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Reanalysis of unsolved prenatal exome sequencing for structural defects: diagnostic yield and contribution of postnatal/postmortem features
No full textInternational audienceIn 30-40% of fetuses with structural defects, the causal variant remains undiagnosed after karyotype, chromosomal microarray, and exome sequencing. This study presents the results of a reanalysis of unsolved prenatal ES (pES) cases and investigates how postnatal/postmortem phenotyping contributes to identifying relevant variants. pES data was prospectively reanalyzed for unsolved cases enrolled in the AnDDI-Prénatome cohort study. Postnatal/postmortem data were included with prenatal features using Human Phenotype Ontology terms up to 3 years after pES. The reanalysis involved updating bioinformatic processing and querying raw data using a GREP query. We reanalyzed 58/94 (62%) unsolved pES cases, including 8 variants of unknown significance. Data for clinical examination at birth was available for all live newborns, and postmortem examination was available in 12 terminated fetuses. Additional features were identified at birth in 27/58 cases (44%): 9 terminated fetuses, 2 stillbirths, and 16 live newborns. One diagnosis (SNAPC4) was obtained through a periodic query following recent associations with human disease, and without additional clinical data. Three additional VUS were identified through reanalysis with the addition of new clinical features, illustrating the limited contribution of updated postnatal/postmortem phenotyping in identifying relevant variants after negative pES. In conclusion, the benefit of prospective reanalysis of unsolved pES is limited, even over time. Postnatal genome sequencing may be a more appropriate option than reanalysis with postnatal/postmortem phenotyping to establish a causal diagnosis
Effectiveness of the ARTHE-e app for exercise adherence in people with knee osteoarthritis: protocol for a randomised controlled trial
No full textInternational audienceIntroduction Osteoarthritis, the most prevalent joint disease, poses a significant challenge due to its progressive nature and impact on the whole joint and periarticular structures. Although exercise is crucial for symptom improvement and progression slowdown, adherence to exercise programmes remains a concern. In response, we have developed a novel smartphone-based m-health application, ARTH-e, specifically designed to enhance adherence to adapted physical activity in individuals with knee osteoarthritis. We aim to perform a prospective,multicenter, randomized (1:1) controlled trial to compare the effectiveness of m-health application ARTH-e (intervention group) with standard care (control group) on exercise adherence in people with knee osteoarthritis. We hypothesise that adherence will be stronger among users of the ARTH-e application. Methods and analysis We will recruit 120 participants from 5 hospitals in France. The participants will undergo a comprehensive assessment, including the Exercise Adherence Rating Scale (EARS) at 2, 4 and 6 months, Knee Injury and Osteoarthritis Outcome Score, Evaluation of the Perception of Physical Activity, Tampa Scale of Kinesiophobia, European Quality of Life 5 Dimensions and 3 Lines and a Visual Analogue Scale rating of pain at baseline and 6 months. Adherence will be monitored using a connected bracelet. The intervention group will use the ARTH-e application for 6 months, while the control group will follow stay-active advice from their physician. The primary outcome will be the difference between groups in the evolution of the EARS score at 6 months. Ethics and dissemination The study has been approved by the medical ethics committee (Comité de Protection des Personnes) XI of Saint Germain en Laye (27 March 2024) (ID for ethics approval: 24.00330.000201). Eligible individuals will sign the informed consent form before enrolment. Study results will be reported in peer-reviewed publications and at scientific meetings. Trial registration number NCT06359171
Development and Stability of a New Brain Phantom for Leachables Screening from Deep Brain Stimulations Probes
No full textInternational audienceAbstract Implantable medical devices must meet biocompatibility requirements before clinical use, making the profiling of extractables and leachables crucial for assessing risks. Although guidelines outline methods for identifying extractables, they lack guidance on the monitoring of leachables. This study evaluates the stability of a brain phantom stored at 37 °C for 180 days for leachables monitoring. White matter (WM) and gray matter (GM) components, creating an emulsion‐gel with cholesterol, agar, and carboxymethylcellulose, are separated. Homogeneity is assessed using polydispersity index (PDI), and stability is investigated using Young's modulus (YM), rheological behavior, and apparent diffusion coefficient of water (ADCs) immediately after preparation and after 180 days of storage. PDI values are 0.258 ± 0.009 for WM and 0.362 ± 0.008 for GM. YM values are 2.32 ± 0.14 kPa for WM and 1.11 ± 0.11 kPa for GM. Dynamic viscosities are 16.62 ± 6.36 kPa s for WM and 5.99 ± 2.79 kPa s for GM at 0.1 rad s −1 . ADCs are 1130 ± 64 µm 2 s −1 for WM and 1449 ± 34 µm 2 s −1 for GM. All parameters remain within physiological range during 180 days at 37 °C. Comparison with clinical data is necessary to validate this medium for leachable studies
Outcomes of patients with relapsed or refractory primary mediastinal B‐cell lymphoma treated with anti‐CD19 CAR‐T cells: CARTHYM, a study from the French national DESCAR‐T registry
No full textInternational audiencePrimary mediastinal B-cell lymphoma (PMBL) is often cured with dose-dense anthracycline-based regimens but the prognosis at relapse or progression remains poor. While anti-CD19 CAR-T cell therapy has dramatically improved outcomes in relapsed or refractory large B-cell lymphoma, far less is known about their efficacy in PMBL. Using the systematic record of all patients treated with CAR-T cells prospectively included in the DESCAR-T registry in France, along with centrally reviewed positonemission tomography (PET) imaging, we describe the outcomes and key determinants of treatment success in PMBL patients treated over a 6-year period. Among 82 patients infused in the registry we observed a best complete response (CR) rate, 2-year progression-free survival (PFS), and 2-year overall survival (OS) of 68.1%, 57.4%, and 73.8%, respectively. Outcomes were even better for the 62 patients infused with axicabtagene ciloleucel, with best CR rate, 2-year PFS, and 2-year OS reaching 74.5%, 70.4%, and 86.9%, respectively. Achieving a Deauville score of 1-4 or a ΔSUVmax reduction of more than 24% at the 1-month evaluation was associated with excellent outcomes, whereas increased total metabolic tumor volume baseline PET increased the risk of treatment failure. Surprisingly, neither the response to bridging therapy nor the type of bridging therapy (chemotherapy versus immune checkpoint inhibitors) were associated with long-term outcomes. In conclusion, this study confirms that anti-CD19 CAR-T cells as a valid standard-of-care for relapsed and refractory PMBL and highlights key determinants of treatment success
Physicochemical Properties and Bioreactivity of Sub‐10 μm Geogenic Particles: Comparison of Volcanic Ash and Desert Dust
No full textInternational audienceExposure to ambient particulate matter (PM) with an aerodynamic diameter of <10 μm (PM 10 ) is a well-established health hazard. There is increasing evidence that geogenic (Earth-derived) particles can induce adverse biological effects upon inhalation, though there is high variability in particle bioreactivity that is associated with particle source and physicochemical properties. In this study, we investigated physicochemical properties and biological reactivity of volcanic ash from the April 2021 eruption of La Soufrière volcano, St. Vincent, and two desert dust samples: a standardized test dust from Arizona and an aeolian Gobi Desert dust sampled in China. We determined particle size, morphology, mineralogy, surface texture and chemistry in sub-10 μm material to investigate associations between particle physicochemical properties and observed bioreactivity. We assessed cellular responses (cytotoxic and pro-inflammatory effects) to acute particle exposures (24 hr) in monocultures at the air-liquid interface using two types of cells of the human airways: BEAS-2B bronchial epithelial cells and A549 alveolar type II epithelial cells. In acellular assays, we also assessed particle oxidative potential and the presence of microorganisms. The results showed that volcanic ash and desert dust exhibit intrinsically different particle morphology, surface textures and chemistry, and variable mineralogical content. We found that Gobi Desert dust is more bioreactive than freshly erupted volcanic ash and Arizona test dust, which is possibly linked to the presence of microorganisms (bacteria) and/or nanoscale elongated silicate minerals (potentially clay such as illite or vermiculite) on particle surfaces
Home noninvasive ventilation in pediatric patients: Does one size fit all?
No full textInternational audienceBackground: A French national survey showed that 1447 children were treated with long-term continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) in 2019. Data about the ventilatory settings for children are scarce. The aim of the study was to report the CPAP/NIV settings from the survey according to the patients’ age and disorders.Methods: CPAP and NIV settings were compared between 5 age groups (<1, 1–5, 6–11, 12–17 and ≥ 18 years), and 6 disease categories (upper airway disorders; neuromuscular disease, NMD; disorder of the central nervous system; cardiorespiratory disorder; congenital bone disease, CBD; and other).Results: Age correlated positively with constant CPAP pressure (r = 0.364, p < 0.0001), and negatively with CPAP adherence (r = −0.173, p < 0.0001). Mean age at CPAP initiation, CPAP pressures and adherence did not differ between disorders. Regarding NIV, mean inspiratory positive airway pressure (IPAP) increased with age (r = 0.152, p = 0.0001), whereas respiratory rate (RR; r = −0.593, p < 0.0001) and adherence to NIV decreased with age (r = −0.154, p = 0.0002). NIV settings were quite similar between disease categories, with the CBD group having the highest IPAP, and NMD group having the lowest expiratory positive airway pressure and RR. Adherence tended to be higher with NIV than CPAP.Conclusions: CPAP pressure and IPAP increase with age, while settings seem quite similar between diseases. Even if our study provides some information about CPAP/NIV settings, they should always be individually adapted according to the severity of the diseas
Comparison of two strategies of glucocorticoid withdrawal in patients with rheumatoid arthritis in low disease activity (STAR): a randomised, placebo-controlled, double-blind trial
No full textInternational audienceObjectives To compare two strategies—a hydrocortisone replacement strategy and a prednisone tapering strategy—for their success in glucocorticoid discontinuation in patients with rheumatoid arthritis (RA) with low disease activity (LDA). Methods The Strategies for glucocorticoid TApering in Rheumatoid arthritis (STAR) study was a double-blind, double-placebo randomised controlled trial including patients with RA receiving a stable dose of glucocorticoid 5 mg/day for ≥3 months and were in LDA for ≥3 months. Patients were randomly assigned in a 1:1 ratio to either replace prednisone with 20 mg/day of hydrocortisone for 3 months, then reduce to 10 mg/day for 3 months before discontinuation or to taper prednisone by 1 mg/day every month until complete discontinuation, contingent on maintaining LDA. The primary outcome was the percentage of patients achieving glucocorticoid discontinuation at 12 months. Other secondary outcomes were proportion of flares, need for additional glucocorticoid use, disease activity, patient-reported outcomes and the results of adrenocorticotropic hormone (ACTH) stimulation tests. Results Of the 102 patients randomised in the trial (mean age 62.4 years, 70.6% females), 53 had hydrocortisone replacement and 49 tapered prednisone. At 12 months, 29 patients (55%) in the hydrocortisone replacement group and 23 patients (47%) in the prednisone tapering group achieved glucocorticoid discontinuation (p=0.4). No difference was observed between groups in the secondary outcomes. No cases of acute adrenal insufficiency were observed; however, 17 patients still had an abnormal ACTH stimulation test at 12 months, with no differences between arms. Conclusion A hydrocortisone replacement strategy was not superior to a prednisone tapering strategy for achieving glucocorticoid discontinuation success in patients with RA in LDA. Trial registration number NCT02997605
Neuropsychiatric drug development: Perspectives on the current landscape, opportunities and potential future directions
No full textInternational audienc
The R-Vessel-X Project
No full textInternational audience1) Objectives: This technical report presents a synthetic summary and the principal outcomes of the project R-Vessel-X (“Robust vascular network extraction and understanding within hepatic biomedical images”) funded by the French Agence Nationale de la Recherche, and developed between 2019 and 2023. 2) Material and methods: We used datasets and tools publicly available such as IRCAD, Bullitt or VascuSynth toobtain real or synthetic angiographic images. The main contributions lie in the field of 3D angiographic image analysis: filtering, segmentation, modeling and simulation, with a specific focus on the liver. 3) Results: We paid a particular attention to open-source software diffusion of the developed methods, by means of 3D Slicer plugins for the liver anatomy segmentation (SlicerRVXLiverSegmentation) and vesselness filtering (Slicer-RVXVesselnessFilters), and an online demo for the generation of synthetic and realistic vessels in 2D and 3D (OpenCCO). 4) Conclusion: The R-Vessel-X project provided extensive research outcomes, covering various topics related to 3D angiographic image analysis, such as filtering, segmentation, modeling and simulation. We also developed open-source and free softwares so that the research communities in biomedical engineering can use these results in their future research
Interlaboratory assays from the fungal PCR Initiative and the Modimucor Study Group to improve qPCR detection of Mucorales DNA in serum: one more step toward standardization
No full textInternational audienceThe aim of this study was to identify parameters influencing DNA extraction and PCR amplification efficiencies in an attempt to standardize Mucorales qPCR. The Fungal PCR Initiative Mucorales Laboratory Working Group distributed two panels of simulated samples to 26 laboratories: Panel A (six sera spiked with Mucorales DNA and one negative control serum) and Panel B (six Mucorales DNA extracts). Panel A underwent DNA extraction in each laboratory according to the local procedure and were sent to a central laboratory for testing using three different qPCR techniques: one in-house qPCR assay and two commercial assays (MucorGenius and Fungiplex). Panel B DNA extracts were PCR amplified in each laboratory using local procedures: nine in-house qPCR assays and two commercial kits (MucorGenius and MycoGENIE). All data were compiled and anonymously analyzed at the central laboratory. For Panel A, a total of six different automated platforms and five manual extraction methods were used. Positive rates were 64%, 70%, and 89%, for the MucorGenius, Fungiplex, and the in-house qPCR assay, respectively. Using a large volume of serum for DNA extraction provided the highest analytical sensitivity (82.5% for 1 mL compared with 62.7% for smaller volumes, P < 0.01). For Panel B, five in-house qPCR assays and two commercial kits had >78% positivity. Using larger PCR input volumes (≥7 µL) was associated with the highest sensitivity at 95.5% compared to 58.3% when lower input volumes were used ( P < 0.01). Using larger sample volumes for nucleic acid extraction and DNA template volumes for PCR amplification significantly improves the performance of Mucorales qPCR when testing serum. IMPORTANCE Mucormycosis is a life-threatening mold infection affecting immunosuppressed patients but also other patients with diabetes or trauma. Better survival is linked to shorter delays in diagnosis and treatment initiation. Detection of Mucorales-free DNA in serum or plasma using quantitative PCR allows a prompt diagnosis and earlier treatment. Several techniques and protocols of quantitative Mucorales PCR are used in Europe, and improving performance remains a common objective of laboratories participating in the fungal PCR Initiative Working Group. This study, which combined results from 26 laboratories in Europe, showed that the main parameters underpinning sensitivity are the preanalytical variables (volume of serum used for DNA extraction and DNA template volume), irrespective of the extraction platforms and qPCR assay/platform