Navarre Institute of Health Research

Blood-brain barrier (BBB) disruption and immune cell infiltration increase the pathological outcomes present in aging, neurodegenerative diseases, and stroke. NADPH oxidase 5 (NOX5) is a ROS-producing enzyme that promotes BBB-permeability in vivo by altering the endothelial junctions (EJs). The aim of this project was to elucidate the mechanisms by which NOX5 dysregulates EJs in endothelial cells and whether it increases immune infiltrates in a systemic inflammatory condition, using a murine model of ischemic stroke. A brain microvascular endothelial cell line (hCMEC/D3) and HUVECs infected with a NOX5 overexpressing adenovirus were used to study the effects of this protein on EJs, endothelial phenotype, and immune cell adhesion and infiltration in vitro . An endothelial NOX5 knock-in mouse was used to study EJs expression in the brain. Finally, in an experimental model of ischemic stroke induced by FeCl 3 we analyzed the potential effects of NOX5 on the infiltration of immune cells to the brain. NOX5 overexpression dysregulated EJs and increased permeability in hCMEC/D3 cells. In HUVECs, overexpression of NOX5 promoted the remodeling of the cytoskeleton and increased inflammatory cell adhesion and infiltration. Under inflammatory conditions, such as those present in ischemic stroke, mice expressing endothelial NOX5 exhibited an increase in the infiltration of immune cells in the brain across the vasculature of the non-infarcted (contralateral) hemisphere and increased inflammatory markers in the infarcted (ipsilateral) hemisphere. NOX5 promotes the dysregulation of EJs and cytoskeletal changes in endothelial cells, which leads to an increased immune cell infiltration in the brain at proinflammatory situations.

Schizophrenia and autism share neurobiological mechanisms and overlapping clinical features, often resulting in the emergence of autistic traits in early stages of psychosis. The PANSS Autism Severity Score (PAUSS) provides a rapid measure of autistic features within the standard PANSS assessment. We aimed to determine the prevalence of autistic features in first-episode psychosis (FEP), characterise their clinical, cognitive, and functional profile, and examine their impact on 2-year outcomes. A total of 328 FEP patients were included from the PEPs multicentre cohort, followed for 2 years. Autistic features were rated using PAUSS (cut-off ≥ 30), yielding autistic (n = 38) and non-autistic (n = 290) groups. Sociodemographic, clinical, cognitive, and functional variables were analysed. Longitudinal analyses examined symptomatic remission rates and trajectories of psychopathology and functioning using logistic regression and mixed-model ANOVA. The autistic group represented 11.6% of the sample. At baseline, they exhibited lower birth weight, greater medication side effects, higher general psychopathology and depressive severity, and poorer global functioning. Cognitively, they showed significant deficits in working memory, social cognition, and cognitive reserve compared to the non-autistic group. Over 2 years, this group was 3.6 times less likely to achieve symptomatic remission and consistently exhibited higher symptom severity and lower functioning across all follow-ups. Autistic features in FEP identify a subgroup with a possible distinct profile of neurodevelopmental markers, greater cognitive and functional impairments, and poorer clinical outcomes. Early identification may guide more personalised interventions, although further research is needed to refine PAUSS specificity and develop targeted, tailored treatments.

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.

Abstract Purpose Drug (or medicine) recalls represent a public health risk and may contribute to shortages, potentially affecting supply continuity and, consequently, patient care. This study analyzed drug recalls issued by the Spanish Agency of Medicines and Medical Devices (AEMPS) and conducted an additional descriptive recall-related shortage assessment to estimate their potential impact on supply continuity in Spain. Methods A descriptive retrospective regulatory analysis was conducted on drug recalls in Spain over a 14-year period (2010–2023). Data from the AEMPS website were analyzed, and drug recalls recorded during the last 4 years of the study period (2020–2023) were cross-referenced with national shortage records to assess their supply impact. Results A total of 1,120 drug recalls were identified, 87.86% ( n = 984) involved prescriptions and 57.32% ( n = 642) were classified as Class 2, recalls with a moderate risk of temporary or medically reversible adverse health consequences. The presence of nitrosamines (22.50%, n = 252) was the leading cause of recalls, driven by a phase-specific crisis (2018–2019), with the highest number of issued recalls (19.19%, n = 215) observed in 2018. Five manufacturers of active substances and finished products accounted for 27.32% ( n = 306) of all recalls. Drug recalls issued between 2020 and 2023 ( n = 195) resulted in a total of 55 drug shortages. Of these shortages, 10.91% ( n = 6) were considered to have a high clinical impact on supply continuity. Conclusion Nitrosamines emerged as the leading cause of recalls in Spain during the study period. A subset of recalls was linked to shortages affecting supply continuity, posing a potential risk to patients’ health. These findings underscore the importance of monitoring recalls and addressing supply chain vulnerabilities to mitigate negative effects on patients’ health and access to essential medications.

Medieval biblical exegesis in the twelfth century was largely dominated by allegorical interpretation, often at the expense of the literal sense of Scripture. Richard of Saint Victor stands out as a significant exception. This article argues that his commitment to the literal sense of Scripture constitutes not merely a methodological requirement but a theological conviction that operates consistently across works of very different character. Through an analysis of Beniamin Minor, Beniamin Maior, and In Visionem Ezechielis, it shows that the literal sense functions in all three as the indispensable foundation upon which allegorical and tropological meanings are constructed. In the Beniamins, predominantly received as works of spiritual and allegorical theology, the literal sense quietly sustains the entire interpretative edifice—through etymology, onomastics, and precise biblical description. In In Visionem Ezechielis, by contrast, the littera itself becomes the object of an explicit and historically remarkable defence: Richard translates the complex architectural descriptions of Ezekiel’s Temple into architectural drawings that constitute some of the earliest known examples of representation in plan, elevation, and section. In doing so, he demonstrates not only that the literal sense of this contested passage is fully intelligible, but that word and image together can bear the weight of God’s revealed Word, enabling the reader to move from the literal and historical sense towards the spiritual meanings of Scripture and, ultimately, towards the contemplation of God.

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.

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.

Polyphenols represent the largest and most diverse class of dietary antioxidants. Epidemiological evidence linking specific (poly)phenol classes, such as flavonoids and lignans, to breast cancer (BC) risk remains limited and largely inconclusive in prospective studies. The aim of this study is to examine the association between the intake of total (poly)phenols-and its classes and subclasses-and BC risk-overall and by subtypes (estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2))-in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The EPIC cohort includes 257,960 adult women from seven European countries. During a mean follow-up of 14 years, there were 10,722 incident overall BC cases. Associations were computed using Cox regression models adjusted for potential confounders. No significant associations were found between total (poly)phenol intake and overall BC risk (HRQ5 vs. Q1 = 1.02; 95% CI: 0.95-1.11). In addition, null associations were mostly found between classes and subclasses of (poly)phenols and BC subtypes. After stratifying by menopausal status, no significant associations were observed. In conclusion, this study found no evidence of associations between the intake of any class or subclass of (poly)phenols and BC risk in the European population.

Background/Objectives: Antimicrobial peptides (AMPs) represent a promising class of therapeutics with diverse biological functions, including antibacterial, anti-fungal, anti-parasitic and anti-tumoral activities. Previous works demonstrated the successful repurposing of the two synthetic AMPs 19-2.5 and 19-4LF for cutaneous leishmaniasis, when the compounds were administered in solution on skin lesions caused by Leishmania major in a BALB/c mouse model. In this research project, we assessed the activity of 19-4LF, 19-2.5, and their hybrid 19-2.5LF derivative when formulated as a cream for topical administration in the same animal model. Methods: The peptides were formulated in DAC cream and applied to the wound of BALB/C mice for 30 days. Lesion progression was monitored using a digital caliper. Parasite burden was measured by qPCR. Parasite viability was assessed using MTT and microscopy imaging assays. Results: The three peptides in cream formulation succeeded in reducing the skin lesion. Peptide 19-4LF was the most potent, followed by 19-2.5LF and then 19-2.5. In addition, 19-4LF was able to significantly reduce the parasite burden in the skin lesions of infected mice, as measured by quantifying L. major Lm18S ribosomal gene mRNA levels using qPCR. Moreover, when combined, the peptides exhibited synergistic effects on L. major promastigotes and significantly reduced the number of amastigotes in infected macrophages. Conclusions: These studies support the approach of repurposing these AMPs as antileishmanial drugs and identify 19-4LF as a lead candidate for further studies. While historical barriers to peptide therapeutics included high production costs, recent advancements in biological fermentation and synthesis strategies have significantly improved their economic viability. Furthermore, the use of nanotechnology delivery systems can reduce the required dosage, further making peptide therapy a sustainable option for neglected diseases, including leishmaniasis.

Hypertension is a public health problem with serious social, economic, and health consequences. The World Health Organization (WHO) estimates that 1 in 3 adults worldwide suffers from hypertension. In Cameroon, the prevalence of hypertension is estimated at 35%, with nearly 17,000 deaths recorded each year. This study aimed to determine the factors associated with the occurrence and complications of hypertension at the Sangmelima Referral Hospital (SRH). A total of 528 patients treated in the cardiology department of the SRH were identified between January and December 2023. The data were analyzed using SPSS 28 software. Binary logistic regression determined the odds ratios and 95% confidence intervals associated with each variable. Differences were statistically significant for a p-value < 0.05. At the SRH, the annual incidence of hypertension was 16.13%. Hypertension was present in 78.8% of patients. The factors associated with the occurrence and complications of hypertension were age (OR=1.028; p=0.003 ), level of education (OR=15.49; p=0.023), marital status (OR=3.859; p=0.04), hypercholesterolemia (OR=2.856; p=0.01), monthly income (OR=0.882; p=0.026), number of dependents (OR=1.231; p=0.025), food security (OR=16.666; p p<0.001), tobacco consumption (OR=8.592; p=0.041), fruit and vegetable consumption (OR=0.027; p=0.031), salt/sugar consumption (OR=8.129; p<0.001), place of residence (OR=4.794; p=0.005), access to essential technologies (OR=8.851; p=0.002), and use of traditional care (OR=3.137; np=0.032). HTA at the HRS is associated with several factors. In order to limit the impact of hypertension, it is crucial to emphasize improving socioeconomic and health conditions.