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Abstract Background Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults with the lowest survival rates five years post-diagnosis. Oncolytic viruses (OVs) selectively target and damage cancer cells, and for this reason they are being investigated as new therapeutic tools also against GBM. Methods An oncolytic herpes simplex virus type 1 (oHSV-1) with deletions in the γ34.5 neurovirulence gene and the US12 gene, expressing enhanced green fluorescent protein (EGFP-oHSV-1) as reporter gene was generated and tested for its capacity to infect and kill the murine GL261 glioblastoma (GBM) cell line. Syngeneic mice were orthotopically injected with GL261cells. Seven days post-implantation, EGFP-oHSV-1 was administered intratumorally. Twenty-one days after parental tumor challenge in the opposite brain hemisphere, mice were sacrified and their brains were analysed by immunohistochemistry to assess tumor presence and cell infiltrate. Results oHSV-1 replicates and induces cell death of GL261 cells in vitro. A single intracranial injection of EGFP-oHSV-1 in established GL261 tumors significantly prolongs survival in all treated mice compared to placebo treatment. Notably, 45% of treated mice became long-term survivors, and rejected GL261 cells upon rechallenge in the contralateral brain hemisphere, indicating an anamnestic antitumoral immune response. Post-mortem analysis revealed a profound modification of the tumor microenvironment with increased infiltration of CD4 + and CD8 + T lymphocytes, intertumoral vascular collapse and activation and redistribution of macrophage, microglia, and astroglia in the tumor area, with the formation of intense fibrotic tissue suggestive of complete rejection in long-term survivor mice. Conclusions EGFP-oHSV1 demonstrates potent antitumoral activity in an immunocompetent GBM model as a monotherapy, resulting from direct cell killing combined with the stimulation of a protective adaptive immune response. These results open the way to possible application of our strategy in clinical setting.

Introduction: Extreme obesity (BMI ≥50 kg/m2) is a complex pathology to treat. One of the complications of extreme obesity is massive localized lymphedema (MLL), due to compromised lymphatic drainage. There is a lack of literature guiding the medical management of these conditions. Case Presentation: We present a 43-year-old male who was admitted to our specialized obesity center for weight management. His initial weight was 255 kg and BMI was 93.7 kg/m2. He suffered from massive multifocal lymphedema of his left leg. He was bedridden due to his condition and malnourished, as shown by multiple vitamin deficiencies. The patient received care from our multidisciplinary team including nurses, dieticians, physical therapists, and psychologists. Treatment with semaglutide was started in hospital and continued at home. The maximal dose used was 1 mg/week but decreased during follow-up to 0.25 mg/week to avoid malnutrition. Protein and nutritional supplements were added. At 28 weeks of therapy, the patient had lost 40 kg or 15.7% of his total body weight. His lymphedema decreased; he had lost at least 16 cm of his left thigh circumference. He was able to walk again and regain autonomy of his daily activities of living. Conclusion: Semaglutide can be effective in patients with extreme obesity, with the support of a multidisciplinary team in a specialized obesity center. It can also help decrease MLL. More data are needed to guide medical treatment of patients with extreme obesity and MLL.

Background: Physical exercise (PE) can regulate inflammation, cardiovascular health, sarcopenia, anaemia, and bone health in the chronic kidney disease (CKD) population. Experimental and clinical studies both help us better understand the mechanisms that underlie the beneficial effects of the exercise, especially in renal anaemia and CKD-mineral bone disorders (CKD-MBDs). Here, we summarize this evidence, exploring the biological pathways involved, locally released substances, and crosstalk between tissues, but also the shortcomings of current knowledge. Summary: Anaemia: Both in healthy and CKD subjects, PE may mimic hypoxia, inhibiting PHDs; so hydroxylate HIF-α subunits may be translocated into the nucleus, resulting in dimerization of HIF-1α and HIF-1β, recruitment of p300 and CBP, and ultimately, binding to HREs at target genes to cause activation. However, in CKD subjects acute PE causes higher levels of lactate, leading to iron restriction by upregulating hepatic hepcidin expression, while chronic PE allows an increased lactate clearance and HIF-α and VEGFα levels, stimulating both erythropoiesis and angiogenesis. CKD-MBD: PE may improve bone health decreasing bone resorption and increasing bone formation throughout at least three main pathways: (a) increasing osteoprotegerin and decreasing RANKL system; (b) decreasing cytokine levels; and (c) stimulating production of myokines and adipokines. Key Messages: Future research needs to be defined to develop evidence-based exercise guidance to provide optimal benefit for CKD using exercise interventions as adjuvant therapy for CKD-related complications such as anaemia and CKD-MBD.

The art of looking is a museum and art gallery teaching tool at the core of the Visual Thinking Strategies, a Harvard School of Education pedagogy initiated as an educational experiment for schools across the United States almost two decades ago. Today, a large number of schools implement this teaching method to increase student engagement in a non-hierarchical setting that promotes inclusive learning experiences. Students analyze works of art basic elements (colors, shapes, and textures) and complexities (meanings and intentions and ties to cultures and emotions) with an inquiry-based approach. Facilitators are central to the process, but not the authoritative source. At a moment in which racial inequality and injustice flood the media, anti-racist intentional teaching is necessary to produce social change. The discomfort generated by magnifying racism through the lens of art moves the participants to explore how racism can deeply shape social, political, and cultural institutions, acknowledging the root causes of racism and identifying the spaces that perpetuate segregation and discrimination on the basis of race beyond stereotypes. Rather than shying away from difficult issues, this pedagogy encourages the audience to address complex topics and combat social issues head-on. This article contains five essays that highlight the beauty of truthful young voices from a multidisciplinary, higher-education setting that call for racism awareness and action through the art of looking.

The Antisecretory Factor (AF) is a protein that can reduce intestinal hypersecretion and various inflammation disorders in vivo. Discovered in many mammalian tissues and plasma, its mechanism of action remains unknown. Interestingly, its induction has been found to counteract vertigo in patients with Méniere's disease. This suggests an inherent ability to control body balance and posture, an activity that may play a role in cerebellar function. Therefore, it may be worthwhile to investigate whether this activity can inhibit neuronal cells involved in cerebellar circuitries and its potential action on enteric nervous system ganglia, which could explain its antisecretory effect in the intestine.Previously, we studied the role of AF on GABAA receptors in cerebellar granule cells, taking advantage of electrophysiology and evaluating the effects of the administration of AF-16, an AF peptide. Treatment with AF-16 increased GABAA receptor responses, especially those containing the α6 subunit. Here, we performed immunofluorescence experiments by staining α1 and α6 subunits before and after incubation with AF-16, analyzed super-resolved images comparing pre- and post-treatment maps and critically examined these experimental results with our previous electrophysiological data to shed light on the mechanisms of action of AF protein on GABAA receptor subpopulations, specifically the ''fast'' receptors of αn β2/3 γ2 composition that contain either the α1 or the α6 subunit.The results indicate that the α6 subunit is redistributed, with a decrease in neurites and an increase in soma. Conversely, the α1 subunit shows opposite results, with an increase in neurites and a decrease in soma.

Abstract Background Around 18% of the population in Chile has disabilities. Evidence shows that this population has greater healthcare needs, yet they face barriers to accessing healthcare due to health system failures. This paper aims to assess the inclusion of people with disabilities in health policy documents and to explore the perceptions of key national stakeholders regarding the policy context, policy processes, and actors involved. Methods A policy content analysis was conducted of 12 health policy documents using the EquiFrame framework, adapted to assess disability inclusion. Documents were reviewed and rated on their quality of commitment against 21 core concepts of human rights in the framework. Key national stakeholders (n = 15) were interviewed, and data were thematically analysed under the Walt and Gilson Policy Analysis Triangle, using NVivo R1. Results Core human rights concepts of disability were mentioned at least once in nearly all health policy documents (92%). However, 50% had poor policy commitments for disability. Across policies, Prevention of health conditions was the main human rights concept reflected, while Privacy of information was the least referenced concept. Participants described a fragmented disability movement and health policy, related to a dominant biomedical model of disability. It appeared that disability was not prioritized in the health policy agenda, due to ineffective mainstreaming of disability by the Government and the limited influence and engagement of civil society in policy processes. Moreover, the limited existing policy framework on disability inclusion is not being implemented effectively. This implementation gap was attributed to lack of financing, leadership, and human resources, coupled with low monitoring of disability inclusion. Conclusions Improvements are needed in both the development and implementation of disability-inclusive health policies in Chile, to support the achievement of the right to healthcare for people with disabilities and ensuring that the health system truly “leaves no one behind”.

Abstract Anemia is a common but often underdiagnosed and undertreated geriatric syndrome in hospitalized older patients. In this retrospective multicenter study, we aimed at characterizing the prevalence, risk factors, diagnostic and treatment approach to anemia in older patients admitted to acute care hospitals, focusing on differences between nephrology and geriatrics units. Prevalence and risk factors for anemia, diagnostic inertia (lack of iron, vitamin B12, and folate status assessment), replacement inertia (omitted treatment with iron, vitamin B12 or folic acid), and erythropoiesis-stimulating agents (ESA) inertia were explored. 1963 patients aged 82.7 (6.8) years were included in the study; 66.7% of the study population had anemia; among anemic patients, diagnostic inertia and replacement inertia were common with rates of 22–31% and 50–87%, respectively; omitted treatment with ESA affected 67.2% of patients and was more prevalent in geriatric units. In most cases, patients with ESA inertia were not routinely screened for iron tests. COPD, cancer, eGFR 45–60 ml/min were associated with increased tendency to ESA inertia. In conclusion, anemia had a high prevalence in older patients discharged from acute care units, but it is often underdiagnosed and undertreated.

Abstract Background Artificial intelligence (AI) has become a pivotal tool in advancing contemporary personalised medicine, with the goal of tailoring treatments to individual patient conditions. This has heightened the demand for access to diverse data from clinical practice and daily life for research, posing challenges due to the sensitive nature of medical information, including genetics and health conditions. Regulations like the Health Insurance Portability and Accountability Act (HIPAA) in the U.S. and the General Data Protection Regulation (GDPR) in Europe aim to strike a balance between data security, privacy, and the imperative for access. Results We present the Gemelli Generator - Real World Data (GEN-RWD) Sandbox, a modular multi-agent platform designed for distributed analytics in healthcare. Its primary objective is to empower external researchers to leverage hospital data while upholding privacy and ownership, obviating the need for direct data sharing. Docker compatibility adds an extra layer of flexibility, and scalability is assured through modular design, facilitating combinations of Proxy and Processor modules with various graphical interfaces. Security and reliability are reinforced through components like Identity and Access Management (IAM) agent, and a Blockchain-based notarisation module. Certification processes verify the identities of information senders and receivers. Conclusions The GEN-RWD Sandbox architecture achieves a good level of usability while ensuring a blend of flexibility, scalability, and security. Featuring a user-friendly graphical interface catering to diverse technical expertise, its external accessibility enables personnel outside the hospital to use the platform. Overall, the GEN-RWD Sandbox emerges as a comprehensive solution for healthcare distributed analytics, maintaining a delicate equilibrium between accessibility, scalability, and security.

(Series Information) European Papers - A Journal on Law and Integration, 2024 9(1), 131-144 | European Forum Insight of 18 June 2024 | (Table of Contents) I. The citizenship of the Union: an evolving, slippery ground. - II. The case-law concerning the loss of the EU citizenship. - ii.1. Case-law overview: characterization and main features. - ii.2. Legal principles of EU citizenship law established by the Court. - III. The proportionality test and its effectiveness. - iii.1. Individual examination. - iii.2. Effective possibility to recover the nationality ex tunc. - IV. Individual examination and due process rights: information and reasonable time. - V. Concluding Remarks | (Abstract) The judgment in Stadt Duisburg, concerning the loss of German (and, thus, EU) citizenship in the context of naturalization proceedings, adds a new chapter to the “judicial saga” of loss of a Member State’s citizenship and compatibility of its national measures with EU law. This Insight focuses on such a case-law of the Court of Justice (“ECJ” or “the Court”), which reflects the compromise between the “untouchable” State sovereign competence in nationality matters and the gradual consolidation of a “procedural armour” assisting the loss of the EU citizenship and the rights attached thereto. Building on this assumption, the Insight retraces and examines the main principles of EU citizenship law elaborated by the Court via its case-law, inaugurated with its 2010 leading case Rottmann, and complemented with the latest additions of the 2024 judgment in Stadt Duisburg. The main idea emerging from this jurisprudence is that, essentially, the competence to establish criteria for the loss of nationality is, and remains, firmly in the Member States’ hands. Its exercise, though, is increasingly made contingent on the respect of basic, legal principles of EU procedural law, i.e., proportionality, effectiveness and due process of law. In other words, the ECJ does not intervene on the substantial side of the Member States’ competence (the “if”), but rather on the procedural one (the “how”), thereby influencing its concrete exercise.

Background: Antimicrobial peptides (AMPs) are a critical component of the innate immune system, playing a key role in defending against a variety of pathogenic microorganisms. While many AMPs act primarily on the cell membrane of target pathogens, leading to lysis and subsequent cell death, less is known about their nonlytic membrane activity. This nonlytic activity allows AMPs to target and disrupt bacterial cells without causing lysis, leading to bacterial death through alternative mechanisms.Understanding these nonlytic properties of AMPs is crucial, as they present a promising alternative to traditional antibiotics, which can induce bacterial resistance and have adverse effects on human health and the environment. The mechanisms by which AMPs exhibit nonlytic membrane activity are still being explored. However, it is believed that AMPs penetrate the bacterial membrane and interact directly with internal cellular components such as DNA, RNA, and various enzymes essential for microbial survival and replication. This interaction disrupts metabolic homeostasis, ultimately resulting in bacterial death.The nonlytic activity of AMPs also results in minimal damage to host cells and tissues, making them attractive candidates for the development of new, more effective antibiotics. This review emphasizes the mechanisms by which AMPs nonlytically target cellular components, including DNA, proteins, RNA, and other biomolecules, and discusses their clinical significance. Understanding these mechanisms may pave the way for developing alternatives to conventional antibiotics, offering a solution to the growing issue of antibiotic resistance.

Objective To investigate factors associated with the prevalence and incidence of gallstone disease (GSD) in women and men of the MAUCO population-based prospective cohort.Design 8948 MAUCO participants (aged 38–74 years) underwent abdominal ultrasound at baseline (2015–2019); 4385 received follow-up ultrasound at years 2 or 4. Factors associated with prevalent GSD were assessed using Poisson multiple regression and with incident GSD using Cox regression models.Results GSD prevalence was 40.4% in women (13.1% gallstones, 27.3% cholecystectomies) and 17.1% in men (8.9% gallstones, 8.2% cholecystectomies). In men, GSD prevalence rate ratio (PRR) by age in >64 years was 3.85 (95% CI 3.00 to 4.94), doubling that of women’s PRR 1.78 (95% CI 1.57 to 2.01). In women, waist circumference and diabetes were stronger GSD factors; a higher number of children and worse metabolic and socioeconomic conditions were also highlighted. GSD men had higher cardiovascular disease and a family history of GSD and gallbladder cancer. 198 GSD cases developed during follow-up, with incidence increasing by 2% (95% CI 1.005% to 1.03%) per each centimetre above the ideal waist circumference, statistically significant only in women. In men, age was the strongest factor for incidence, followed by a family history of GSD and low high-density lipoprotein increased incidence risk.Conclusions GSD burden was high in this population; a third of women had their gallbladder removed, which may pose them at risk of other health problems. Abdominal obesity was the only preventable GSD risk factor, highlighting the need for effective public health policies promoting obesity reduction.