stroke persisted up to 70-79 years, peaking at 40-49 years (OR = 2.99, 95% CIs = 2.63-3.41). Patterns were consistent across SMI subtypes. These findings highlight the need for earlier and more systematic neurological and cardiometabolic screening and management within psychiatric care and support policies that recognize SMIs as risk factors for vascular diseases and dementia.
Efficacy and safety of adjunctive treatment with the fatty acid amide hydrolase inhibitor JNJ-42165279 in participants with major depressive disorder with anxious distress: A double-blind, placebo-controlled, randomised study
(Elsevier B.V., 2026-05-01) Schmidt, Mark E.; Gargano, Cynthia; Zhou, Xianhuang; Palmer, James A.; Saad, Ziad S.; Vieta i Pascual, Eduard, 1963-; Drevets, Wayne C.; Stuyckens, Kim; Pandina, Gahan
JNJ-42165279 is a potent, selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid N-arachidonoylethanolamide (anandamide), which plays a role in regulation of fear and anxiety responses. This double-blind, randomised, placebo-controlled, phase 2a study assessed the efficacy, safety and pharmacodynamics of adjunctive treatment with JNJ-42165279 in participants with major depressive disorder (MDD) with anxious distress and inadequate response to selective serotonin reuptake inhibitors (SSRI) or serotonergic/noradrenergic reuptake inhibitors (SNRI). Eligible participants (18-64 years; N = 153) were randomised (1:1) to receive JNJ-42165279 (25 mg) or placebo orally once daily and were maintained on their current SSRI/SNRI treatment. The primary endpoint was the change from baseline at week 6 in the 17-item Hamilton Depression Rating Scale (HDRS17). The study results did not show a significant treatment effect of adjunctive JNJ-42165279 on the primary endpoint versus placebo (least square mean difference [standard error]: -0.2 [1.04]; one-sided p=0.416) in the enriched intent-to-treat population. Findings for the key secondary efficacy endpoints also did not demonstrate an additional benefit of adjunctive JNJ-42165279 treatment over placebo. Treatment with JNJ-42165279 produced substantial increases in the mean concentrations of fatty acid amides in plasma, and the plasma JNJ-42165279 and anandamide levels were strongly correlated. The safety results were consistent with the known safety profile of JNJ-42165279. Overall, adjunctive treatment with JNJ-42165279 at the dose tested did not provide significant benefit in reducing depression/anxiety symptoms versus placebo but showed no new safety signals in participants with MDD and anxious distress.
Recommendations for the Deprescribing of Psychotropic Medications: A Consensus Statement From the American Society of Clinical Psychopharmacology Task Force
(American Medical Association (AMA), 2026-02-25) Goldberg, Joseph F.; McIntyre, Roger S.; Swartz, Holly A.; Freeman, Marlene P.; Mago, Rajnish; Citrome, Leslie; Rosenblat, Joshua D.; Thase, Michael E.; Tohen, Mauricio; Vieta i Pascual, Eduard, 1963-; Malhi, Gin S.; Sajatovic, Martha; Shelton, Richard C.; Macaluso, Matthew; Berk, Michael; Perlis, Roy H.; Ostacher, Michael J.; Khan, Arifulla; Iosifescu, Dan V.; Sanacora, Gerard; Rubio, José Manuel; Kane, John M.; Goodman, David W.; Nierenberg, Andrew A.; Correll, Christoph U.; Kupka, Ralph; Kasper, Siegfried; Furukawa, Toshi A.; Davis, Lori; Aaronson, Scott T.; Gitlin, Michael J.; Jha, Manish K.; Cohen, Lawrence J.; Papakostas, George I.; Mitchell, Philip B.; Gorwood, Philip; Gupta, Swapnil; Frye, Mark A.; Young, Allan H.; Zohar, Joseph; Steingard, Sandra; Zarate, Carlos A.; Clayton, Anita H.
Importance There is a need for greater recognition of clinical psychopharmacology endpoints, including instances where specific psychotropic medications may become unnecessary, redundant, contradictory, or otherwise inappropriate and therefore merit deprescribing. Objective To address circumstances warranting psychotropic medication deprescribing. Evidence Review The American Society of Clinical Psychopharmacology convened a panel of 45 international psychopharmacology experts who developed and completed a multiround Delphi survey and conducted a focused literature review between January and May of 2025, in order to identify areas of consensus or disagreement on key aspects of the deprescribing of psychotropic medications. These included collaborative risk-benefit assessments with patients; pharmacokinetic and pharmacodynamic factors; pharmacogenomics; distinguishing redundant or conflictual from complementary mechanisms of action; managing adverse effects; assuring medication adherence; drug tolerance or tachyphylaxis; medication misuse; and the psychological context and ramifications of deprescribing. Findings Consensus was achieved on 44 of 50 final Delphi statements (88%). Panelists unanimously agreed that components of a pharmacotherapy regimen should undergo periodic review to ensure that treatments target relevant symptoms and have favorable risk-benefit ratios. Key points of consensus were that deprescribing: (1) should not occur without first assessing medication adherence; (2) merits consideration if less than partial therapeutic response is apparent, or if treatment goals have been reached and relapse prevention is not a long-term objective; (3) involves psychological ramifications that warrant attention; (4) should be followed by close clinical monitoring; and (5) risk-benefit decisions should ideally involve active patient participation within a shared decision-making model. Conclusions and Relevance Through this Consensus Statement, the Task Force identified circumstances in which the selective elimination of certain psychotropic medications may be clinically indicated. Empirical trials are needed to assess the implementation of deprescribing protocols and gauge their safe, effective, and acceptable outcomes.
Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for posttraumatic stress disorder: A systematic review and meta-analysis of clinical and functional outcomes
(Elsevier B.V., 2026-06-01) Fares Otero, Natalia Elena; Furukawa, Yuki; Sijbrandij, Marit; Leucht, Stefan; Vieta i Pascual, Eduard, 1963-; Cuijpers, Pim; Harrer, Mathias; Seedat, Soraya
Posttraumatic stress disorder (PTSD) is a chronic and disabling condition and identifying beneficial therapies is timely and important. We aimed to estimate the efficacy of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) compared with control on clinical and functional outcomes in PTSD. A PRISMA-compliant search (PROSPEROCRD42022353261) up to August 14, 2025, covered nine databases and manual searches to identify randomised controlled trials (RCTs). Methodological quality was assessed using the Cochrane Risk of Bias tool (RoB2), and the certainty of the evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Of 1035 records identified, 14 studies met inclusion criteria for qualitative synthesis; eight trials provided sufficient data for quantitative synthesis (k = 24). Random-effects meta-analyses indicated that MDMA-AT was associated with reductions in PTSD symptom severity (n = 298, k = 9, SMD = -1.19, 95 % CI [-1.95, -0.42]; I² = 68.8 %, τ2 = 1.02), dissociative symptoms (n = 148, k = 5, SMD = -0.37, 95 % CI [-0.70, -0.04]; I² = 0.0 %, τ2 = 0), and may improve functioning (n = 227, k = 4, SMD = -0.83, 95 % CI [-1.47, -0.19]; I² = 61.2 %, τ2 = 0.27). No clear evidence of benefit was observed for depressive symptoms. Most studies showed a high risk of bias in the measurement of the outcome, and some concerns due to deviations from the intended intervention; the overall certainty of the evidence was very low. The number of trials remains limited, with considerable heterogeneity in certain outcomes, small sample sizes, and the absence of active controls in most studies, which likely compromised blinding integrity. Current findings suggest that MDMA-AT may warrant further investigation as a potential treatment for PTSD; however, larger, higher-quality RCTs with active controls and long-term follow-up are needed to determine its efficacy.
Facial emotion recognition deficits in bipolar disorder: a systematic review and meta-analysis
(Cambridge University Press (CUP), 2026-01-12) De Prisco, Michele; Oliva, Vincenzo; Possidente, Chiara; Fico, Giovanna; Montejo Egido, Laura; Fortea González, Lydia; Kjærstad, Hanne Lie; Miskowiak, Kamilla W.; Anmella, Gerard; Hidalgo Mazzei, Diego; Miola, Alessandro; Fornaro, Michele; Murru, Andrea; Vieta i Pascual, Eduard, 1963-; Radua, Joaquim
Background: Bipolar disorder (BD) is associated with impairments in facial emotion recognition (FER), affecting social functioning and quality of life. Understanding FER deficits in BD is crucial for tailoring interventions and improving treatment outcomes. This systematic review and meta-analysis aims to evaluate FER differences among individuals with BD, unaffected first-degree relatives (FDRs), and healthy controls (HCs), exploring predictors related to patient and study characteristics. Methods: We systematically searched PubMed/MEDLINE, Scopus, EMBASE, and PsycINFO databases from inception to March 28, 2024. Random-effects meta-analyses were conducted to explore differences in accuracy and reaction time during FER identification and discrimination tasks. Results: A total of 100 studies were included, comprising 4920 individuals with BD (females = 56%, mean age = 34.1 ± 9.1), 676 FDRs (females = 55%, mean age = 36.1 ± 12), and 4909 HCs (females = 53.2%, mean age = 32.5 ± 9.5). Compared to HCs, adults with BD exhibited significantly lower accuracy (SMD = -0.47; 95% CIs = -0.56, -0.38) and higher reaction time (SMD = 0.57; 95%CIs = 0.33, 0.81) during facial emotion identification tasks. During facial emotion discrimination tasks, adults with BD had significantly lower accuracy than HCs (SMD = -0.59; 95%CIs = -0.78, -0.4), but similar speed. No significant differences were observed between BD and FDRs. Meta-regressions identified several predictors of FER performance, including manic symptom severity, stimulus duration, and presence of practice before task. Conclusions: FER deficits appear to be a core feature of BD and require specialized, systematic assessment. Identifying these deficits may help guide interventions aimed at improving affective cognition and social outcomes in individuals with BD.
α-Synuclein Gene Hypomethylation in LRRK2 Parkinson's Disease Patients
(Wiley, 2024-12-23) Mena, Lorena de; Parés, Guillem; Garrido Pla, Alicia; Pilco-Janeta, Daniel F.; Fernández Sánchez, Manel; Pérez, Jesica; Tolosa, Eduardo; Cámara Lorenzo, Ana; Valldeoriola Serra, Francesc; Ezquerra Trabalón, Mario; Martí Domènech, Ma. Josep; Fernández Santiago, Rubén
Background α-Synuclein (SNCA) gene hypomethylation was reported in idiopathic Parkinson's disease (iPD). Based on a high clinical resemblance between iPD and leucine-rich repeat kinase 2 (LRRK2)-driven Parkinson's disease (L2PD), we investigated the epigenetic status of SNCA in an extensive LRRK2 clinical cohort from Spain. Methods We assessed the methylation levels of 23 CpG sites in the SNCA promoter region using peripheral blood DNA from L2PD patients (n = 151), LRRK2 nonmanifesting carriers (n = 55), iPD patients (n = 115), and healthy control subjects (n = 154) (total: N = 475). Results Compared with control subjects, we found significant SNCA hypomethylation in 11 of 23 CpGs in L2PD (48%), whereas 22 CpGs (96%) were hypomethylated in iPD. In line with a healthy status, asymptomatic mutation carriers had similar SNCA methylation profiles to control subjects. Conclusions This study shows for the first time that SNCA hypomethylation occurs in patients with L2PD. Further studies addressing SNCA methylation status in additional worldwide LRRK2 cohorts are warranted. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stages
(Frontiers Media, 2025-06-06) Fuster, Carla; Corominas, Josep; Marsal García, Aida; Llarch, Neus; Iserte, Gemma; Sanduzzi Zamparelli, Marco; Forner González, Alejandro; Ferrer Fàbrega, Joana; Holguin Arce, Víctor Emilio; Morales, Albert; Saavedra Morales, Anny Carolina; Reig, María; Boix i Ferrero, Loreto; Marí, Montserrat; Diaz Lorca, Maria Alba
Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy. However, their efficacy in hepatocellular carcinoma (HCC) is limited, highlighting the need to further explore immune microenvironments and novel biomarkers. This study examined lymphocyte populations and immune checkpoint dynamics in early, advanced, and post-progression HCC to better understand immune dynamics in HCC and to help identify predictive biomarkers and immune modulation strategies.Methods: Tumoral and non-tumoral liver tissues were analyzed from HCC patients across early (n=25), advanced (n=22), and advanced-beyond-progression (n=15) stages. Lymphocyte profiling was performed using immunohistochemistry and flow cytometry, focusing on NK cells, T cells, and immune exhaustion markers. An exploratory analysis of this profile and its association with disease progression and recurrence was conducted.Results: Early HCC exhibited higher liver-resident NK (lrNK) cell densities in non-tumor regions, which diminished with advanced stages. Increased CD56+ cell infiltration in the tumor core was associated with recurrence. Tumor region showed elevated PD-1, NKG2A, and CD39 expression in CD4+ and CD8+ T cells, indicating progressive immune exhaustion. Advanced HCC stages demonstrated altered NK cell phenotypes, with reduced cytotoxic activation (CD16) and increased residency markers (CXCR6/CD69) in tumor-isolated lymphocytes.Conclusions: Progressive immune exhaustion and dysregulation of lrNK and T cells in HCC reflect the evolution of the immune microenvironment originating in the tumor and leaking into the non-tumoral liver, progressively diminishing the cytotoxic capacity of NK and T cells. CD56+ cell density and immune checkpoint profiles are potential biomarkers for therapeutic response and disease monitoring, underscoring the need for personalized immunotherapy strategies.
Heterogeneity of reduced FEV1 in early adulthood: A looking forward, looking backwards analysis
(Blackwell, 2025-01-12) Olvera Ocaña, Núria; Agustí García-Navarro, Àlvar; Vonk, Judith M.; Wang, Guangchuan; Hallberg, J.; Boezen, H.M.; Berge, Maarten van den; Melén, Erik; Faner, Rosa
Background Some individuals never achieve normal peak FEV1 in early adulthood. It is unknown if this is due to airflow limitation and/or lung restriction. Methods To investigate this, we: (1) looked forward in 19,791 participants in the Dutch Lifelines general population cohort aged 25–35 years with 5-year follow-up; and (2) looked backwards in 2032 participants in the Swedish BAMSE birth cohort with spirometry at 24 years of age but also at 16 and/or 8 years. Results (1) In Lifelines 8.5% of participants had reduced FEV1 at 25–35 years, 68% due to Preserved Ratio Impaired Spirometry (‘PRISm’) and 32% to airflow limitation (‘low-limited’); besides, 3.8% participants with normal FEV1 showed airflow-limitation (‘normal-limited’). Low-limited and normal-limited, but not PRISm, reported higher smoking exposures and asthma diagnosis than normal (p < 0.05). At 5-year follow-up, 91.2% of participants remained in the same group, and FEV1 decline was similar in normal and normal-limited participants, but statistically smaller (p < 0.05) in PRISm and low-limited; (2) these observations were largely reproduced in BAMSE at 24 years of age; and, (3) in BAMSE, low-limited or PRISm individuals were already identifiable at 8–16 years of age. Conclusion Low peak FEV1 in early adulthood is most often due to PRISm and results in a significant burden of respiratory symptoms. Only low-limited and normal-limited, but not PRISm, associate with a doctor diagnosis of asthma, and FEV1 decline was statistically different in PRISm indicating a need for differentiated clinical approaches. These spirometric abnormalities can be already identified in childhood and adolescence.
Clinical trial protocol for continuous glucose monitoring in critical care at Hospital Clinic of Barcelona (CGM-UCI23)
(Wiley, 2024-10-28) Pañero-Moreno, Marc; Guix Comellas, Eva Maria; Villamor Ordozgoiti, Alberto
Background: Hyperglycaemia is common in intensive care units (ICUs), with a prevalence of up to 86.2%, increasing mortality. Technology has evolved towards continuous glucose monitoring (CGM), and its use in ICUs began especially during the coronavirus pandemic (COVID-19). Various studies have evaluated the reliability of CGM, indicating that it is safe for use in critically ill patients. Aim: The aim of this study was to compare the use of CGM with point-of-care glucose (POC-G) testing in ICU. Specific objectives include evaluating the glycaemic control, the frequency of POC-G measurements, the incidence of hyperglycaemia, hypoglycaemia and morbidity and mortality at 90 days. Study Design: An experimental, controlled and randomized clinical trial with a singleblind design will be conducted at Hospital Clinic of Barcelona (HCB). A sample size of 376 participants will be recruited and randomly assigned to two groups: an experimental group, where glycaemic management will be based on CGM; and a control group, where glucose will be managed through POC-G testing, with a blinded CGM. Results: The primary variable considered will be time in range (TIR), with secondary outcomes including, time above range (TAR), time below range (TBR), number of POC-G measurements, incidence of hyperglycaemia and hypoglycaemia, and mortality. Hypothesis testing will use the Kolmogorov–Smirnov test to assess data normality, with appropriate statistical tests applied, considering a p-value <.05. Relevance to Clinical Practice: The results obtained will help us understand the impact of CGM on critically ill patients. CGM could potentially reduce the workload of nurses and improve the efficiency of decision-making by the ICU team, enabling early identification and treatment of glucose complications, thereby enhancing safety. Patient safety, a reduction in patient fingerstick and a decreased care burden are the criteria that add value to this research.
Mortality risk in relation to diet quality assessed by the 2023 nutri-score nutrient profiling model: a prospective analysis
(Springer-Verlag GmbH Germany, 2026-03-24) Khoury, Nadine; Fernández Cao, Jose Cándido; Mohammadifard, Noushin; Martínez González, Miguel Ángel, 1957-; Corella, Dolores; Fitó, Montserrat; Estruch, Ramón; Tojal Sierra, Lucas; Gómez Gracias, Enrique; Fiol, Miquel; Lapetra, José; Serra Majem, Lluís; Pinto, Xavier; Vázquez Ruiz, Zenaida; Sorli, Jose V.; Schröder, Helmut, 1958- ; Salas Salvadó, Jordi; Babio, Nancy
Background The updated Nutri-Score nutrient profiling model (uNS-NPM), revised in 2023, aims to better align with dietary guidelines and improve health outcomes prediction. However, evidence assessing its validity and applicability remains limited, particularly in Spanish populations.ObjectiveTo investigate the prospective association between diet quality, assessed using the uNS-NPM dietary index (DI), and the risk of all-cause and cause-specific mortality in older adults at high cardiovascular risk. Methods A prospective analysis within the PREDIMED cohort, with 7,212 participants aged 55-80 years at high cardiovascular risk was conducted. Diet was assessed by validated food frequency questionnaires, and the uNS-NPM DI was computed to quantify overall dietary quality. Time-dependent Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular, cancer, and other-cause mortality across quintiles of the average cumulative uNS-NPM DI, adjusting for relevant confounders. Results Over a median follow-up of 6 years, 425 deaths occurred (103 cardiovascular, 169 cancers, 153 other causes). Participants in the highest quintile of the uNS-NPM DI (reflecting poorer diet quality) had a higher risk of all-cause mortality (HR: 1.64; 95% CI: 1.19-2.28; p-trend = 0.007) and a higher risk of cardiovascular mortality (HR: 3.21; 95% CI: 1.29-7.95; p-trend = 0.002) compared to those participants in the lowest quintile. Participants in the highest quintile of uNS-NPM DI had also an increased risk of death from other causes (HR: 1.84; 95% CI: 1.11-3.07), although the trend was not statistically significant p-trend = 169). For cancer mortality, no significant association was observed (HR for highest vs. lowest quintile: 1.16; 95% CI: 0.69-1.92 p-trend = 0.695). Conclusions In this Mediterranean cohort of older adults at high cardiovascular risk, lower dietary quality, assessed with the uNS-NPM DI, was prospectively associated with higher risks of all-cause, cardiovascular, and other-cause mortality. These findings support the uNS-NPM DI as a valuable tool for diet quality assessment.
In vitro and in vivo activity of daptomycin plus ceftaroline for the treatment of experimental endocarditis due to Enterococcus faecalis with and without high-level aminoglycoside resistance
(Oxford University Press, 2026-05-01) Cañas, María Alexandra; García González, Javier; Luque Paz, David; Cuervo Requena, Guillermo; Krivak, Filip; Nin Blanch, Judit; Hernández Meneses, Marta; Falces Salvador, Carles; Maristany Bosch, Marta; Perissinotti, Andrés; Vidal, Bàrbara; Tolosana, José M. (José María); Quintana, Eduard; Llopis Pérez, Jaime; Moreno Camacho, Ma. Asunción; García de la Mària, Cristina; Miró Meda, José M. (José María), 1956-; Hospital Clínic Endocarditis Study Group
Objectives Effective alternatives to standard of care treatment for E. faecalis infective endocarditis (EFIE) are needed. Some in vitro studies have suggested daptomycin and ceftaroline have synergistic activity against E. faecalis. We aimed to assess the in vitro and in vivo activity of daptomycin in combination with ceftaroline against E. faecalis clinical isolates with and without high-level of aminoglycoside resistance (HLAR). Materials and methods A panel of six endocarditis-associated E. faecalis isolates were used for time–kill assays at initial standard and high inocula. Daptomycin (10 mg/kg/day intravenously) and daptomycin (10 mg/kg/day iv) plus ceftaroline (600 mg q12 hours intravenous) were compared in vivo using a human-like pharmacokinetic model in two treatment groups using the experimental EFIE model in rabbits. Results The combination of daptomycin plus ceftaroline achieved synergy against all three HLAR and all three non-HLAR strains in time–kill assays at initial standard inoculum. A bactericidal effect was observed in two of the three HLAR E. faecalis isolates. For HLAR EFAE-188, the use of daptomycin plus ceftaroline significantly decreased the bacterial density in vegetations compared with daptomycin alone (median density 5.2 versus 6.7 log10 cfu/g; P = 0.028). For non-HLAR EFAE-468, the bacterial density in vegetations was lower with the combination therapy than with daptomycin alone (median density 5.2 versus 6.8 log10 cfu/g; P = 0.072). Adding ceftaroline prevented the development of daptomycin-resistant E. faecalis isolates in all cases. Conclusions Daptomycin plus ceftaroline represents a promising alternative for treating EFIE. Further clinical studies are needed to confirm these findings.
In vitro activity of amoxicillin combined with oral cephalosporins against endocarditis-associated E. faecalis clinical isolates
(Oxford University Press, 2026-04-03) Luque Paz, David; Cañas, María Alexandra; Cuervo Requena, Guillermo; Espasa, Mateu; Hernández Meneses, Marta; Quintana, Eduard; Falces Salvador, Carles; Tolosana, José M. (José María); Vidal, Bàrbara; Perissinotti, Andrés; Llopis Pérez, Jaime; Moreno Camacho, Ma. Asunción; García de la Mària, Cristina; Miró Meda, José M. (José María), 1956-
Objectives: Aminopenicillin associated with parenteral cephalosporins provides synergistic activity against Enterococcus faecalis. Oral consolidation treatment is an option for infective endocarditis E. faecalis (EFIE), but optimal oral regimen remains under debate. We aimed to assess the in vitro activity of combinations based on amoxicillin plus an oral cephalosporin, namely, cephalexin or cefixime, against E. faecalis strains. Methods: MIC and MBC values were determined against 6 clinical isolates of endocarditis-associated E. faecalis. Time-kill (TK) experiments were performed using amoxicillin (½MIC) plus cephalexin or cefixime at different concentrations (Cmax, ½Cmax and Cmin). Comparator regimens were amoxicillin/cefazolin and amoxicillin/ceftriaxone. TK experiments were carried out at standard (∼5 × 105 cfu/mL) and high inoculum (∼108 cfu/mL). Results: Using amoxicillin combined with Cmax, ½Cmax or Cmin of oral cephalosporin at standard inoculum, synergy or additivity was observed in 66, 33 and 0% of E. faecalis isolates with adjunctive cephalexin; and in 83, 50 and 33% of isolates with adjunctive cefixime, respectively. In comparator regimens, synergy was found in all isolates at standard inoculum. At high inoculum, amoxicillin/cefixime at Cmax had similar efficacy to amoxicillin/ceftriaxone, showing synergy in 50% of E. faecalis isolates, while amoxicillin/cephalexin at Cmax and amoxicillin/cefazolin only achieved synergy in 17% of isolates. Conclusions: The combination of amoxicillin/cefixime exhibits synergy in most E. faecalis strains at standard inoculum. Cefixime could represent an interesting adjunctive therapy to amoxicillin for oral consolidation treatment of EFIE.
Palbociclib with adjuvant endocrine therapy in early breast cancer: 5-year follow-up analysis of the global multicenter, open-label, randomized phase III PALLAS trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13)
(Oxford University Press, 2026-02) Mayer, Erika L.; Hlauschek, D.; Gnant, Michael F. X.; O'Brien, Peter J.; Bellet Ezquerra, Meritxell; Goetz, Matthew P.; Ruiz Borrego, Manuel; Chan, Andrew T.; Clifton, K.; Egle, D.; Lake, D.; Cabrera, P.; Mamounas, T.; Pristauz Telsnigg, G.; Dayao, Z.; Gil Gil, Miguel; Cameron, David A.; Traina, Tiffany A.; Morris, Patrick Glyn; Sabanathan, D.; Rinnerthaler, Gabriel; Meisel, Jane Lowe; Prat Aparicio, Aleix; Wolff, A. C.; Tseng, Lingming; Isaacs, Claudine; Singer, Christian F.; Rubovszky, Gábor; Foukakis, Theodoros; Jassem, Jacek; Winer, Eric P.; Vetter, Marcus; Federmann, J.; Metzger Filho, Otto
Background: In the phase III PALLAS trial, the addition of 2 years of palbociclib to adjuvant endocrine therapy (ET) did not improve short-term invasive disease-free survival (iDFS) compared with ET alone in high-risk early-stage hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this article, we report 5-year efficacy outcomes, including updated iDFS and overall survival (OS). Patients and methods: PALLAS is an international, open-label, randomized phase III trial evaluating the addition of 2 years of palbociclib to adjuvant ET in patients with stage II-III HR-positive/HER2-negative breast cancer. The primary endpoint was iDFS. Results: The trial enrolled 5753 patients, with 2883 randomized to receive palbociclib plus ET and 2870 to receive ET alone. With a median follow-up of 59.8 months, the 5-year iDFS was 84.2% [95% confidence interval (CI) 82.7% to 85.6%] in the palbociclib plus ET arm and 82.4% (95% CI 80.8% to 83.9%) in the ET-alone arm [hazard ratio (HR) 0.88, 95% CI 0.77-1.01, log-rank P = 0.0614]. No significant iDFS benefit of palbociclib was observed in any subgroup, including analyses by anatomic stage, T-stage, N-stage, tumor grade, prior (neo)adjuvant chemotherapy, age, or clinical risk. The 5-year OS was 92.6% (95% CI 91.5% to 93.6%) in the palbociclib plus ET arm and 93.2% (95% CI 92.1% to 94.1%) in the ET-alone arm (HR 1.09, 95% CI 0.89-1.33, log-rank P = 0.4051). More patients in the ET-alone arm (65.7%) than in the palbociclib plus ET arm (33.0%) received cyclin-dependent kinase 4/6 inhibitors after recurrence. Conversely, more patients in the palbociclib plus ET arm (52.5%) than in the ET-alone arm (41.0%) received chemotherapy after recurrence. Conclusions: In conclusion, 5-year follow-up from the PALLAS trial confirms initially reported results. These long-term findings will provide investigators with important benchmarks for clinical outcomes in the contemporary management of HR-positive/HER2-negative breast cancer, and may be further used to guide adjuvant therapy for patients with high-risk early-stage HR-positive/HER2-negative breast cancer.
Implementation of the precision oncology program in catalonia's public health system: results, lessons learned, and future prospects
(Springer Verlag, 2026-03) Mur, Pilar; Pozuelo, Anna; Tabernero Caturla, Josep; Albanell Mestres, Joan; Bellosillo Paricio, Beatriz; Bosch Albareda, Francesc; Briones, Javier; Brunet, Joan; Colomer Pujol, Dolors; Domenech, Montserrat; Fontanet, Manel; Matias-Guiu, Xavier, 1958-; Salazar Soler, Ramón; Vivanco Hidalgo, Rosa Maria; Mollà, Meritxell; Moreno, Lucas; Prat Aparicio, Aleix; Ribera, Josep M.; Clèries Soler, Ramon; Guarga, Alex; Espinàs Piñol, Josep Alfons; Borràs Andrés, Josep Maria
Purpose: The Precision Oncology Program (POP) in Catalonia aims to provide equitable access to molecular testing for individuals with cancer, integrating Next-Generation Sequencing (NGS) into clinical practice to inform diagnosis, prognosis, and treatment decisions for both adult and pediatric patients with solid and hematologic malignancies, including somatic and germline alterations. This study evaluates the program's outcomes and impact. Methods: This evaluation covers the period from the program’s implementation in July 2021 through December 2023, with a more detailed analysis focusing on 2022–2023. The program involved 12 reference centers utilizing NGS technology for cancer genetic analysis, coordinated by CatSalut, the regional public health service payer. Data collected from each reference laboratory included the number of tests performed, types of tumor panels used, clinical indications, and associated outcomes. Results: Between July 2021 and December 2023, a total of 23,135 molecular tests were performed on 22,501 patients. The most frequently analyzed panels were for solid tumors (38.1%), hematologic cancers (17.3%), and germline mutations (42.2%). Pediatric patients accounted for 2.4% of the total. Notably, 24.7% of patients underwent a change in clinical management, contributing to more targeted treatment strategies, particularly in solid tumors (58.7%). Reports were delivered within an average of four weeks, meeting program benchmarks and facilitating timely decision-making. Sample submission compliance was high, reaching 98.5%. Conclusions: This POP successfully addressed operational, financial, and logistic challenges, ensuring equitable access to molecular testing. This program led to more efficient and personalized clinical management, with growing impact on cancer care and patient outcomes.
Contrasting the clinical and biological characteristics of young and old COPD patients
(European Respiratory Society, 2025-02-25) Vila Muntadas, Marc; Agustí García-Navarro, Àlvar; Vestbo, Jørgen; Celli, Bartolome R.; Cosío, Borja G.; Silverman, Edwin K.; Sibila Vidal, Oriol; Badia, Joan Ramon; Bakke, Per; Tal-Singer, Ruth; MacNee, William; Faner, Rosa
Background The ECLIPSE study was a large, international, prospective, controlled, observational study that included COPD patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 2–4), as well as smoking and non-smoking participants with normal spirometry, aged 40–75 years, who were followed-up regularly for 3 years. Here we sought to contrast the clinical and biological characteristics of young COPD versus controls of similar age and older COPD patients included in ECLIPSE. Methods We compared 106 young (<50 years) and 488 old (>70 years) COPD patients, as well as 119 young smokers and 92 nonsmoker controls (<50 years) with normal spirometry. Results Young COPD patients: 1) were more symptomatic than young controls, often reported a family history of chronic bronchitis, emphysema and asthma, as well as a personal history of asthma and bronchitis, and suffered from a similar disease burden to older patients; 2) were at higher risk of substantial forced expiratory volume in 1 s decline over time; and 3) had reduced serum levels of CC16 (a lung-derived anti-inflammatory protein that relates to lung damage) and, at the same time, reduced pro-inflammatory markers compared to older COPD patients. Conclusions Young COPD patients suffer from significant disease burden, display an altered biomarker and disease progression profile reflected by an accelerated risk of lung function decline highlighting the need for early life diagnosis, prevention approaches and treatment.

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