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Antagonistic SMAD2/3 control of TIMP-1, VEGF-A, and hypoxia signaling in myofibroblasts shapes histotype-specific angiogenesis in lung cancer
(Nature Publishing Group, 2026-03-30) Díaz Valdivia, Natalia; Duch, Paula; Ikemori, Rafael; Parker, Amelia L.; Arshakyan, Marselina; Llorente, Alejandro; Bernardo, Alejandro; Rodríguez Rojas, José; Carrasco Jordan, Josep Lluís; Park, Danielle; Sahai, Erik; Fillat i Fonts, Cristina; Juan, Manel; Nadal, Ernest; Reguart, Noemí; Radisky, Derek C; Casanovas, Oriol; Alcaraz,Jordi
Non-small cell lung cancer (NSCLC) exhibits disparate responses to anti-angiogenic therapies between its two major histologic subtypes, lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), suggesting a histotype-dependent angiogenesis regulation. Tumor-associated fibroblasts (TAFs) exhibit an activated/myofibroblast-like phenotype in NSCLC, and are emerging as major regulators of tumor progression; yet, their role in controlling angiogenesis in NSCLC remains undefined. Here we analyzed angiogenesis/hypoxia markers in NSCLC, and combined transcriptomics (bulk RNA-seq, scRNA-seq), angiogenesis arrays, genetic perturbations and functional in vitro and in vivo assays to dissect the histotype-dependent production of pro-angiogenic factors in TAFs. We observed greater angiogenesis and reduced necrosis/hypoxia in LUAD compared to LUSC across multiple patient cohorts. The LUAD-TAF secretome was primed for angiogenesis through SMAD3-dependent overproduction of key regulators, particularly TIMP-1 and VEGF-A. We also uncovered a novel function for TIMP-1 in promoting endothelial cell hyperbranching over basal VEGF signaling. Conversely, LUSC-TAFs displayed diminished angiogenic effects despite upregulating HIF-1α and a hypoxia-associated transcriptional signature, owing to their lower SMAD3 and compensatory increase in SMAD2. Our study unveils the critical influence of TAFs in shaping the distinct angiogenic landscapes in LUAD and LUSC through the opposing SMAD2/3 regulation of TIMP-1, VEGF-A and hypoxia signaling. These results also highlight the therapeutic potential of targeting stromal SMAD3/TIMP-1 in LUAD or microenvironmental stressors such as hypoxia and acidosis in LUSC. In addition, these findings provide a biological framework for understanding the histotype-dependent patterns of dissemination, immune evasion, and response to anti-angiogenic therapies in NSCLC.
Latin-American Ambulatory Blood Pressure Registry (MAPA-LATAM): An urgent need Registro Latinoamericano de monitorización ambulatoria de la presión arterial (MAPA-LATAM): una necesidad urgente
(Elsevier, 2021-11-01) Camafort Babkowski, Miguel; Alcocer, L.; Coca, Antonio; Lopez-Lopez, J.P.; López-Jaramillo, P.; Ponte-Negretti, C.I.; Sebba-Barroso, W.; Valdéz, O.; Wyss, F.
La hipertensión arterial (HTA) es el principal factor de riesgo de enfermedad cardiovascular. Aunque es un problema global, independiente de la situación económica, región, raza o cultura, los datos disponibles con respecto a Latinoamérica no son muy abundantes. Por otra parte, las guías clínicas enfatizan la importancia de obtener lecturas fiables de la presión arterial. Por ello, se recomienda el uso de la monitorización ambulatoria de la presión arterial (MAPA), que mejora su precisión y reproducibilidad, ayudando a un mejor diagnóstico, en la toma de decisiones terapéuticas, y representa una mejor estimación pronóstica que las medidas en consulta. Lamentablemente, no existe ningún registro prospectivo global de MAPA para toda Latinoamérica que analice la prevalencia de HTA, el grado de su conocimiento, su porcentaje de tratamiento y el grado de control. En consecuencia, los autores de este artículo consideran prioritaria su puesta en marcha.
Problematic usage of the internet: A policy map of the use of internet and its possible mental health consequences in adolescents across United Kingdom, France, Germany, Italy, Australia, Canada, the United States, and New Zealand
(Elsevier B.V., 2026-06) Snegg, Julia; Larrain, Blanca; Mosler, Kristin; Van Kessel, Robin; Achab, Sophia; Corazza, Ornella; Penazzi, Gabriele; Stein, Dan J., 1962-; Ekhtari, Hamed; Bowden Jones, Henrietta; Ioannidis, Konstantinos; Barbati, Vittoria; Demetrovics, Zsolt; Chamberlain, Samuel R.; Carmi, Lior; Zohar, Joseph; Rumpf, Hans‐Jürgen; Hall, Natalie; Menchón Magriñá, José Manuel; Sales, Célia M. D.; Montag, Christian; Lindenberg, Katajun; Susi, Mart; Huizink, Anja; Potenza, Marc N.; Pallanti, Stefano; Morgan, Nick; Moreno, Carmen; Purper-Ouakil, D.; Brand, Matthias; Yücel, Murat; Czakó, Andrea; Walitza, Susanne; Burkauskas, Julius; Felvinczi, Katalin; Smith, Megan; Wellsted, David; Jones, Julia; Dias, Teresa Silva; Foster, Simon; Mohler Kuo, Meichum; Neumann, Ina; Fongaro, Erica; Fally, Sara; Oliveira, Hernani; Abregú Crespo, Renzo; Sepúlveda Palomo, Marta; Fineberg, Naomi A.; Roman-Urrestarazu, Andrés
This work analyses policies related to the Problematic Usage of the Internet (PUI) and its relationships to adolescent mental health across the United Kingdom, France, Germany, Italy, Australia, Canada, the United States, and New Zealand. Using a policy path dependency framework, national legislation was examined to assess relationships with PUI. The study maps policy by reviewing governmental legislation and databases, analysing them on macro (societal), meso (market/intermediary organisations), and micro (citizen rights, duties, and protection) levels. It explores legal instruments related to PUI, including data protection, cybersecurity, content regulation, and harassment, offering both historical and comparative analyses across the eight countries. Findings indicate that while several countries have policies indirectly regulating PUI, significant legislative gaps persist relating to adolescent mental health. Most policies address broader internet concerns without specifically targeting PUI or its effects on mental health. Overall, the analysis highlights the need for more targeted public health policies to address the root causes of PUI, advocating for tailored interventions focused on adolescent well-being.
Immunomodulatory therapy, risk factors and outcomes of hospital-acquired bloodstream infection in patients with severe COVID-19 pneumonia: a Spanish case-control matched multicenter study (BACTCOVID).
(European Society of Clinical Microbiology and Infectious Diseases, 2021-07-07) Abelenda Alonso, Gabriela; Rombauts, Alexander; Gudiol González, Carlota; Oriol, Isabel; Simonetti, Antonella Francesca; Coloma Conde, Ana; Rodríguez-Molinero, Alejandro; Izquierdo, Elisenda; Díaz Brito, Vicens; Sanmartí Vilamala, Montserrat; Padullés Zamora, Ariadna; Grau, Inmaculada; Ras, Mar; Bergas, Alba; Guillem, Lluïsa; Blanco Arévalo, Alejandro; Alvarez-Pouso, Claudia; Pallarès, Natàlia; Videla, Sebastià; Tebé, Cristian; Carratalà, Jordi
Objectives The effect of the use of immunomodulatory drugs on the risk of developing hospital-acquired bloodstream infection (BSI) in patients with COVID-19 has not been specifically assessed. We aim to identify risk factors for, and outcomes of, BSI among hospitalized patients with severe COVID-19 pneumonia. Methods We performed a severity matched case–control study (1:1 ratio) nested in a large multicentre prospective cohort of hospitalized adults with COVID-19. Cases with BSI were identified from the cohort database. Controls were matched for age, sex and acute respiratory distress syndrome. A Cox proportional hazard ratio model was performed. Results Of 2005 patients, 100 (4.98%) presented 142 episodes of BSI, mainly caused by coagulase-negative staphylococci, Enterococcus faecalis and Pseudomonas aeruginosa. Polymicrobial infection accounted for 23 episodes. The median time from admission to the first episode of BSI was 15 days (IQR 9–20), and the most frequent source was catheter-related infection. The characteristics of patients with and without BSI were similar, including the use of tocilizumab, corticosteroids, and combinations. In the multivariate analysis, the use of these immunomodulatory drugs was not associated with an increased risk of BSI. A Cox proportional hazard ratio (HR) model showed that after adjusting for the time factor, BSI was associated with a higher in-hospital mortality risk (HR 2.59; 1.65–4.07; p < 0.001). Discussion Hospital-acquired BSI in patients with severe COVID-19 pneumonia was uncommon and the use of immunomodulatory drugs was not associated with its development. When adjusting for the time factor, BSI was associated with a higher mortality risk.
Mapping policies related to problematic usage of the internet in seven European countries: Netherlands, Spain, Hungary, Lithuania, Portugal, Estonia and Switzerland
(Elsevier B.V., 2026-06) Larrain, Blanca; Van Kessel, Robin; Mosler, Kristin; Penazzi, Gabriele; Corazza, Ornella; Achab, Sophia; Stein, Dan J., 1962-; Ekhtari, Hamed; Bowden Jones, Henrietta; Ioannidis, Konstantinos; Barbati, Vittoria; Demetrovics, Zsolt; Chamberlain, Samuel R.; Carmi, Lior; Zohar, Joseph; Rumpf, Hans‐Jürgen; Hall, Natalie; Menchón Magriñá, José Manuel; Sales, Célia M. D.; Montag, Christian; Lindenberg, Katajun; Susi, Mart; Huizink, Anja; Potenza, Marc N.; Pallanti, Stefano; Morgan, Nick; Moreno, Carmen; Purper-Ouakil, D.; Brand, Matthias; Yücel, Murat; Czakó, Andrea; Walitza, Susanne; Burkauskas, Julius; Felvinczi, Katalin; Smith, Megan; Wellsted, David; Jones, Julia; Dias, Teresa Silva; Foster, Simon; Mohler Kuo, Meichum; Neumann, Ina; Fongaro, Erica; Fally, Sara; Oliveira, Hernani; Abregú Crespo, Renzo; Sepúlveda Palomo, Marta; Fineberg, Naomi A.; Roman-Urrestarazu, Andrés
This work presents a policy analysis regarding Problematic Usage of the Internet (PUI) across seven countries (Netherlands, Spain, Hungary, Lithuania, Portugal, Estonia, and Switzerland) belonging to or associated with the European Union (EU). I It examines legislative instruments addressing PUI and its multifaceted impacts on society, including social, economic, and political dimensions. Despite the growing prevalence of PUI, particularly among adolescents, and its association with various mental health concerns, the study reveals a notable gap in direct policy interventions targeting PUI within these countries. Existing regulations largely focus on broader digital governance issues like data protection, cybersecurity, and market regulation, offering only indirect approaches to mitigating PUI's adverse effects. Our findings highlight a pressing need for innovative policy frameworks that incorporate mental health considerations into digital governance, promoting a balanced approach that fosters market innovation while ensuring robust public health protections. Building on the policy discourse examined in this study, future research should focus on developing targeted, multidimensional strategies to mitigate the risks associated with problematic internet use (PUI), with particular emphasis on safeguarding the well-being of vulnerable populations.
Dupilumab-induced eosinophilia in severe asthma: 2-year follow-up real-life evidence from biologic naïve and previously treated patients
(Elsevier B.V., 2026-06) Bellver Asperilla, Cristina; Muñoz Esquerre, Mariana; Romero-Ortiz, Ana Maria; Cabrerizo-Carreño, Héctor; Orozco Echeverría, Sandra; Gonzalez Compta, Francesc Xavier; Golet Fors, Mireia; Andújar Ruiz, Alexandra; Suárez Cuartín, Guillermo Rafael; Padullés Zamora, Núria; Ardanuy Tisaire, María Carmen; Santos Pérez, Salud
Data from real-life settings regarding dupilumab-associated eosinophilia remains limited, particularly concerning potential risk factors for developing hypereosinophilia after treatment initiation. Methods. We conducted a prospective observational study including an initial cohort of 36 patients with severe asthma treated with dupilumab and followed for up to two years. Blood eosinophil count (BEC), asthma outcomes, and treatment response — including ACT score, lung function, exacerbations, oral corticosteroid use, and the EXACTO scale as a multidimensional response measure — were assessed at baseline and at weeks 24, 52, and 104. Eosinophilia was categorized as mild (>500 cells/μL), moderate (>1500 cells/μL), or severe (>5000 cells/μL), and hypereosinophilia as moderate-severe eosinophilia. Results. Transient eosinophilia occurred in 47.2% of patients and transient hypereosinophilia in 19.4%, with most cases being asymptomatic. Two patients (5.6%) developed a clinical presentation suggestive of eosinophilic granulomatosis with polyangiitis (EGPA). Hypereosinophilia was more frequent among patients who had switched from prior anti–IL-5/IL-5R therapy. Among the cases that developed hypereosinophilia, 42.9% persisted at the 2-year follow-up, whereas mild eosinophilia persisted in 65% of patients. Nevertheless, dupilumab treatment resulted in significant improvements in asthma control and treatment response outcomes, irrespective of eosinophil levels or prior biologic exposure. Conclusion. Eosinophilia is a common finding in patients receiving dupilumab, generally without significant safety implications. The use of dupilumab is safe and highly effective, even in patients previously treated with anti–IL-5/IL-5R biologics. However, rare cases of severe eosinophilic complications may occur, making long-term systematic monitoring advisable.
Beyond glomeruli: interstitial fibrosis and tubular atrophy predict poor renal outcomes in lupus nephritis
(BioMed Central, 2026-03-21) Vidal Montal, Paola; Narváez, Javier; Mitjavila Villeró, Francesca; Fulladosa, Xavier; Capdevila, Olga; Torras Ambròs, Joan; Gomà, Montserrat; Nolla Solé, Joan Miquel
Objectives: To evaluate the prevalence, associated factors, and prognostic performance of NIH activity index–defined interstitial inflammation (NIH-TII) and interstitial fibrosis and tubular atrophy (IFTA) in lupus nephritis (LN). Methods: This retrospective cohort study analyzed 195 renal biopsy episodes from 135 LN patients. Tubulointerstitial lesions were graded according to histopathological severity. NIH-TII was assessed semiquantitatively using the interstitial inflammation component of the modified NIH activity index. Results: Among 195 renal biopsies, class IV LN was most frequent (49.2%). Tubulointerstitial involvement was present in 74.3% of cases, with isolated NIH-TII in 14.4%, isolated IFTA in 15.9%, and both in 44.1%. Moderate-to-severe NIH-TII and IFTA were observed in 11.3% and 15.9% of biopsies, respectively. Patients with moderate-to-severe NIH-TII were older, had worse renal function, and more frequently exhibited moderate-to-severe IFTA. Moderate-to-severe IFTA was associated with older age, longer SLE duration, prior LN episodes, higher chronicity index, and impaired renal function, and was strongly associated with non-renal response and ESRD progression. In multivariable logistic regression, prior LN episodes (OR 8.4) and moderate-to-severe IFTA (OR 4.92) predicted non-renal response. In multivariable Cox regression, prior LN episodes (HR 8.55), moderate-to-severe IFTA (HR 8.93), and thrombotic microangiopathy (HR 12.99) predicted ESRD progression. Longitudinal analyses showed frequent progression of IFTA over time with increasing chronicity index. Conclusions: Moderate-to-severe IFTA was a strong predictor of renal non-response and ESRD progression. TII defined according to the NIH activity index, which does not include systematic assessment of tubulitis or total cortical inflammatory burden, was not independently associated with outcomes.
Alcohol consumption and molecular subtypes of colorectal cancer: pooled observational and Mendelian randomization analyses
(Elsevier B.V., 2026-06) Chalitsios, Christos V.; Chan, Wing Ching; Markozannes, Georgios; Aglago, Elom K.; Berndt, Sonja I.; Buchanan, Daniel D; Campbell, Peter T.; Cao, Yin; Dimou, Niki; Drew, David A.; French, Amy J.; Gallinger, Steven; Georgeson, Peter; Giannakis, Marios; Gruber, Stephen B.; Gunter, Marc J.; Harrison, Tabitha A.; Brenner, Hermann; Hoffmeister, Michael; Urruchúa Rodríguez, Mary-Jose; Hsu, Li; Huang, Wen-Yi; Hullar, Meredith Aj.; Huyghe, Jeroen R.; Jenkins, Mark A.; Jayasekara, Harindra; Moreno Aguado, Víctor; Newton, Christina C.; Nowak, Jonathan A.; Obón Santacana, Mireia; Ogino, Shuji; Pellatt, Andrew J.; Peoples, Anita R.; Qu, Conghui; Schmit, Stephanie L.; Steinfelder, Robert; Sun, Wei; Thomas, Claire E.; Toland, Amanda E.; Trinh, Quang M.; Ugai, Tomotaka; Um, Caroline Y.; Van Guelpen, Bethany; Zaidi, Syed H.; Peters, Ulrike; Phipps, Amanda I.; Tsilidis, Konstantinos K.
Background: Alcohol consumption is associated with colorectal cancer (CRC) risk, yet its association with distinct molecular subtypes remains unclear. Clarifying this could reveal insights into alcohol’s carcinogenic mechanisms. Objectives: We examined the association between alcohol consumption and the risk of CRC subtypes defined by individual tumor markers (and marker combinations), namely microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF, and KRAS mutations. Methods: Pooled observational (ncases = 11,826, ncontrols = 10,888; nstudies = 10) and genome-wide association data (ncases = 8178, ncontrols = 10,472; nstudies = 10) were used. Multivariable logistic regression models and Mendelian randomization (MR) analyses were conducted to assess the association between alcohol consumption, modeled in MR as genetically predicted mean drinks per week per 1 SD increase (≈2.9 drinks/wk), and risk of CRC subtypes defined by individual tumor markers (and marker combinations). Case-only analyses tested for differences between molecular subtypes. Bonferroni correction was applied for multiple tests. Results: Among drinkers, each additional 14 g/d of alcohol was associated with a 10% higher CRC risk [odds ratio (OR) = 1.10; 95% confidence interval (CI): 1.07, 1.13], but this association was primarily driven by heavy alcohol consumption (>28 g/d). Including nondrinkers revealed a J-shaped association (P-nonlinearity = 0.002). The associations with higher alcohol consumption were stronger in males compared with females. No significant heterogeneity was observed across MSI, CIMP, BRAF, or KRAS-defined subtypes. All associations were similar across smoking status, folate intake, tumor anatomical site, study design, early/late-onset CRC, and across individual studies (P-heterogeneity > 0.05). MR analyses supported that higher genetically predicted alcohol consumption was associated with CRC risk (ORIVW-per 1SD = 1.25; 95% CI: 1.01, 1.57), but similarly to the observational analysis, without evidence of heterogeneity across molecular subtypes. Conclusions: Heavy alcohol consumption may initiate colorectal carcinogenesis through mechanisms that operate across all examined molecular pathways for CRC. Although the largest available data were used, power is lower for subtype heterogeneity analyses, and modest interaction effects cannot be excluded.
Phenotypes associated with problematic online gaming and gambling: A clustering approach among young adults
(Elsevier, 2026-06) Granero, Roser; Fernández Aranda, Fernando; Demetrovics, Zsolt; Jimenez Murcia, Susana
Background and objectives: Excessive engagement in online gaming and gambling is increasingly prevalent among young individuals, particularly first-year university students, and is associated with significant psychosocial damage. The aim of the present study was to identify empirical clusters among university students reporting problematic online gaming and gambling behaviors and to examine the extent to which these clusters differ from a control group of students without gaming- and gambling-related problems. Method: The sample included 273 first-year university students (180 women and 93 men, aged 18–25 years). Participants were first classified into a subgroup with problematic online gaming or gambling (n = 100) and a non-problematic (control) group (n = 173), based on DSM-5 criteria. A two-step cluster analysis was then conducted exclusively within the problematic subgroup to identify latent profiles, using indicators of addictive behavior severity, engagement with social networks and the internet, impulsivity, emotion dysregulation, gambling-related cognitive distortions, and psychological distress. Subsequently, the identified clusters were compared with each other and with the control group across a broad range of psychological and behavioral indicators. Results: Two clusters were identified, primarily differentiated by the severity of gaming-gambling involvement and associated psychological vulnerabilities. Cluster profiles revealed distinct patterns of impulsivity, emotional deficit, and cognitive biases. Both clusters significantly differed from the control group, with higher scores on all clinical and cognitive measures except for the social internet use and sensation seeking. Conclusion: The findings provide empirical support for the heterogeneity of problematic gaming and gambling among young university students. The identification of discrete subgroups underscores the relevance of individualized prevention and intervention strategies, tailored to the severity and psychological correlates of the addictive behavior(s). These results also highlight the need to refine screening and diagnostic tools within this target population.
A taste of (dis)trust: do social cynicism and gratitude predict and reciprocate addiction-like eating?
(BioMed Central, 2026-04-06) Yang, Hong Mian; Hui, Bryant P. H.; Zhang, Hengyue; Ling, Haofeng; Jimenez Murcia, Susana; Fernández Aranda, Fernando; Wu, Anise M.S.
Background: Addiction-like eating, characterized by impaired impulse control over food consumption and intense food cravings, is closely linked to overweight and poses both physical and mental health risks. Drawing on a social cognitive perspective, this study examined whether and how social beliefs (i.e., social cynicism) and social emotions (i.e., gratitude) are associated with addiction-like eating and tested their longitudinal interplay. Methods: A two-wave longitudinal survey with a six-month interval was administered via an online crowdsourcing platform in mainland China. At Wave 1 (W1), the sample comprised 1448 adults (50% females, Mage = 32.46 years, SD = 7.72), of whom 660 remained at Wave 2 (W2). Cross-lagged panel modeling was conducted to examine the reciprocal associations among social cynicism, gratitude, and addiction-like eating over time. Results: Social cynicism at W1 predicted higher levels of addiction-like eating at W2 (β = 0.07, p = .008), and vice versa (β = 0.08, p = .012). Gratitude at W1 predicted lower addiction-like eating at W2 (β = –0.10, p < .001), whereas W1 addiction-like eating predicted reduced W2 gratitude (β = –0.05, p = .031). Moreover, a significant unidirectional path was observed from gratitude at W1 to reduced W2 social cynicism (β = –0.16, p < .001). Conclusions :Findings revealed a bidirectional link between lower gratitude/higher social cynicism and greater risks of addiction-like eating. Targeted intervention strategies such as gratitude-centered reappraisal may serve as a complement to traditional symptom-focused approaches in addressing addiction-like eating patterns.
Distinct protein and metabolic profiles in patients with advanced clear-cell renal cell carcinoma treated with sunitinib: a study of the Spanish oncology genitourinary group
(Frontiers Media, 2026-04-29) Quintás, Guillermo; Sanmartín, Elena; Garcia Gimenez, Alicia; Muñoz Langa, José; Collado, Aida; Suárez, Cristina; García del Muro Solans, Xavier; Méndez-Vidal, María José; García-Sánchez, José; Salvador Coloma, Carmen; Lainez, Nuria; Gallardo, Enrique; Munárriz, Javier; Vázquez, Sergio; Molins, Carmen; Font de Mora, Jaime; Reynes, Gaspar
Background: New biomarkers are needed to improve treatment selection in patients with metastatic clear cell renal cell carcinoma (CCRCC). This study aims to identify predictive biomarkers through the investigation of serum proteins related to angiogenesis and tumor immune escape, alongside metabolic patterns associated with clinical outcomes. Methods: We conducted a prospective, multicenter study in patients with locally advanced or metastatic CCRCC receiving first-line sunitinib. Serum protein levels, including those related to angiogenesis and immune escape, were measured. Additionally, untargeted lipidomic and targeted metabolic analyses focused on tryptophan metabolism and amino acid profiles were performed. Routine blood test results were recorded, and correlations among all parameters were analyzed. Results: Thirty-eight patients from ten Spanish hospitals were included. Median progression-free survival (PFS) was 9.87 months, and median overall survival (OS) was 21.10 months. Multivariate analysis identified higher interleukin-6 (IL-6), arginase-1, and S100 calcium binding protein A9 (S100A9) concentrations as significant predictors of shorter OS. We defined three distinct risk groups based on the combined levels of S100A9 and IL-6: high levels of both proteins, high levels of either one protein, or low levels of both proteins confer a poor, intermediate and favorable prognosis, respectively. Metabolomic analysis revealed significant differences in the tryptophan-kynurenine pathway between patients with extreme PFS and OS phenotypes. Elevated levels of tryptophan metabolites were associated with poorer PFS, while alterations in amino acids and tryptophan metabolites correlated with OS extremes. Notably, significant correlations were observed between IL-6 levels and increased tryptophan metabolism. Conclusions: This study underscores the prognostic value of specific proteins and metabolites in metastatic CCRCC, proposing potential biomarkers for patient stratification and treatment response prediction.
What to do when the first TNF inhibitor fails in rheumatoid arthritis: stratified expert recommendations from a scoping review and Delphi consensus
(SAGE Publications, 2026-02-28) Narváez, Javier; García Vicuña, Rosario; Tornero Molina, Jesús; Romero Yuste, Susana; Pereira da Silva, José A.; Loza Santamaria, Estíbaliz
Background: Despite widespread use of tumor necrosis factor inhibitors (TNFi) as first-line therapy in rheumatoid arthritis (RA), up to 40% of patients fail initial treatment. Subsequent therapeutic choices remain poorly structured, with limited evidence-based guidance to inform individualized post-TNFi decision-making. Objective: To develop evidence-informed, profile-based recommendations to guide treatment selection after inadequate response to a first TNFi in RA, combining evidence and expert consensus. Design: Delphi-based consensus study informed by a PRISMA-guided scoping review (ScR) and nominal group methodology. Methods: A PRISMA-guided ScR of biologic and targeted synthetic biologic disease-modifying antirheumatic drug (tsDMARDs) after TNFi failure was conducted. Patient profiles were identified by a steering committee, and draft recommendations were evaluated through an anonymized Delphi process. A profile-based decision tree integrated direct and indirect evidence, with evidence strength graded using the Oxford Centre for Evidence-Based Medicine approach. Results: The ScR included 43 studies, mostly exploratory analyses of randomized trials. Scenarios included age ⩾65 years; failure of ⩾2 TNFi; monotherapy; rheumatoid factor/anti-citrullinated peptide antibody status; prominent systemic inflammation; interstitial lung disease (ILD); rheumatoid vasculitis; high cardiovascular (CV) risk or prior CV event; venous thromboembolism (VTE) risk; obesity; high infection risk; osteoporosis; nociplastic pain, depression and fatigue; prior solid cancer; hematologic cancer/lymphoproliferative disease; non-melanoma skin cancer; and pregnancy. Seventeen recommendations were formulated; 15 achieved consensus. Agreed positions included caution with JAK inhibitors (JAKi) in older patients and in those with CV/VTE risk; preference for IL-6 receptor inhibitors or JAKi for monotherapy or prominent systemic inflammation; in RA-ILD, use a b/tsDMARD with a non-TNFi mechanism; rituximab as first choice in rheumatoid vasculitis; abatacept in infection-prone patients; discouraging JAKi in prior malignancy; and TNFi as acceptable during pregnancy. Two statements did not reach consensus: preferential use of non-TNFi in obesity and heightened caution with tofacitinib in osteoporosis or fracture risk. Conclusion: This Delphi-validated, profile-based framework provides a practical tool to support evidence-informed clinical decision-making.
Consensus-based validation of key quality indicators in pancreatic cancer surgery in Catalonia: a modified Delphi study
(Elsevier España, 2026-05-05) Guarga, Laura; Sánchez Velázquez, Patricia; Badia, Josep M.; Ballesteros, Mónica; Esteban, Laura; Busquets Barenys, Juli; Espín Álvarez, Francisco; Sánchez Cabús, Santiago; Ausania, Fabio; Pando, Elizabeth; Jorba Martin, Rosa; García Domingo, María I.; López Ben, Santiago; Escartín, Alfredo; Burdío, Fernando; García Borobia, Francisco; Borràs Andrés, Josep Maria; Manchon Walsh, Paula
Introduction: Pancreatic cancer surgery is highly complex and associated with significant perioperative risk, high mortality and morbidity, low quality of life, and increased healthcare costs. Establishing quality indicators to monitor these procedures may improve care quality and outcomes. This study aims to define a set of quality indicators to evaluate pancreatic cancer surgery in Catalonia. Methods: A preliminary list of quality indicators was developed based on a literature review. Subsequently, a modified Delphi study was undertaken, involving 11 expert pancreatic surgeons, one from each center where these complex surgeries are authorized in Catalonia, to achieve consensus on quality indicators for pancreatic cancer surgery. Results: The literature review yielded 21 potential quality indicators. After 4 rounds of voting, the expert panel accepted 17 indicators and rejected 4. The final set of quality indicators encompasses critical aspects including positive tumor resection margin, lymph nodes retrieved, postoperative complications, hospital readmission, reoperation, 90-day mortality and one-year survival. Conclusion: The outcome of this study is a set of agreed quality indicators to measure, describe and monitor the quality and outcomes of pancreatic cancer surgery. These quality indicators can be used as a foundation for benchmarking studies and systematic evaluations of quality of care and enhanced surgical performance in pancreatic cancer.
NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts
(Springer Nature, 2025-08-18) Amengual, Josep; González Sánchez, Ester; Yáñez Bartolome, Mariana; Sererols Viñas, Laura; Ravichandra, Aashreya; Guiton, Celia; Fusté, Noel P.; Alay, Ania; Hijazo Pechero, Sara; Martín Mur, Beatriz; Gut, Marta; Esteve Codina, Anna; Cantos Cortes, Ana; Espinosa Sotelo, Rut; Ramos, Emilio; Serrano Piñol, M. Teresa; Calvo, Mariona; Laquente, Berta; Ferrer i Jané, Joan; Pons, Gabriel; Méndez Lucas, Andrés; Dooley, Steven; Ilyas, Sumera I.; Vallette, Marie; Aoudjehane, Lynda; Lequoy, Marie; Fouassier, Laura; Coulouarn, Cédric; Affò, Silvia; Scheiter, Alexander; Calvisi, Diego F.; Tian, Tian V.; Fabregat Romero, Isabel; Vaquero Rodríguez, Javier
Transforming growth factor beta (TGF-β) signalling has become an attractive therapeutic target due to its pro-tumorigenic actions on epithelial cells and its immunosuppressive effects in the tumour microenvironment. In intrahepatic cholangiocarcinoma (iCCA), a highly aggressive malignancy of the biliary tract with poor prognosis, the latest clinical trials using TGF-β inhibitors have failed indicating that the specific actions carried out by TGF-β in iCCA are yet not well delineated. Here, we show that TGF-β signalling is highly active in iCCA and exerts a prominent suppressor effect on tumour cell lines and organoids established from iCCA metastases biopsies, that relies on a functional canonical SMAD2/3/4 signalling. Thus, TGF-β inhibitors promote, instead of inhibiting, tumour cell growth. In this context, a promising strategy is to target intracellular proteins downstream the TGF-β receptors accounting only for TGF-β pro-tumorigenic actions. NADPH oxidase 4 (NOX4), a downstream mediator of the TGF-β signalling pathway, is strictly expressed in cancer-associated fibroblasts (CAF) of iCCA and acts in concert with NOX1 to regulate CAF functions. Use of a dual NOX4/NOX1 inhibitor impaired CAF actions and reduced tumour growth in vitro and in two different in vivo iCCA experimental models. Collectively, our findings reveal an actionable way to specifically target TGF-β pro-tumorigenic actions in CAF from iCCA without undesirable side effects on tumour cells, suggesting a potentially bright future for dual NOX4/NOX1 inhibitors in the clinics, alone or in combination with other therapies.
Good Short- and Mid-term Outcome After Cross-Linked Hyaluronic Acid Infiltration for Hallux Rigidus: A Case Report
(SAGE Publications, 2024) Capell Morera, Annabel; Planell i Mas, Elena de; Pérez Palma, Laura; Manzanares Céspedes, María Cristina
We report a first case of hallux rigidus successfully treated in an elderly patient by intra-articular infiltration of cross-linked hyaluronicacid (HA) 21 mg/mL with mannitol (Desirial Plus) and review the previous literature on the different compositions of HA infiltrative treatmentapplied to hallux rigidus. A 77-year-old female patient with moderate unilateral pain of 6 months of evolution and stiffness of the movement of thefirst metatarsophalangeal joint of the left foot, corresponding to grade 2 of the classification proposed by Coughlin and Shurnas. The objectiveof the study was to perform a pilot test to (a) evaluate the correct technique of intra-articular infiltration as well as (b) the use of a commercialcross-linked HA 21 mg/mL with mannitol, to a voluntary patient diagnosed with hallux rigidus. A single cross-linked HA infiltration is applied tothe first metatarsophalangeal joint with an administered amount of 1 mL. The loaded dorsiflexion, the unloaded dorsiflexion, and the unloadedplantarflexion angles of the first metatarsophalangeal joint improved from 15°, 20°, and 10°, respectively, before injection to 45°, 52°, and 22°,respectively, at 14 days after injection. Moreover, these improvements maintained until the final follow-up (400 days). The intensity of pain,according to the visual analog scale, improved from 7 of 10 before the injection, passing through 4 of 10 at 14 days after the injection, to 1 of 10at 60 days after the injection. Cross-linked HA 21 mg/mL with mannitol improves symptomatology, joint mobility of the first metatarsophalangealjoint, and quality of life in the patient with stiff hallux submitted to the pilot test. These effects have been maintained for more than 14 months.
Práctica clínica tutelada: donde el estudiante aprende actitudes y valores
(Fundación Letamendi Forns, 2022-02-03) Peguero-Rodríguez, Eva ; Mascort Roca, Juanjo; Borrell i Carrió, F. (Francesc)
La rotación de los estudiantes de medicina por servicios de salud es una oportunidad para mostrarles cómo se aplican valores, habilidades y criterios en el día a día. En general, existe una cierta disociación entre lo que el estudiante considera estándar de calidad y lo que observa en los servicios asistenciales, presionados por una falta de tiempo y recursos crónicos. El presente artículo explora estrategias para que este salto de la teoría a la práctica sea una experiencia positiva para el estudiante. Y, así, evitar el peligro de instaurar un currículo oculto inaparente que prioriza sobrevivir, en un territorio hostil, a la aplicación de habilidades y a la reflexión crítica de cada paciente. Enseñar a reflexionar en un contexto de presión asistencial es una de las grandes aportaciones que puede realizar las prácticas tuteladas en centros asistenciales, sobre todo de Atención Primaria de Salud.
Musculoskeletal comorbidities in patients with transthyretin amyloid cardiomyopathy: a systematic review
(John Wiley & Sons, 2024-04) Formiga Pérez, Francesc; Saumell Baeza, Laia; Chivite, David; Yun, Sergi
The prevalence of transthyretin-associated amyloidosis cardiomyopathy (ATTR-CM) has grown because of newer non-invasive diagnosis tools. Detecting the presence of extra-cardiac ATTR manifestations such as musculoskeletal pathologies considered ‘red flags’, when there is minimal or non-cardiac clinical involvement is primordial to carry out an early diagnosis. The aim of this systematic review is to examine the prevalence of musculoskeletal, ATTR-deposition-related co-morbidities in patients already diagnosed with ATTR-CM, specifically carpal tunnel syndrome, ruptured biceps tendon, spinal stenosis, and trigger finger. We performed a systematic review using PRISMA guidelines. Inclusion criteria were all studies in English and Spanish language and participants had to be patients diagnosed with ATTR-CM, by any diagnostic method, with the musculoskeletal co-morbidities subject of this review. The quality of the studies was based on the Risk of Bias Tool. This systematic review included 22 studies for final analysis. Carpal tunnel syndrome is reported in 21 studies, brachial biceps tendon rupture is reported in three, and spinal stenosis in eight studies. No articles that accomplished all the inclusion criteria for trigger finger were found. Regarding to the quality of the studies, all of them were categorized as being of high and moderate quality. The frequent association between ATTR-CM and carpal tunnel syndrome, ruptured biceps tendon, and lumbar spinal is confirmed, and the onset of these co-morbidities usually precedes the diagnosis of by years. This association defines them as red flags that should be search proactively due to the current treatment possibilities and the severity of the presentation of cardiac amyloidosis.
Prognosis of cardiogenic shock secondary to culprit left main coronary artery lesion-related myocardial infarction.
(John Wiley & Sons, 2023-02-01) Galván Román, Francisco; Fernández Herrero, Ignacio; Ariza Solé, Albert; Sánchez Salado, Jose Carlos; Puerto, Elena; Lorente, Victòria; Gómez Lara, Josep; Martín-Asenjo, Roberto; Gómez Hospital, Joan Antoni; Comín Colet, Josep
Aims: This study aimed to assess, in patients with cardiogenic shock secondary to unprotected left main coronary artery-related myocardial infarction (ULMCA-related AMICS), the incidence and predictors of no recovery of left ventricular function during the admission. Methods and results: This was an observational study conducted at two tertiary care centres (2012–20). The main outcome measured was death or requirement for heart transplantation (HT) or left ventricular assist devices (LVAD) during the admission. A total of 70 patients were included. Percutaneous coronary intervention (PCI) was successful in 53/70 patients (75.7%). The combined endpoint of death or requirement of HT or LVAD during the admission occurred in 41/70 patients (58.6%). The highest incidence of the primary endpoint was observed among patients with profound shock and occluded left main coronary artery (LMCA) (20/23, 87%, P < 0.001). Although a successful PCI reduced the incidence of the event in the whole cohort (51.9% vs. 82.4% in failed PCI, P = 0.026), this association was not observed among this last group of complex patients (86.7% vs. 87.5% in failed PCI, P = 0.731). The predictive model included left ventricular ejection fraction, baseline ULMCA Thrombolysis In Myocardial Infarction flow, and severity of shock and showed an optimal ability for predicting death or requirements for HT or LVAD during the admission (area under the curve 0.865, P < 0.001). Conclusions: ULMCA-related AMICS was associated with a high in-hospital mortality or need for HT or LVAD. Prognosis was especially poor among patients with profound shock and baseline occluded LMCA, with a low probability of recovery regardless of successful PCI.
Systematic review and meta-analysis of intravenous iron-carbohydrate complexes in HFrEF patients with iron deficiency
(John Wiley & Sons, 2023-02) Sindone, Andrew; Doehner, Wolfram; Comín Colet, Josep
Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF). The present meta-analysis evaluates the effect of intravenous (IV) iron-carbohydrate complex supplementation in patients with HF with reduced ejection fraction (HFrEF) and ID/iron deficiency anaemia (IDA). Randomized controlled trials (RCTs) comparing IV iron-carbohydrate complexes with placebo/standard of care in patients with HFrEF with ID/IDA were identified using Embase (from 1957) and PubMed (from 1989) databases through 25 May 2021. Twelve RCTs including 2381 patients were included in this analysis. The majority (90.8%) of patients receiving IV iron-carbohydrate therapy were administered ferric carboxymaltose (FCM); 7.5% received iron sucrose and 1.6% received iron isomaltoside. IV iron-carbohydrate therapy significantly reduced hospitalization for worsening HF [0.53 (0.42–0.65); P < 0.0001] and first hospitalization for worsening HF or death [0.75 (0.59–0.95); P = 0.016], but did not significantly impact all-cause mortality, compared with control. IV iron-carbohydrate therapy significantly improved functional and exercise capacity compared with the control. There was no significant difference in outcome between IV iron-carbohydrate formulations when similar endpoints were measured. No significant difference in adverse events (AE) was observed between the treatment groups. IV iron-carbohydrate therapy resulted in improvements in a range of clinical outcomes and increased functional and exercise capacity, whereas AEs were not significantly different between IV iron-carbohydrate and placebo/standard of care arms. These findings align with the European Society of Cardiology's 2021 HF guidelines, which recommend the consideration of FCM in symptomatic patients with a left ventricular ejection fraction < 45% and ID.
Performance characteristics of five antigen-detecting rapid diagnostic test (Ag-RDT) for SARS-CoV-2 asymptomatic infection: a head-to-head benchmark comparison
(Elsevier, 2021-06-01) Baro, Barbara; Rodó, Pau; Ouchi, Dan; Bordoy, Antoni E.; Saya Amaro, Emilio N.; Vaqué Salsench, Sergi; Molinos, Sònia; Alemany Ortiz, Andrea; Ubals Cazorla, Maria; Corbacho Monné, Marc; Millat-Martínez, Pere; Marks, Michael; Clotet, Bonaventura, 1953-; Prat, Núria; Estrada, Oriol; Vilar, Marc; Ara Escario, Jorge; Vall Mayans, Martí; G-Beiras, Camila; Bassat Orellana, Quique; Blanco Guillermo, Ignacio; Mitjà Villar, Oriol
Background Mass testing for early identification and isolation of infectious COVID-19 individuals is efficacious for reducing disease spread. Antigen-detecting rapid diagnostic tests (Ag-RDT) may be suitable for testing strategies; however, benchmark comparisons are scarce. Methods We used 286 nasopharyngeal specimens from unexposed asymptomatic individuals collected between December 2020 and January 2021 to assess five Ag-RDTs marketed by Abbott, Siemens, Roche Diagnostics, Lepu Medical, and Surescreen. Results For the overall sample, the performance parameters of Ag-RDTs were as follows: Abbott assay, sensitivity 38.6% (95%CI 29.1–48.8) and specificity 99.5% (97–100%); Siemens, sensitivity 51.5% (41.3–61.6) and specificity 98.4% (95.3–99.6); Roche, sensitivity 43.6% (33.7–53.8) and specificity 96.2% (92.4–98.5); Lepu, sensitivity 45.5% (35.6–55.8) and specificity 89.2% (83.8–93.3%); Surescreen, sensitivity 28.8% (20.2–38.6) and specificity 97.8% (94.5–99.4%). For specimens with cycle threshold (Ct) <30 in RT-qPCR, all Ag-RDT achieved a sensitivity ≥70%. The modelled negative- and positive-predictive value for 1% prevalence were >99% and <50%, respectively. Conclusions When screening unexposed asymptomatic individuals, two Ag-RDTs achieved sensitivity ≥80% for specimens with Ct<30 and specificity ≥96%. The estimated negative predictive value suggests the suitability of Ag-RDTs for mass screenings of SARS-CoV-2 infection in the general population.

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