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L'hepcidine est un peptide principalement hépatique, régulateur central du métabolisme du fer et protecteur contre la perte osseuse en situation d'hémochromatose. Néanmoins, plusieurs études ont mis en évidence une production extra-hépatique d'hepcidine, dans des tissus périphériques. Cette production tissulaire périphérique joue un rôle pro-inflammatoire en participant à la réponse antimicrobienne dans le rein et la peau [1] et en contribuant au recrutement des neutrophiles dans le psoriasis [2]. En condition inflammatoire, la signalisation IL-6/JAK1-2/STAT3 régule la production d'hepcidine. Cette voie intervenant également dans la physiopathologie des arthrites, telles que la polyarthrite rhumatoïde (PR), nous avons souhaité évaluer si, dans un contexte d'arthrite, l'hepcidine est induite localement au sein de l'articulation et si elle module la synovite et les mécanismes de destruction ostéo-articulaire. La production et le rôle de l'hepcidine dans l'arthrite a été déterminé à partir de prélèvements humains provenant de patients atteints de PR, rhumatisme psoriasique (RPso) et arthrose (Ar). La présence du peptide a été évaluée dans la membrane synoviale et le liquide synovial, respectivement par immunofluorescence et par LC-MS/MS (chromatographie liquide couplée à de la spectrométrie de masse), tandis que l'expression génique a été mesurée dans les différents types cellulaires présents dans le liquide synovial par RT-PCR. Afin de mimer l'infiltrat inflammatoire synovial, des cellules mononucléées du sang périphérique ont été stimulées avec des liquides synoviaux de patients atteints d'arthrite en présence de différents inhibiteurs thérapeutiques, pour comprendre le rôle spécifique des cytokines arthritogènes dans la production articulaire d'hepcidine. Afin d'étudier le rôle fonctionnel de l'hepcidine dans l'inflammation articulaire et le remodelage osseux inflammatoire, nous avons évalué l'impact in vitro de son ajout sur des cultures d'ostéoclastes dérivés de monocytes (ostéoclastogenèse) et sur un explant synovial et des fibroblastes de PR (expression de médiateurs inflammatoires). Nous avons pu confirmer la présence d'hepcidine à la fois dans la membrane synoviale (Figure 1) et dans le liquide synovial de patients atteints d'arthrite (Figure 2). Cette hepcidine locale, produite par les cellules immunitaires mononucléées, principalement par les monocytes, est induite par l'environnement inflammatoire de l'articulation. Des médiateurs locaux, dépendant de la voie JAK-STAT tels que l'IL-6 et d'autres tels que l'IL-17 et le M-CSF, sont responsables de cette production (Figure 3). Cette hepcidine diminue la différenciation des ostéoclastes et pourrait ainsi avoir un rôle protecteur sur la destruction osseuse inflammatoire. Cependant, le niveau d'hepcidine articulaire est également corrélé au pourcentage de neutrophiles dans l'articulation et est impliqué dans la production de CXCL1 (chimiokine attractante de ces neutrophiles) par les fibroblastes, participant ainsi potentiellement à l'infiltrat inflammatoire. Le potentiel effet modulateur de l'hepcidine dans l'arthrite et la perte osseuse inflammatoire, devra être confirmé in vivo en modèle murin et évalué dans d'autres formes d'arthrite (septique, microcristalline). L'hepcidine est produite localement dans l'articulation en conditions inflammatoires et pourrait moduler l'inflammation et le remodelage osseux de l'arthrite. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions Our objective was to explore how women living with HIV aged ≥40 years perceive their care in relation to their HIV infection, comorbidities, and menopausal health and to evaluate the extent to which the care they receive meets their expectations, comparatively across World Health Organization (WHO) European regions.We conducted a cross‐sectional survey (May–December 2023) among women living with HIV aged ≥40 years from the WHO European region. Five dimensions of care were assessed: content of care, information, relationship with caregiver, organization of care, and patients' rights and privacy, in addition to management of non‐HIV comorbidities and menopause.In total, 600 women completed the survey; they were predominantly from the Western European region (70.2%), followed by the Eastern (20.2%) and Central (9.6%) regions. The majority of women (46.5%–95.1%) described positive experiences, responding that they were ‘always’ or ‘usually’ satisfied with the five dimensions of HIV care. The concordance between perceptions and experiences of HIV care ranged from 49.4% to 96.1% and was lower in the Eastern region. Among menopausal women, 58.5% were ‘very satisfied’ or ‘satisfied’ with the care they received; satisfaction was significantly lower in Eastern European countries than in Western countries.Our results highlighted a generally high concordance between respondents' expectations and the services provided, including both HIV and non‐HIV care. Women aged ≥40 years living with HIV face several challenges that should be addressed. These findings inform stakeholders and decision‐makers about the need to adopt a more inclusive and sensitive approach in healthcare systems. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway have transformed urothelial cancer (UC) therapy. The correlation between PD-L1 expression and ICI effectiveness is uncertain, leaving the role of PD-L1 as a predictive marker for ICI efficacy unclear. Among several ways to enhance the efficacy of ICI, trials are exploring combining ICIs with serine/threonine-protein kinase mTOR (mTOR) inhibitors in different tumor types. The potential interaction between mTOR inhibitors and PD-L1 expression in UC has not been well characterized. In our study, we investigated how phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway inhibitors (TAK-228, everolimus and TAK-117) affect PD-L1 expression and function in preclinical bladder cancer cell models. TAK-228 increased cell surface levels of glycosylated PD-L1 in all but one of the seven cell lines, regardless of baseline levels. TAK-228 promoted the secretion of epidermal growth factor (EGF) and interferon-β (IFNβ), both linked to PD-L1 protein induction. Blocking EGF and IFNβ receptors reversed the TAK-228-induced PD-L1 increase. Additionally, TAK-228 enhanced IFN-γ-induced PD-L1 expression and intracellular HLA-I levels in some cells. TAK-228-treated bladder cancer cells exhibited resistance to the cytotoxic effects of peripheral blood mononuclear cells (PBMCs) and cluster of differentiation 8 (CD8)+ T cells. The addition of an anti-PD-L1 antibody diminished this resistance in T24 cells. Increased expression of PD-L1 under TAK-228 exposure was confirmed in patient-derived explants (PDEs) treated ex vivo. These preclinical findings suggest that mTOR inhibition with TAK-228 can increase PD-L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Actinobacteriophage Magritte was isolated from soil in Columbia, TN using Microbacterium foliorum as a host. Magritte is a singleton with a siphovirus morphology and a large genome of 133,228 bp encoding 250 predicted genes, including 26 tRNA genes., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2024 by the authors.)

Objective: To assess the impact and feasibility of a telehealth program using continuous glucose monitoring (CGM) and a connected insulin pen cap (CIPC) in nursing homes for older adults with insulin-treated diabetes. Research Methods: This multicenter, prospective, sequential, single-arm study consisted of three phases: (1) baseline, blind CGM ( Freestyle Libre Pro® ); (2) intervention 1, CGM ( Freestyle Libre2® ) without alarms; and (3) intervention 2, CGM with alarms for hypo and hyperglycemia. Two telehealth visits from reference diabetes units were conducted to adjust antidiabetic treatments. Insulin treatment was tracked using the Insulclock® CIPC. The study's primary objective was to evaluate the reduction of hypoglycemia rate. Results: Of 82 eligible patients at seven nursing homes, 54 completed the study (age: 87.7 ± 7.1, 68-102 years, 56% women, duration of diabetes: 18.7 years, baseline glycated hemoglobin: 6.9% [52 mmol/mol]). The mean number of hypoglycemic events was significantly reduced from baseline (4.4) to intervention 1 (2.8; P = 0.060) and intervention 2 (2.1; P = 0.023). The time below range 70 mg/dL (3.9 mmol/L) significantly decreased from 3.7% at baseline to 1.4% at intervention 2 ( P = 0.036). The number of insulin injections significantly decreased from baseline to intervention 1 (1.2 to 0.99; P = 0.027). Nursing home staff expressed a positive view of the program, greater convenience, and potential to reduce hypoglycemia with the Freestyle Libre2® CGM versus the glucometer. Conclusions: A telehealth program using CGM and a CIPC was associated with improved glycemic profiles among institutionalized older individuals with diabetes receiving insulin and was well perceived by professionals.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Challenge tests are commonly employed to evaluate the growth behavior of L. monocytogenes in food matrices; they are known for being expensive and time-consuming. An alternative could be the use of predictive models to forecast microbial behavior under different conditions. In this study, the growth behavior of L. monocytogenes in different fresh produce was evaluated using a predictive model based on the Gamma concept considering pH, water activity (a w ), and temperature as input factors. An extensive literature search resulted in a total of 105 research articles selected to collect growth/no growth behavior data of L. monocytogenes. Up to 808 L. monocytogenes behavior values and physicochemical characteristics were extracted for different fruits and vegetables. The predictive performance of the model as a tool for identifying the produce commodities supporting the growth of L. monocytogenes was proved by comparing with the experimental data collected from the literature. The model provided satisfactory predictions on the behavior of L. monocytogenes in vegetables (>80% agreement with experimental observations). For leafy greens, a 90% agreement was achieved. In contrast, the performance of the Gamma model was less satisfactory for fruits, as it tends to overestimate the potential of acid commodities to inhibit the growth of L. monocytogenes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder clinically characterized by endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of the oxytocin (OXT) on it, have never been investigated in human neurons., Methods: We studied the methylation marks in induced pluripotent stem-derived dopaminergic neurons carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neuron differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from the iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in these iPSC-derived dopaminergic neurons differentiated with or without OXT., Results: The analysis revealed that 153,826 cytosines were differentially methylated between SNORD116 MD neurons and control neurons. Among the differentially methylated genes, we determined a list of genes also differentially expressed. Enrichment analysis of this list encompassed the dopaminergic system with COMT and SLC6A3. COMT displayed hypermethylation and under-expression in SNORD116 MD, and SLC6A3 displayed hypomethylation and over-expression in SNORD116 MD. RT-qPCR confirmed significant over-expression of SLC6A3 in SNORD116 MD neurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation., Conclusion: SNORD116 MD dopaminergic neurons displayed differential methylation and expression in the COMT and SLC6A3 genes, which are related to dopaminergic clearance., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To assess organ damage, with emphasis on the cardiovascular system, over the different stages of the disease in a large SLE cohort., Methods: Multicentre, longitudinal study of a cohort of 4219 patients with SLE enrolled in the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We longitudinally analysed SDI (globally and for each domain) over time only in the 1274 patients whose dates of damage events had been recorded., Results: During the first year after diagnosis of SLE, 20% of the 1274 patients presented with new damage manifestations. At years 2 and 3, new damage was recorded in 11% and 9% of patients. The annual percentage of patients with new damage after year 5 decreased to 5%. In the first year with the disease, most damage was accumulated in the musculoskeletal, neuropsychiatric and renal systems; in later stages, most damage was in the musculoskeletal, ocular and cardiovascular systems. Considering 'cerebrovascular accident' and 'claudication for 6 months' as cardiovascular items, the cardiovascular system was the second most affected system during the early stages of SLE, with 19% of the patients who presented with damage affected at first year after diagnosis. During the late stages, 20-25% of the patients presenting with new damage did so in this modified cardiovascular domain of the SDI., Conclusions: New damage occurs mainly during the first year following diagnosis of SLE. Cardiovascular damage is relevant in both the early and the late stages of the disease. Strategies to prevent cardiovascular damage should be implemented early after diagnosis of SLE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)