Clinica Universidad de Navarra

Erythropoietin (EPO) is a glycoprotein hormone primarily known for its central role in red blood cell production, but it is now also recognized for its immunomodulatory effects on a range of immune effectors. Several studies indicate that EPO helps regulate intestinal barrier integrity, although its effect on intraepithelial lymphocytes (IELs) is still unknown. Using multiparameter flow cytometry and both conventional and unsupervised analyses, we conducted an in-depth phenotypic assessment of IELs from the murine duodenum, jejunum, ileum and colon. Our results revealed that in EPO-treated C57BL/6 mice, the absolute IEL count in the colonic epithelium was more than twice that observed in control mice without changes in the frequencies of the various subpopulations, indicating a global increase. This was accompanied by integrin α4β7 overexpression. Furthermore, EPO treatment alters the intestinal microbiota, increasing bacterial load while reducing diversity, with a notable decrease in Muribaculaceae, a taxon involved in microbial cross-feeding. This alteration may contribute to epithelial imbalance and indirectly to the observed increase in IEL density. Importantly, EPO treatment did not trigger colonic mucosal inflammation, although the affected IELs show a microbiota-dependent decrease in CD8αα expression (known to downregulate IEL activity). The present study is the first to provide a phenotypic mapping of IEL populations in the digestive tract of C57BL/6 mice and highlighted a novel regulatory role of EPO on colonic IELs. These results raise important questions about the impact of exogenous EPO supplementation and endogenous EPO fluctuations on intestinal immune responses - particularly in the context of inflammatory diseases.

Background: Nurses transitioning into first-line nurse manager (FLNM) roles often receive unclear expectations, limited support, and inadequate preparation.These gaps raise concerns about regulatory readiness, as leadership competence underpins workforce stability and care quality.Experience-based co-design (EBCD) engages stakeholders to create relevant, context-sensitive programs.Purpose: To co-design a comprehensive educational program that supports novice FLNMs by addressing both technical competencies and emotional preparedness based on stakeholder input and contextual realities in two divisions of a highly specialized tertiary hospital.Methods: This study implemented a co-design process using the EBCD approach guided by the Medical Research Council Framework for complex interventions.Data collection included nonparticipant observation, seven focus groups, and two semi-structured interviews.Insights informed a persona archetype and journey map, which were the central tools used in four co-design workshops.Participants collaboratively identified priorities, which directly informed the content and structure of the intervention. Results:Participants in Stages 2 and 3 of the EBCD process included FLNMs (n = 26), nursing directors (n = 5), chief nursing officers (n = 2), and bedside nurses (n = 25).The co-design process generated a structured program comprising an onboarding phase and a multicomponent module-based curriculum.Validation workshops confirmed relevance, adaptability, and alignment with organizational and regulatory standards.A phased implementation plan and evaluation based on the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) Framework were endorsed to guide sustainability and scalability.Conclusion: Integrating EBCD with the Medical Research Council Framework produced a feasible, contextually grounded intervention.The program enhances regulatory readiness by combining technical, emotional, and relational preparation, offering a transferable model for leadership J o u r n a l P r e -p r o o f development.This study provides a replicable framework for transition programs to support novice FLNMs and strengthen workforce capacity in alignment with regulatory standards.

Hepatocyte growth factor (HGF)/hepatocyte growth factor receptor (MET) signaling plays a critical role during liver regeneration upon acute and chronic damage, and is therefore an interesting target for therapeutic intervention. Nevertheless, the molecular mechanisms underlying the pro-regenerative effects of HGF/MET signaling are not fully elucidated, particularly during cholestatic injury. Our aim was to analyze the impact of moderately enhanced MET on the hepatic response to cholestatic injury, and uncover the mechanisms behind it. For that, Alb-R26Met mice expressing a wild-type Met transgene in albumin-positive liver cells were fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diet, used as a model simulating human primary sclerosing cholangitis. Results indicate that increased MET expression diminished liver damage in DDC-fed mice, evidenced by lower serum levels of bilirubin and alkaline phosphatase, and decreased cell apoptosis. However, decreased ductular expansion was observed, which together with enhanced hepatocyte proliferation suggests that hepatocytes act as the main cellular defense. Both invivo and in vitro studies using Alb-R26Met liver-derived hepatocytes under cholestasis-simulated in vitro conditions demonstrated an enhanced upregulation of nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the Nfe2l2 gene), parallel to an upregulation of glutathione biosynthesis enzymes, increased levels of glutathione, and decreased reactive oxygen species, along with decreased activation of transforming growth factor beta (TGF-β)-induced signaling. Consistently, MET transgenic hepatocytes were protected against TGF-β-induced oxidative stress and apoptosis in vitro. In conclusion, our work evidences that moderate upregulation of wild-typeMET in hepatocytes is sufficient to promote a strong antioxidant response in the liver that efficiently protects against chronic cholestasis, thus allowing optimal liver regeneration.

Patient: Male, 35-year-oldFinal Diagnosis: Delayed gastric emptyingSymptoms: Gastrointestinal dysfunctionClinical Procedure: —Specialty: Critical Care MedicineObjective: Unusual clinical courseBackgroundPoint-of-care ultrasound (POCUS) is increasingly used as an extension of the physical examination during daily intensive care unit (ICU) rounds and has become a valuable bedside diagnostic tool. Gastric POCUS, in particular, offers a noninvasive method to evaluate gastric content and motility, and to identify patients at risk for impaired gastric emptying. Such dysfunction can lead to aspiration, delayed enteral feeding, and challenges in procedural planning or sedation. As the use of POCUS continues to expand in critical care practice, its gastrointestinal applications show increasing clinical relevance.Case ReportWe describe a 50-year-old male patient admitted to the ICU with suspected cytokine release syndrome and possible coinfection. During hospitalization, he developed a progressive decline in consciousness, prompting plans for brain magnetic resonance imaging (MRI). Despite stable hemodynamic and respiratory status, a routine pre-transport POCUS assessment was performed. Gastric POCUS revealed a markedly distended gastric antrum with clear fluid mixed with gastric contents, corresponding to an antral grade 2 appearance and indicating a high residual gastric volume. Based on these findings, a nasogastric tube was placed for gastric decompression, the MRI was postponed, and triple prokinetic therapy was initiated. These interventions were implemented promptly at the bedside, demonstrating the role of gastric POCUS in real-time clinical decision-making.ConclusionsThis case underscores the value of gastric POCUS in detecting gastrointestinal dysfunction and preventing complications such as aspiration in ICU patients. Routine gastric ultrasonography may enhance patient safety and guide management during critical care evaluations.

Endotrophin is a matrikine released from the C-terminus of the alpha-3 chain of type VI collagen, gaining increasing attention both as a biomarker and as a therapeutic target in the cardiometabolic space. So far, it has been quantified in circulation by the PRO-C6 assay, which detects different-sized proteolytic fragments of the C-terminus, including endotrophin. Here, we developed and evaluated a novel immunoassay targeting the full-length endotrophin, explored its biological relevance in two clinical cohorts of HFpEF, and investigated its potential as a prognostic biomarker. Increased circulating Endotrophin levels were associated with cardiovascular and all-cause mortality in both cohorts. When adjusting for relevant confounders, Endotrophin remained independently associated with both endpoints only in cohort 1. This work emphasizes the importance of the extracellular matrix in disease, confirms the prognostic value of endotrophin, and provides a novel tool for further exploration of its biological role.

ABSTRACT In some cancers, patients responding to immune checkpoint inhibitors (ICI) usually harbor tumors with a higher tumor mutational burden and increased lymphocyte infiltration targeting mutation-derived neoantigens (neoAgs). In the NASIR-HCC trial, patients with hepatocellular carcinoma (HCC) received selective internal radiation therapy and the anti-PD-1 antibody Nivolumab, but many of them did not achieve clinical benefit (B). Since neoAg-based vaccination could enhance tumor infiltration and ICI responses, we studied neoAg-specific immunity in these patients and assessed whether patients with no benefit (NB) harbored sufficient immunogenic neoAgs for therapeutic vaccination. Using predicted neoAgs from 6 B and 4 NB patients, we tested immune reactivity in vitro. NeoAg-specific responses were detected in 75% of B and 83% of NB patients, recognizing 37% and 63% of neoAgs tested, respectively. In vivo immunization experiments in HLA transgenic HHD-DR1 mice using HLA-A*02.01- or HLA-DRB1*01-predicted neoAgs from four NB patients revealed responses against most neoAgs (87% and 73%, respectively), expanding the repertoire of immunogenic epitopes. Finally, polyepitopic peptide vaccination containing neoAgs from an NB patient induced stronger and broader T-cell responses compared to polyepitopic DNA vaccine. Our results demonstrate the immunogenicity of neoAgs in our cohort, supporting their potential utility in therapeutic vaccines designed to boost antitumor immunity.