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The Pregnane-X receptor regulates steroid synthesis in mouse Leydig cells
No full textInternational audienceIntroduction Pregnane X Receptor (PXR, NR1I2) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily, that can be activated by a wide variety of endogenous and exogenous ligands. It is a major actor of the endo- and xeno-biotic detoxification process. It also regulates biological processes such as lipid metabolism in large number of tissues. Pxr was shown to be expressed in human, mouse, rat and pig testis, however its roles in the regulation of testicular functions have been little explored so far. Methods To determine the potential involvement of PXR in the regulation of steroidogenesis, experiments were performed on a wild type (MLTC-1WT) and a Pxr knock-down (MLTC-1PxrKD) mouse Leydig cell line (MLTC-1 cells), treated with a PXR agonist (SR-12813) in acute and chronic conditions. Results Our analyses confirmed the presence of Pxr transcripts in the mouse testis, particularly in Leydig cells. In addition, A lower testosterone concentration was measured in MLTC-1PxrKD cells compared to wild type cells. Moreover, both acute and chronic stimulation of MLTC-1WT cells with SR-12813 led to a decrease in testosterone concentration, associated with a lower expression of some steroidogenic genes. This negative impact of SR-12813 on Leydig cell steroidogenesis was counteracted by Pxr knock down. Discussion Overall, these results support the involvement of PXR in the regulation of testosterone homeostasis in mouse Leydig cells and open new avenues of research into the involvement of this receptor in the deleterious effects of certain endocrine disruptors on the steroidogenic activity of Leydig cells
Association Between Opioid Analgesics and Suicide Attempts: A Nationwide French Case-Crossover Study
No full textInternational audienceBackground and objectives: The rising prescription rates and opioid-related harms in France highlight the need for local data. Evaluating this association may help identify vulnerable subgroups and guide safer prescribing practices. This study aimed to assess the association between opioid analgesic dispensation and the risk of suicide attempt in the French population. Secondary objectives included evaluation of a dose-response relationship and examination of the potential additive effects of co-prescriptions with benzodiazepines or gabapentinoids.Methods: We conducted a nationwide, population-based case-crossover study using data from the French National Health Insurance Database (Système National des Données de Santé, SNDS), covering 98.8% of the French population. Adults aged 18 years or older who were hospitalized for a first suicide attempt between 1 January 2013 and 31 December 2020, and who had received at least one opioid analgesic dispensation in the preceding year (excluding buprenorphine and methadone) were included. Opioid analgesic exposure during the 84 days before the attempt was compared with three earlier 84-day control periods.Results: Among 158,400 patients (mean age 47.0 years; 64.0% women), opioid analgesic dispensation was associated with a higher risk of suicide attempt (odds ratio [OR] = 1.26; 95% confidence interval 1.25-1.28). The risk was greater for strong opioid analgesics (OR = 1.73) and higher morphine-equivalent doses. Co-prescription with benzodiazepines or gabapentinoids further increased risk.Conclusions: Opioid analgesic use, especially at higher doses or in combination with benzodiazepines or gabapentinoids, was associated with an increased risk of suicide attempt. Clinical vigilance is warranted when prescribing these medications.Trial registration: NCT04211077, registered 3 January 2020 (retrospectively registered)
Influence of body composition on energy metabolism in females with constitutional thinness
No full textInternational audienceIndividuals with constitutional thinness are characterized by an atypical resting energy metabolism and body composition. The aim of the present study was to compare patterns of energetic changes from a fasted resting state to i) postprandial resting, ii) fasted exercise, and (iii) postprandial exercise between females with constitutional thinness and normal-weight, considering body weight and composition characteristics. Subjects/MethodsBody composition (X-ray absorptiometry) and maximal aerobic capacities were assessed in 17 female adults with constitutional thinness and 17 normal-weight controls. Their energy expenditure and substrate oxidation were assessed by indirect calorimetry on four occasions: i) in a fasted resting state, ii) two hours after a calibrated meal in a resting state, iii) after a 30-min cycling exercise performed postprandially, and iv) after a 20-min walking exercise in a fasted state. ResultsFemales with constitutional thinness had significantly lower body weight (p < 0.001), absolute fat-free mass (p < 0.001) and percentage of fat mass (p = 0.04). Energy expenditure was lower for all the energetic stimuli considered (from p = 0.02 to p < 0.001) in participants with constitutional thinness compared to normal-weight controls, and differences disappeared after adjustment for body weight or composition. ConclusionsThe present results do not indicate any impaired energetic responses to any energetic stimuli in females with constitutional thinness. Results challenge the hypothesis of a spender energy profile in individuals with constitutional thinness, and highlight the necessity to gain insight into the role of body composition in energetic regulation in this population
Comparative effectiveness of tofacitinib versus upadacitinib for the treatment of acute severe ulcerative colitis
No full textInternational audienceBackground and aims: Tofacitinib and upadacitinib are Janus kinase (JAK) inhibitors that are increasingly used for the treatment of acute severe ulcerative colitis (ASUC). However, comparative analyses of safety and effectiveness have not been performed for their use in this setting.Methods: This multicenter, retrospective study enrolled hospitalized adult patients treated with tofacitinib or upadacitinib for ASUC between January 2019 and June 2024. The main outcomes were clinical response, clinical remission, and colectomy-free survival. Propensity-adjusted analyses using inverse probability treatment weighting (IPTW), and double robust estimations (DRE) were used to control for confounding factors.Results: In total, 111 patients (60 tofacitinib, 51 upadacitinib) were enrolled across 23 international centers. JAK inhibitors were used to induce response in 86 (77%) patients and used to maintain response after adequate intravenous steroid response in 25 (23%). The median follow up was 31 weeks (IQR 13-64). Between days 3-7 after treatment initiation, upadacitinib was associated with greater response rates 84% vs.54%,p=0.02 but response/remission were comparable at day 98 (45%/36% vs 55/48%) and day 182 (29/29% vs. 39/34%). Sub-analyses for JAK inhibitor use as salvage therapy (tofacitinib (n=35) vs. upadacitinib (n=31)) showed similar effectiveness outcomes across both groups. The probabilities of colectomy-free survival at days 98/182 for tofacitinib and upadacitinib were 79%/75% and 80%/78%, respectively, with no significant differences in the comparison of survival curves, p=0.99. Treatment failure rates (where JAK inhibitor was used to maintain remission) were similar at days 98 and 182. The frequency of adverse events was comparable.Conclusion: Tofacitinib and upadacitinib appear to have similar effectiveness and safety profiles when used for the treatment of ASUC
Harmonisation of quality control tests for academic production of CAR-T cells: a position paper from the WP-bioproduction of the UNITC consortium
No full textInternational audienceThis position paper from the Bioproduction Working Group of the UNITC Consortium seeks to harmonize quality control (QC) procedures for academic production of autologous CAR-T cells. The primary objective is to standardize QC testing for batch release in academic cell therapy units. Academic CAR-T manufacturing under the hospital exemption pathway enables faster, more cost-effective production and the use of fresh cells, eliminating the need for cryopreservation. Standardized QC processes are critical to ensure consistent product quality and safety. This paper focuses on key QC measures, including mycoplasma detection using validated commercial kits or in-house methods with on-site validation, endotoxin testing via Limulus Amebocyte Lysate (LAL) or Recombinant Factor C (rFC) assays with validated protocols to prevent matrix interference, vector copy number (VCN) quantification through validated qPCR or ddPCR techniques, and potency assessment through IFN-γ ELISA following antigenic stimulation. Emphasizing method validation and standardized testing, this work underscores the importance of robust QC strategies to ensure the safety and efficacy of CAR-T cell therapies, with ongoing efforts dedicated to optimizing these processes. This workshop focuses on addressing the harmonization of some quality control (QC) measures required for the validation of academic CAR-T cell production :mycoplasma detection; endotoxin testing; vector copy number (VCN) quantification; potency testing and the use of surrogate markers, if applicable. Sterility testing and characterization/identity/purity assessments are not covered in this work
Amikacin use in critically ill patients requiring renal replacement therapy: the AMIDIAL-ICU study
No full textInternational audienceBACKGROUND: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is common in intensive care units (ICUs), yet optimal amikacin dosing in this context remains poorly understood. METHODS: We conducted a prospective observational study across 18 French hospitals from April 2020 to January 2022. Adult ICU patients (aged \textgreater 18 years) receiving their first amikacin dose while on RRT were included. Data on demographics, RRT modalities, amikacin dosing, and therapeutic drug monitoring were collected. Using a pharmacokinetic modeling approach, we evaluated various amikacin regimens and simulated target attainment probabilities across different minimum inhibitory concentrations (MICs). RESULTS: A total of 111 patients were included, with approximately two-thirds receiving continuous RRT. The median amikacin dose was 27 (25-30) mg/kg. Amikacin peak (Cmax) and trough concentrations were monitored in 53 (47.8%) and 76 (68.5%) patients, respectively. Continuous RRT and a history of chronic kidney disease reduced dialytic clearance. For a MIC ≤ 4 mg/L, a 15 mg/kg amikacin dose achieved Cmax/MIC and AUC/MIC targets in ≥ 90% of patients on intermittent dialysis, while 20 mg/kg was required for those on continuous dialysis. For a MIC = 8 mg/L, a 30 mg/kg dose was necessary to achieve Cmax/MIC ≥ 8. CONCLUSIONS: Our findings highlight suboptimal adherence to amikacin monitoring guidelines in ICU patients on RRT. Using pharmacokinetic modeling, we identified amikacin dosing recommendations ranging from 15 to 35 mg/kg to optimize efficacy and minimize risks, depending on MIC and dialysis modality
Neuropsychiatric fluctuations in Parkinson's disease: A French multicenter study of the NFS psychometric properties
No full textInternational audienceBackground: Neuropsychiatric fluctuations (NpsyF) are common in advanced Parkinson's disease patients (PD). In the OFF-medication condition, they manifest as minus symptoms such as anxiety and fatigue, while in the ON-medication condition, plus symptoms like euphoria appear. These fluctuations significantly impact the quality of life for patients and caregivers, making their identification crucial for effective PD management. The Neuropsychiatric Fluctuation Scale (NFS) was developed to assess NpsyF in real time, and a recent study indicated that the NFS has good psychometric properties.Objective: To evaluate and confirm the psychometric characteristics of the NFS in a prospective multicenter study (NFS-VALID).Method: The NFS was administered to PD patients with motor fluctuations in both ON and OFF-medication conditions, alongside other assessment scales, including motor scale and evaluations of emotional and behavioral aspects. Internal structure was evaluated using principal component analysis (PCA), and internal consistency was assessed with Cronbach's alpha. External validity was measured through correlations with other scales. Specificity was assessed by comparing NFS scores between controls and PD patients, as well as between PD patients with and without NpsyF. Sensitivity was evaluated using t-tests comparing NFS in ON and OFF conditions.Results: 128 PD patients and 131controls were included. PCA revealed two components with a main one explaining 35-42 % of the variance. Internal consistency was good (alpha >.85 in ON and OFF). The NFS showed good specificity and sensitivity.Conclusion: This study confirms that the NFS is a reliable tool to evaluate NpsyF in PD patients in an acute setting
Features of Invasive Aspergillosis Caused by Aspergillus flavus , France, 2012–2018
No full textInternational audienceInvasive aspergillosis (IA) caused by Aspergillus flavus remains poorly described. We retrospectively analyzed 54 cases of IA caused by A. flavus reported in France during 2012–2018. Among cases, underlying IA risk factors were malignancy, solid organ transplantation, and diabetes. Most (87%, 47/54) infections were localized, of which 33 were pleuropulmonary and 13 were ear-nose-throat (ENT) infection sites. Malignancy (70% [23/33]) and solid organ transplantation (21% [7/33]) were the main risk factors in localized pulmonary infections, and diabetes mellitus was associated with localized ENT involvement (61.5%, [8/13]). Fungal co-infections were frequent in pulmonary (36%, 12/33) but not ENT IA (0 cases). Antifungal monotherapy was prescribed in 45/50 (90%) cases, mainly voriconazole (67%, 30/45). All-cause 30-day case-fatality rates were 39.2% and 90-day rates were 47.1%, and rates varied according to risk factor, IA site, and fungal co-infections. Clinicians should remain vigilant for A. flavus and consider it in the differential diagnosis for IA
Adjunctive corticosteroids in non-AIDS patients with severe Pneumocystis jirovecii pneumonia (PIC): a multicentre, double-blind, randomised controlled trial
No full textInternational audienceBackground: Pneumocystis jirovecii pneumonia in HIV-negative immunocompromised patients has a hospital mortality rate of 30-50%. Adjunctive corticosteroids improve outcomes of P jirovecii pneumonia in HIV-positive patients. The aim of this trial was to assess the effects of early adjunctive corticosteroid therapy for 21 days in HIV-negative patients with P jirovecii pneumonia responsible for acute hypoxaemia respiratory failure.Methods: This multicentre, double-blind, randomised controlled trial was conducted at 27 hospitals in France. We included patients with acute respiratory failure, aged 18 years or older with mild-to-severe hypoxaemia, microbiological documentation of P jirovecii pneumonia, and anti-Pneumocystis treatment duration of less than 7 days. Patients were randomly assigned (1:1) to the corticosteroid group (adjunctive corticosteroid therapy of methylprednisolone intravenously, 30 mg twice per day from days 1 to 5, 30 mg once per day from days 6 to 10, and 20 mg once per day until day 21) or placebo group (2 mL or 3 mL syringes of isotonic saline intravenously) using a web-based system. Permutation blocks of fixed size unknown to the local investigators were used. Stratification factors were centre, long-term corticosteroid treatment started more than 1 month before enrolling in the trial, underlying disease (malignancy vs other), and oxygen needs at randomisation (<6 vs ≥6 L per min). The primary outcome was all-cause 28-day mortality defined as the proportion of patients who died within 28 days, analysed in the intention-to-treat (ITT) population. This trial was registered on ClinicalTrials.gov, NCT02944045 (closed).Findings: From Feb 23, 2017, to Feb 23, 2024, 466 patients with acute respiratory failure were assessed for eligibility. Of those, 240 were excluded and 226 patients were randomly assigned (114 assigned to the placebo group and 112 assigned to the corticosteroid group). The ITT population included 111 patients in the placebo group and 107 in the corticosteroid group. Median age was 67 years (IQR 59-73). 126 (58%) patients were male and 92 (42%) were female. Nearly all patients (208 [95%]) were in the ICU or intermediate care at randomisation. The median time from P jirovecii pneumonia diagnosis to corticosteroid therapy initiation was 3 days (IQR 2-5). Patients received trial treatment for 13 days (range 7-20). All-cause 28-day mortality occurred in 36 (32·4%) patients in the placebo group versus 23 (21·5%) in the corticosteroid group (mean difference 10·9% [95% CI -0·9 to 22·5]; p=0·069). There were no significant differences in safety outcomes between groups, especially for all secondary infections (38 [34·2%; 95% CI 25·4 to 43·1] patients in the placebo group vs 25 [23·4%; 15·3 to 31·4] in the corticosteroid group) or insulin needs (25 [22·5%; 15·1 to 31·4] vs 33 [30·8%; 22·3 to 40·5]).Interpretation: In immunocompromised HIV-negative patients with P jirovecii pneumonia, adjunctive corticosteroid treatment did not significantly decrease 28-day mortality.Funding: French Ministry of Health
Group-wise deep brain normalization pipeline optimization for speed and quality
No full textInternational audienceAnatomical population templates enable population-wide studies, by providing a common reference ground for normalizing patient-specific observations and enabling statistical analysis. This approach is used for the analysis of clinical data from patients implanted with Deep Brain Stimulation (DBS) systems with the goal to further explore and refine the mechanisms of action of stimulation depending on the disease