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Understanding dopaminergic dose reduction following STN-DBS: mediation analysis
No full textInternational audienceBackground Levodopa equivalent dopaminergic dose (LEDD) reduction after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease varies widely. Identifying predictors may guide patient selection and programming. Our objectives were to identify predictors of LEDD reduction and to test whether motor improvement mediates this association. Methods Data from 144 patients treated by STN-DBS were analysed. Predictors of LEDD reduction were selected using the Boruta algorithm, a machine-learning method comparing variable importance to randomised features and then tested in a structural equation model for direct and motor-mediated effects. Results Mean LEDD reduction was 41.7% (±38.2%) and motor improvement was 48.6% (±26.7%) at 1 year. Among the four predictors identified by Boruta, lower baseline LEDD (β=0.39, p=0.001), greater axial impairment (β=−0.25, p=0.003) and higher total volume of tissue activated (β=−0.17, p=0.031) were directly associated with lower LEDD reduction, independent of motor improvement. Sensorimotor STN overlap was not directly linked to LEDD reduction but was positively associated with motor improvement (β=0.34, p=0.001), which showed a trend-level effect on LEDD reduction (β=0.16, p=0.065). The total effect of sensorimotor STN overlap on LEDD reduction was not significant. Discussion Dopaminergic dose reduction after STN-DBS is constrained by preoperative axial symptoms and stimulation spread, independently of motor improvement, while sensorimotor STN overlap improves motor symptoms but not dose reduction. Integrating motor phenotype with anatomical guidance may enhance medication management post DBS
Blocking Sphingosine 1‐phosphate Metabolism With Fingolimod Prevents the Progression of Vascular Smooth Muscle Cells Calcification in Chronic Kidney Disease
No full textInternational audienceABSTRACT Patients with chronic kidney disease, and particularly those under hemodialysis, are prone to develop cardiovascular complications, mostly due to the exacerbation of vascular calcification. Vascular calcification relies on the transdifferentiation of vascular smooth muscle cells into calcifying cells. Sphingosine 1‐phosphate is a pleiotropic sphingolipid and an important regulator of osteogenesis and the cardiovascular system. Therefore, we explored the role of sphingosine 1‐phosphate metabolism in chronic kidney disease‐derived vascular calcification. Vascular calcification progression in chronic kidney disease and sphingosine 1‐phosphate signaling were examined in calcified vascular smooth muscle cells, in aortic explants, in rats with adenine‐induced chronic kidney disease, as well as in serum from hemodialysis patients. Sphingosine kinase 2 activity and sphingosine 1‐phosphate secretion, under the control of phospholipase D1, were exacerbated in calcified vascular smooth muscle cells. Furthermore, phospholipase D1 knockout mice display significantly less circulating sphingosine 1‐phosphate, supporting intertwined signalization cascades. Overall, sphingosine kinase expression and activity were upregulated in calcified aortic explants and in calcified aortas from rats. Sphingosine 1‐phosphate was increased in the serum of rats with mild vascular calcification. The Food and Drug Administration‐approved immunosuppressant drug fingolimod, a general modulator of S1P metabolism, strongly inhibited calcification in vascular smooth muscle cells and aortic explants. Additionally, fingolimod significantly reduced inflammation, attenuated metabolic syndrome and moderately inhibited aortic calcification in rats. Finally, we demonstrated for the first time that serum sphingosine 1‐phosphate was significantly increased in hemodialysis patients with mild abdominal aortic calcification. Our findings open an unexplored therapeutic option, which is targeting sphingosine 1‐phosphate metabolism, eventually with fingolimod, for the prevention and treatment of vascular calcification in chronic kidney disease patients
French-Speaking Network of Pharmacogenetics (RNPGx) Recommendations for Gene Panel Analysis Through Genotyping or Sequencing in Pharmacogenetics
No full textInternational audienceBACKGROUND: The implementation of pharmacogenetics in clinical practice increasingly relies on multigene panels. OBJECTIVES: The objective of this study is to develop harmonized recommendations for the design and analytical implementation of multigene pharmacogenetic panels, defining clinically relevant genes and associated regions of interest (ROIs) based on evidence strength, therapeutic applicability, and compatibility with genotyping or sequencing technologies. METHODS: The French-Speaking Network of Pharmacogenetics (RNPGx) evaluated 81 candidate genes across five therapeutic domains (i.e., oncology and supportive care, anesthesia and pain management, cardiology, neurology and psychiatry and immunology and infectious diseases) using a structured, evidence-based scoring system. Each gene was evaluated using a 25-point scoring system integrating pharmacogenetic importance, regulatory and professional society recommendations, and expert consensus. For the genes ultimately selected for the core panel, clinically relevant regions of interest were defined and assigned to one of three analytical classes. Class 1 includes variants with established clinical actionability; Class 2 adds optional variants suitable for extended testing in specialized settings; and Class 3 covers broader genomic regions mainly intended for rare variant or structural analyses. RESULTS: A 28-gene core panel was retained. Class 1 included 76 prioritized variants (including CYP2D6 CNV variants), and Class 2 comprised 62 additional variants (with extended analysis for CYP2D6). Class 3 eligibility was retained for 18 genes. CONCLUSION: The RNPGx recommendations offer a harmonized and flexible framework for pharmacogenetic panel design and for the extraction and interpretation of pharmacogenetic data from whole-exome or whole-genome sequencing
Genomics of Long-Term Complications of Childhood Leukemia: Rationale and Design of the GenLEA Study
No full textCited by: 0International audienceBackground: Survivors of childhood acute leukemia are at risk of long-term treatment-related complications, but the role of genetic susceptibility remains unclear. We describe here the GenLEA project, which was established to investigate genetic determinants of long-term complications. Methods: GenLEA builds on the French LEA cohort, which prospectively follows acute leukemia survivors since 2004 through standardized dedicated consultations every 2 to 4 years. Patients were selected from the nested CryoLEA biobank. Cases were defined as survivors with at least one of four major complications (anthracycline-related cardiomyopathy, secondary malignant neoplasms, metabolic syndrome, or osteonecrosis) while controls were survivors without these complications, selected with the objective of a 1:3 case-to-control ratio. Genetic data were generated using genome-wide genotyping and whole-exome sequencing. Results: After quality control, 743 patients were included for analyses (241 cases and 502 controls). Fifty-one percent were male with a median age at diagnosis of 7.3 years (IQR 3.9–13.0), and median follow-up reached 14 years (IQR 7.9–19.8). Among the cases, 44 had cardiomyopathy, 50 osteonecrosis, 37 secondary malignant neoplasms, and 163 metabolic syndrome. Planned analyses include genome-wide association studies (GWAS) and downstream analyses such as transcriptome-wide association studies (TWAS) and Mendelian randomization on genotyping data, as well as gene-based tests on exome sequencing data. Perspectives: By integrating these approaches with high-quality clinical information, GenLEA offers a unique opportunity to identify molecular determinants of late complications after childhood acute leukemia. This collaborative resource will support replication efforts, meta-analyses, and ultimately the development of personalized long-term follow-up strategies. © 2026 Wiley Periodicals LLC
EPH275 Urinary Dysfunction Management in Multiple Sclerosis: A Nationwide Real-Life Analysis From the French SNDS Database
No full textInternational audienceAnemia remains a major global public health concern, underscoring the need for innovative nutritional and therapeutic strategies. Indigenous food plants such as Carica papaya (pawpaw) have attracted attention as potential remedies; however, their claimed benefits require rigorous scientific confirmation through well-designed experimental models prior to clinical consideration. This study was designed to formulate and demonstrate a validated, two-stage experimental framework for the systematic assessment of plant-based anti-anemic activity, with C. papaya leaf and seed extracts used as a representative model. Anemia was experimentally induced in Wistar rats using aluminum chloride (AlCl₃) administered orally at 0.5 mg/kg daily for 14 days. The evaluation protocol consisted of two consecutive phases. In Stage 1, crude methanol extracts were screened at graded doses of 100, 300, and 500 mg/kg. Stage 2 focused on the most active extract identified in Stage 1, from which alkaloid and flavonoid fractions were isolated and tested at 75 and 150 mg/kg. Key hematological indices red blood cell count (RBC), hemoglobin concentration (Hb), packed cell volume (PCV), and full blood count were assessed throughout the 14-day treatment period. Administration of AlCl₃ produced marked anemia, evidenced by a decline in RBC from 7.15 to 5.05 × 10¹²/L and a reduction in Hb from 13.65 to 8.55 g/dL in untreated anemic controls. During Stage 1, methanol extracts of C. papaya leaves at 300 and 500 mg/kg demonstrated the strongest hematological recovery, significantly improving RBC, Hb, and PCV values toward normal ranges. In Stage 2, the leaf-derived alkaloid fraction at 150 mg/kg emerged as the most potent intervention, surpassing flavonoid fractions and exhibiting a clear dose-responsive effect. Overall, this work introduces a reliable and reproducible two-stage experimental approach for screening and characterizing plant-derived anti-anemic agents. The results highlight C. papaya leaf methanol extract, particularly its alkaloid fraction, as a promising candidate for anemia management and provide a standardized methodological framework for future studies in this area
Hyperpolypharmacy in patients with chronic kidney disease and its impact on clinical outcomes
No full textInternational audienceHyperpolypharmacy (≥ 10 daily medications) is frequent in patients with chronic kidney disease (CKD), but its impact remains poorly characterized. This study, based on 3,011 non-dialyzed, non-transplant CKD outpatients from the CKD-REIN cohort (eGFR < 60 mL/min/1.73 m2) aimed to describe drug burden and assess associations between hyperpolypharmacy and adverse outcomes. Drug prescription, kidney function, adverse drug reactions (ADRs), hospitalizations, kidney replacement therapy and deaths before KRT were prospectively recorded over five years. Median age was 69 years and mean eGFR was 34 mL/min/1.73 m2. At baseline, 80% of the cohort had polypharmacy (≥ 5 daily medications), and 33% had hyperpolypharmacy. These rates remained stable over time. Diabetes, dyslipidemia, and a history of cardiovascular and respiratory diseases were the main contributors to hyperpolypharmacy status. Hyperpolypharmacy was associated with greater likelihoods of an ADR (hazard ratio (HR) [95% confidence interval (CI)] 1.21 [1.04-1.40]), hospitalization (HR [95%CI] 1.34 [1.18-1.51]) and death before KRT (HR [95%CI] 1.46 [1.17-1.82]). Among patients with eGFR ≥ 30 mL/min/1.73m2, hyperpolypharmacy also raised the risk of KRT initiation (HR [95%CI] 1.46 [1.00-2.13]), but not in those with eGFR < 30 (HR [95%CI] 0.94 [0.78-1.14]). These results identify hyperpolypharmacy as a significant concern in CKD and underscore the importance of regular medication reviews to reduce adverse outcomes
How to perform Unilateral Pectineal Suspension for apical prolapse by robotic assistance: A technical note with Video
No full textInternational audienceSacrocolpopexy remains the gold-standard surgical technique for the management of apical prolapse, whether performed with or without concomitant hysterectomy. However, the use of synthetic mesh has become increasingly debated owing to concerns regarding postoperative complications. Robotic-assisted unilateral pectineal suspension (UPS) has emerged as an innovative, safe, and effective alternative for apical prolapse repair. This minimally invasive, mesh-free procedure achieves uterine suspension by anchoring the anterior cervical surface to Cooper’s iliopectineal ligament. Indications include women of reproductive age seeking a uterus-preserving approach, obese patients, and those unwilling to undergo procedures involving synthetic prostheses; it may also represent a suitable option in selected cases of recurrence following laparoscopic sacrocolpopexy or vaginal repair. We describe the standardized steps of this surgical procedure, along with the specific advantages of the robotic approach, illustrated by a detailed video demonstration to support implementation among surgeons
Patellofemoral alignment safe zones in robotic‐assisted TKA do not affect outcomes but do influence patellar resurfacing rates
No full textInternational audienceAbstract Purpose Anterior compartment management remains a challenging aspect of total knee arthroplasty (TKA), particularly in personalised alignment strategies. This study aimed to assess whether restoring patellofemoral alignment parameters within predefined safe zones—specifically patellar tilt (PTi), patellar translation (PTr) and patellar offset (PO)—is associated with improved clinical outcomes following robotic‐assisted TKA (rTKA). Methods This retrospective study included 283 patients who underwent primary rTKA between March 2021 and January 2023 using functional alignment (FA) or functional knee positioning (FKP) principles. All surgeries were performed using a CT‐based robotic system (Mako, Stryker). Patients were stratified into groups based on radiographic values of PTi, PTr and ΔPO, using thresholds derived from prior robotic studies to define safe zones. Clinical outcomes at a mean follow‐up of 2.8 ± 0.8 years included Knee Society Score (KSS), Forgotten Joint Score‐12 (FJS‐12) and Kujala Anterior Knee Pain Scale (AKPS). Results There were no statistically significant differences in final KSS, FJS‐12 or AKPS between groups within or outside the safe zones for PTi, PTr or ΔPO. However, patients with PTi < 0°, ΔPO > 0 mm (overstuffing) or PTr within ±2 mm showed significantly higher rates of patellar resurfacing ( p < 0.001). No group demonstrated superior clinical outcomes across the three parameters studied. Conclusion Restoring patellofemoral alignment parameters within predefined safe zones was not associated with improved short‐term clinical outcomes in rTKA. Robotic‐assisted FA provides accurate restoration of the anterior compartment, reducing reliance on patellar resurfacing in eligible patients. Our data suggest that target biomechanical parameters can potentially be achieved without resurfacing in cases where it is not indicated. Our hypothesis that patients within the proposed safe zones would demonstrate improved clinical outcomes was not supported by the current results. Further prospective studies are needed to determine whether femoral safe zones can predict long‐term benefit. Level of Evidence Level II
Neurological and psychiatric issues in 187 adults with early-treated PKU: The ECOPHEN study
No full textInternational audienceIntroduction: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the PAH gene leading to phenylalanine hydroxylase deficiency. This results in the accumulation of phenylalanine (Phe) in blood and brain, causing neurological and psychiatric impairments if untreated. Newborn screening (NBS) introduced in the 1960s enables early PKU diagnosis, allowing prompt dietary or sapropterin treatment. The long-term outcomes in adults with early-treated PKU, however, may include subtle neurocognitive deficits alongside somatic neurological and psychiatric complications, which remain incompletely characterized. Patients and methods: The ECOPHEN study was a French 5-year multicenter prospective cohort assessing neuropsychiatric disorders in adults with early-treated PKU. Results: Here are presented the data at inclusion. The study recruited 187 patients who were classified by PKU severity-classic, mild, or mild persistent hyperphenylalaninemia-and diet adherence status. Neurological history revealed symptoms in 11.2 % of patients, exclusively in classic PKU, including tremor, migraines, and balance disorders, without significant differences between diet groups. Neurological examination abnormalities predominantly included abnormal deep tendon reflexes in classic PKU patients. Psychiatric issues affected 25.7 % of patients across severity groups, mainly depressive episodes and anxiety, with no clear influence of diet adherence. Discussion/conclusion: The present study highlights neurological complications persisting despite early treatment, particularly in classic PKU. Diet adherence and current plasma Phe levels did not correlate significantly with neurological or psychiatric outcomes, possibly due to suboptimal metabolic control. Limitations included the cross-sectional design, absence of control group, and retrospective data collection. Overall, adults with early-treated PKU show a generally favorable outcome but remain at risk for neuropsychiatric manifestations, supporting the need for lifelong follow-up including neurologic and psychiatric evaluation
Evolution of multicellular reproduction through co-option of ecological interactions
No full textDuring the transition to multicellularity, cells evolved novel regulatory mechanisms to coordinate cell division and differentiation, which enabled the emergence of group reproduction. These mechanisms were repurposed from molecular and cellular traits that once mediated interactions between single-celled organisms. However, it remains unclear how these traits were evolutionarily integrated to form the first developmental programs in multicellular life. To address this issue, we developed a spatially structured evolutionary model in which cells can migrate, divide, and adhere to their neighbors — behaviors common to most unicellular eukaryotes. When coupled to a selective pressure driven by food scarcity, the model reveals that the ecological context plays a central role in the evolution of multi-cellular reproduction. Depending on the spatial distribution of food in the environment, both unicellular and multicellular life cycles with diverse modes of reproduction could evolve. Among these were multicellular life cycles that reproduce through unicellular propagules, the most prevalent reproductive strategy in multicellular life, which emerged spontaneously as a dispersal strategy in some environments. We show that these propagules are genetically homologous to the lineage’s unicellular ancestors, which were co-opted and repurposed as reproductive structures during evolution. Furthermore, after multicellular lineages with propagules evolved, they could colonize environments that were previously dominated by unicellular life. Altogether, our results show how ecological interactions between single cells can transform into developmental processes during the evolutionary transition towards multicellularity. Significance statement Reproduction is a universal feature of life. Yet, the evolution of multicellularity transformed it fundamentally: while single-celled organisms reproduce via cell division, reproduction in multicellular organisms is a complex process involving the coordination of many cells. How these new forms of multicellular reproduction first evolved is currently unknown. Using a computational model, we study how group reproduction emerges from the collective dynamics of individual cells. The model shows that unicellular ancestral life cycles can be repurposed as propagules used for reproduction in multicellular species, suggesting that genetic co-option is a key mechanism through which early development evolves