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Electronic Structure Dimensionality of the Quantum-Critical Ferromagnet YbNi 4 P 2
No full textInternational audienceYbNi4P2 is the first known ferromagnetic metal showing a second-order quantum phase transition. Current theoretical understanding rules out second order ferromagnetic quantum criticality in centrosymmetric 2D and 3D metals. Thus, studying the electronic structure of YbNi4P2 is of prime fundamental importance. Using angle-resolved photoemission spectroscopy, we experimentally prove the existence of 1D Fermi surface contours. In addition, our results demonstrate that part of the electronic structure of YbNi4P2 is made of states of higher dimensionality, thereby bringing into question the fact that ferromagnetic quantum criticality in centrosymmetric crystals, is exclusively found in 1D systems. Our experimental data show that the electronic structure of YbNi4P2 is a playground of mixed dimensionality, electron correlations, strong hybridization and spin-orbit coupling, all of them providing new insights in understanding the origin of ferromagnetic quantum criticality.</div
Barriers and Facilitators in Implementing a Telemonitoring Application for Patients With Chronic Kidney Disease and Health Professionals: Ancillary Implementation Study of the NeLLY (New Health e-Link in the Lyon Region) Stepped-Wedge Randomized Controlled Trial
No full textInternational audienceBackground The use of telemonitoring to manage renal function in patients with chronic kidney disease (CKD) is recommended by health authorities. However, despite these recommendations, the adoption of telemonitoring by both health care professionals and patients faces numerous challenges. Objective This study aims to identify barriers and facilitators in the implementation of a telemonitoring program for patients with CKD, as perceived by health care professionals and patients, and to explore factors associated with the adoption of the program. This study serves as a process evaluation conducted alongside the cost-effectiveness NeLLY (New Health e-Link in the Lyon Region) trial. Methods A mixed methods approach combining a quantitative questionnaire and semistructured interviews was conducted among nurses, nephrologists, and patients with stages 3 and 4 CKD across 10 renal care centers in France that have implemented telemonitoring. The Technology Acceptance Model (TAM) and the Consolidated Framework for Implementation Research (CFIR) were used to design the questionnaires and interview guides. The dimensions investigated included ease of use, perceived usefulness, and intention to use (TAM), as well as characteristics of the intervention, local and general context, individual factors, and processes (CFIR). The adoption of telemonitoring was assessed based on the frequency with which patients connected to the telemonitoring device. Determinants of telemonitoring use were analyzed using nonparametric tests, specifically the Wilcoxon-Mann-Whitney and Kruskal-Wallis tests. Thematic analysis was conducted on the transcriptions of semistructured interviews. Both quantitative and qualitative results, including data from patients and professionals, were integrated to provide a comprehensive understanding of the factors associated with the use of remote monitoring in CKD. Results A total of 42 professionals and 128 patients with CKD responded to our questionnaire. Among these, 11 professionals and 13 patients participated in interviews. Nurses, who were responsible for patient follow-up, regularly used telemonitoring (8/13, 62%, at least once a month), while nephrologists, who were responsible for prescribing it, were primarily occasional users (5/8, 63%, using it less than once a month). Among professionals, the main obstacles identified were the heavy workload generated by telemonitoring, lack of training, and insufficient support for nurses. Among the 128 patients, 46 (35.9%) reported using the application at least once a week. The main barriers for patients were issues related to computer use, as well as the lack of feedback and communication with health care professionals. The main facilitators identified by both professionals and patients for using telemonitoring were the empowerment of patients in managing their health and the reduction of the burden associated with CKD. Conclusions Improving adherence to telemonitoring in the context of CKD requires collaborative efforts from both professionals and patients. Our results provide insights that can inform the design of effective, theory-driven interventions aimed at improving telemonitoring adoption and usage
Targeting the cell and non-cell autonomous regulation of 47S synthesis by GCN2 in colon cancer
No full textAbstract Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor GCN2 represses the expression of the precursor of ribosomal RNA, 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, GCN2 activity supports cell proliferation through the transcription stimulation of 47S rRNA, independently of the canonical ISR axis. However, impairment of GCN2 activity prevents nuclear translocation of the methionyl tRNA synthetase (MetRS) underlying the generation of a nucleolar stress, mTORC1 inhibition and autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA pol I inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls the ribosome biogenesis according the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and the RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically-stressed COAD cell
Exploring the general practitioners’ perception of the inter-professional care of rheumatoid arthritis patients (GEPRA—II): a qualitative interview study
No full textInternational audienceBackground: A lack of medication adherence among patients with rheumatoid arthritis (RA) has been reported. Inter-professional collaborations seem essential for an optimal therapeutic management of patients. The aim of this study was to analyse the barriers and facilitators of general practitioners (GPs) for the implementation of collaborative support programmes in RA.Methods: A qualitative semi-structured study using face-to-face or telephone interviews was conducted. Eligible participants included French GPs referring patients with RA. Interviews were audio-recorded and then transcribed. Data were analysed using Braun and Clarke's thematic analysis framework with Nvivo®12 software.Results: Nineteen GPs were interviewed between August 2019 and February 2020. Five themes were identified in the care of their patients with RA. GPs reported being mainly involved in diagnosis and orientation, and frequently asked for pain management and explanation/reformulation of previously given information. They perceived their patients to be adherent to their treatments, although they frequently identified reasons for non-adherence. Regarding their perception of the community-hospital relationship, they sometimes considered it insufficient and expected more immediate interactions. Additionally, most interviewed GPs had no expectation regarding increased collaborations with community pharmacists (CPs) and several GPs were motivated to be more involved in a patient support programme. However, barriers were identified: lack of time and training, and insufficient payment.Conclusions: The implementation of a collaborative patient support programme in RA should be developed taking into account the barriers and facilitators identified by GPs who appeared to be aware of the causes of potential non-adherence, and were particularly interested in receiving more information about the therapeutic monitoring of patients by hospital professionals
Optimizing treatment for pediatric multiple sclerosis
No full textInternational audienceIntroduction: Pediatric-onset multiple sclerosis (POMS) differs from adult MS in its clinical characteristics and disease course. POMS exhibits a heightened inflammatory activity with higher relapse rates and lesion load, alongside less early physical disability but more pronounced cognitive impairment and impaired brain growth.Areas covered: This review examines treatment strategy in POMS based on safety and efficacy data from observational studies and randomized controlled trials. This article is based on a literature search conducted using MEDLINE and Google Scholar for the period of 2000 to 2024.Expert opinion: High-efficacy therapies, including fingolimod, natalizumab, and anti-CD20 therapies, have demonstrated superior disease control and disability prevention. Early initiation of HET is increasingly recommended to optimize outcomes and preserve quality of life.Low/moderate-efficacy therapies, such as interferons, glatiramer acetate, teriflunomide, dimethyl fumarate should be reserved for patients with mild disease. While long-term safety data, personalized prognostic markers and de-escalation strategies are still needed, high-efficacy therapies provide a promising standard of care, especially given enhanced neuroinflammatory activity in POMS. Future research should prioritize strategies to balance disease control with adverse effects (AEs), accounting for aging and individual disease trajectories, to improve long-term quality of life in POMS patients
Real-world outcomes of haplo-HSCT with post-transplant cyclophosphamide in pediatric hematologic malignancies: a study on behalf of SFGM-TC and SFCE
No full textCompeting interests: The authors declare no competing interests. Ethics approval and patient consent: Patients or legal guardians provided written informed consent for data collection and use for analysis, in accordance with the Declaration of Helsinki. This study was approved by SFGM-TC and SFCE HSCT committees and registered on Health Data Hub (F20230327154245).International audienceNo abstract availabl
SWS1-complex in premature ovarian insufficiency: SWSAP1 as a new POI gene.
No full textInternational audienceStudy question: What other zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) partners are involved in premature ovarian insufficiency (POI)?Summary answer: This study identifies novel pathogenic variants in zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) and its partner, SWSAP1, which impair interhomolog homologous recombination (IH-HR) and lead to isolated POI.What is known already: Knockout mice models of the SWS1-complex (also known as the SWS1-SWSAP1-SPIDR complex or Shu complex) are infertile due to meiotic arrest. Variants of both SWS1/ZSWIM7 and SPIDR are described in POI, but so far, no SWSAP1 variants have been described in female infertility.Study design, size, duration: Screening for SWS1-complex variants was performed using exome or genome sequencing data from women with POI as ongoing patient care. In silico modelling, IH-HR assays, and western-blot analysis were performed to test the impact of novel variants identified in genes of the SWS1-complex (SWSAP1 and SWS1/ZSWIM7) on homologous recombination, protein expression, and protein interactions.Participants/materials, setting, methods: Five unrelated patients from France were enrolled based on their exome or genome sequencing result as part of ongoing patient care. All the patients were diagnosed with POI and met the European Society of Human Reproduction and Embryology (ESHRE) diagnostic criteria for POI. Functional validation was performed using mouse embryonic stem cells to study the impact of two novel variants found in two patients.Main results and the role of chance: We report five different pathogenic or likely pathogenic variants in five patients. We report the previously described c.231_232del and c.176C>T variants in SWS1/ZSWIM7, as well as two novel variants, c.22del and c.151C>T. Additionally, we report a homozygous frameshift deletion in SWSAP1 (c.353del). All the patients display a similar phenotype of severe isolated POI, associated with primary or early secondary amenorrhea and signs of puberty delay. In silico modelling and IH-HR assays of both SWS1/ZSWIM7 c.176C>T and SWSAP1 c.353del indicated a partial decrease or absence of IH-HR activity in Sws1-/- or Swsap1-/- cells, respectively, and destabilization of the SWSAP1 truncation mutant.Limitations, reasons for caution: Identification of other patients carrying SWSAP1 variants is needed to evaluate in-depth phenotype to genotype correlations. Future studies should evaluate the role of other genes in the SWS1-complex and explore the potential for therapeutic interventions targeting homologous recombination.Wider implications of the findings: These findings provide direct clinical and functional evidence that all three members of the SWS1-complex are implicated in female fertility and recapitulate the observed mouse phenotypes. IH-HR assays provide a relevant functional approach to validate novel variants in homologous recombination genes for POI patients, given the importance of IH-HR for meiotic progression.Study funding/competing interest(s): The French Genomic Medicine Initiative PFMG2025 is supported by grants from the French government, notably by the French National Research Agency under the Programme d'Investissments d'Avenir for the CAD (ANR-21-ESRE0001) and the CRefIX (ANR-10-INBS-09-01). M.J. was supported by R01 HD112624 and R35CA253174 grants. E.J.T. was supported by a Norman Beischer Fellowship and a Centre for Research Excellence for Women's Health in Reproductive Life (CRE-WHiRL) fellowship from the National Health and Medical Research Council (NHMRC). J.F.M. was supported by a Research Training Program scholarship from the Australian Government. The authors declare no competing interests.Trial registration number: This manuscript included genomic analysis performed in clinical practice in patients with RD/CGP and cancers in France. Consequently, a clinical trial NCT number was not required as we reported in this manuscript results obtained in clinical practice. In compliance with the French law on bioethics (2004-800, 06/08/2004), patients had signed written informed consent forms for clinical practice and had been informed of the research use of what remained of their samples after establishing the molecular diagnosis
Testosterone therapy is associated with reduced risk of acute kidney injury, kidney failure with renal replacement therapy, and cardiovascular events in men with diabetes and hypogonadism
No full textInternational audienceBackground: Testosterone deficiency is common in men with diabetes. Effects of testosterone therapy on kidney failure and cardiovascular outcomes in diabetic men remain poorly understood. Our aim was to assess whether testosterone therapy is associated with reduced risk of acute kidney injury and kidney failure requiring replacement therapy in men with diabetes and hypogonadism compared to matched untreated men with diabetes.Methods: Participants were recruited from the TriNetX Research Collaborative network. We identified 26,027 diabetic men with hypogonadism treated with testosterone and matched them 1:1 using propensity score matching to 26,027 untreated diabetic men with hypogonadism. Primary outcomes were acute kidney injury and kidney failure requiring replacement therapy (dialysis or transplantation). Secondary outcomes included myocardial infarction, ischemic stroke, atrial fibrillation, and all-cause mortality. Cox proportional hazard models were used over a mean follow-up of 3.3 years.Results: Men had a mean age of 58 years (SD 12), with 71% being non-Hispanic White. Testosterone-treated men had significantly lower risk of acute kidney injury (HR: 0.93 [95% CI 0.87-0.98], p = 0.01) and kidney failure with replacement therapy (HR: 0.81 [95% CI 0.72-0.92], p = 0.001) compared to untreated men. Testosterone therapy was also associated with reduced risk of myocardial infarction (HR: 0.85 [95% CI 0.78-0.93], p < 0.0001), ischemic stroke (HR: 0.88 [95% CI 0.80-0.97], p = 0.01), atrial fibrillation (HR: 0.91 [95% CI 0.85-0.98], p = 0.01), and all-cause mortality (HR: 0.85 [95% CI 0.79-0.91], p < 0.0001).Conclusions: In this large real-world cohort study, testosterone therapy in diabetic men with hypogonadism was associated with significant reductions in acute kidney injury, kidney failure requiring replacement therapy, major cardiovascular events, and total mortality. These findings suggest that testosterone therapy could be more readily considered for men with diabetes and hypogonadism as a potential intervention to prevent kidney injury
Extracellular vesicle microRNAs are biomarkers of focal epilepsy but not epilepsy‐related respiratory dysfunction
No full textInternational audienceAbstract Objective This study was undertaken to evaluate the diagnostic value of a set of preselected candidate microRNAs (miRNAs) extracted from plasma‐based extracellular vesicles (EVs) to identify patients with seizure‐related respiratory dysfunction. Methods A two‐step design was applied. Step 1 entailed selection of the relevant miRNAs based on the combination of a literature review and an exploratory study in epileptic rats with or without interictal respiratory dysfunction. Step 2 involved evaluation of the diagnostic value of this preselected panel of circulating exosomal miRNAs in a case–control study conducted in 25 healthy subjects and 50 patients with drug‐resistant focal epilepsy undergoing video‐electroencephalographic (EEG) monitoring. Based on video‐EEG data, patients were separated into two groups: those with ictal/postictal hypoxemia (PIH; n = 24) and those without (noPIH; n = 26). Blood samples were collected in the interictal period (>24 h after the last seizure). Expression level of each miRNAs in EVs was compared (1) between all patients with epilepsy and controls and (2) between PIH and noPIH. Receiver operating characteristic (ROC) curves were generated, and the area under the curve (AUC) was calculated. Results Following Step 1, the final set of miRNAs selected for evaluation in the case–control study included 24 miRNAs, with nine selected from published data in patients because of their potential regulatory role in the serotoninergic pathway, brain response to hypoxia, or epilepsy and 15 selected from the preclinical study in epileptic rats. Three miRNAs significantly differed between patients with epilepsy and controls (ROC curve AUC: hsa‐miR‐22‐3p, .74 [95% confidence interval (CI) = .63–.85]; hsa‐miR‐106b‐5p, .69 [95% CI = .57–.82]; and hsa‐miR‐26a‐5p, .72 [95% CI = .58–.85]). Only a trend toward higher expression levels was observed for hsa‐miR‐140‐3p in PIH compared to noPIH (+5%, p = .064). Significance Whereas three miRNAs were robustly associated with epilepsy, none was significantly associated with seizure‐related respiratory dysfunction. Additional studies are required, including analysis of the expression of plasmatic cell‐free miRNAs, especially the miRNAs associated with interictal respiratory dysfunction in epileptic rats
Impact of Corticosteroid-Free Regimen on Interstitial Fibrosis Following Kidney Transplantation
No full textInternational audienceIntroduction: In kidney transplantation, concerns remain about whether corticosteroids (CS) avoidance could favor interstitial fibrosis (IF) and its progression. We conducted a multicenter randomized noninferiority clinical trial to evaluate the histopathological progression of IF using an innovative automated method in patients receiving CS or not.Methods: Low immunological risk recipients of a kidney allograft for whom an analyzable biopsy was available at implantation were randomly assigned to receive a CS-free regimen (CS-) or a standard CS tapering regimen (CS+). All patients received induction therapy with basiliximab, and conventional maintenance therapy. The primary outcome was the difference in the percentage change of IF between the baseline and the 1-year protocol biopsy with a prespecified 10% noninferiority margin.Results: A total of 108 patients were analyzed in the full analysis set (FAS) population as follows: 52 patients in the CS+ group and 56 patients in the CS- group. Complete avoidance of CS was reached in 36 (64%) CS- patients (per-protocol [PP] population). In the FAS population, the mean percentage of IF at implantation was 19.5% ± 7.9% in the CS- group (n = 51) and 17.9% ± 7.8% in the CS+ group (n = 49; P = 0.3), and 25.9% ± 11% (n = 43) and 21.5% ± 11.2% (n = 39; P = 0.03) at 1 year. Considering the difference in IF change, the CS- group was noninferior to the CS+ group neither in the FAS and PP population: 4.45% 95% confidence interval [CI]: [-0.4% to 9.3%] and 3.0% 95% CI: [-2.7% to 8.6%], respectively.Conclusion: Progression of IF during the first year following kidney transplantation was not inferior among patients without CS compared with patients with CS