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Human PrP E219K: a new and promising substrate for robust RT-QuIC amplification of human prions with potential for strain discrimination
No full textInternational audienceMammalian prion diseases are fatal neurodegenerative disorders caused by the conformational conversion of the host-encoded prion protein (PrP) into a pathogenic, misfolded isoform, known as PrP Sc . Definitive diagnosis currently relies on post-mortem histopathological examination of the central nervous system. Among emerging diagnostic tools, in vitro amplification techniques such as Real-Time Quaking-Induced Conversion (RT-QuIC) have demonstrated high sensitivity, specificity, and speed, although certain prion strains remain difficult to amplify. Here, we evaluate a novel recombinant substrate for RT-QuIC: human PrP E219K, a naturally occurring polymorphism in which lysine substitutes glutamic acid at codon 219. Using this substrate, we successfully amplified six sporadic Creutzfeldt-Jakob disease (sCJD) strains and the variant Creutzfeldt-Jakob disease (vCJD) strain from both human PrP transgenic (tg650) mouse brain homogenates and directly from patients’ samples. In tg650-passaged prions, amplification reactions were initiated between 3 and 36 hours for sCJD prions and between 11 and 31 hours for vCJD prions, covering a 5- to 7-log dilution range depending on the strain. For patient brain homogenates, amplification reactions started between 0 and 27 hours for sCJDs and between 17 and 35 hours for vCJD, covering a 5- to 8-log dilution range depending on the strain. VV1 prions from a patient sample could only be amplified over a 2-log dilution range. Moreover, lag times of amplification reactions enabled reliable discrimination between vCJD and all tested sCJD subtypes. These findings represent a significant advance toward ante-mortem typing of human prion diseases. IMPORTANCE Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder within the prion disease family. Definitive diagnosis and strain typing currently require post-mortem analyses. In this study, we demonstrate that the human PrP E219K variant serves as an effective substrate for prion in vitro amplification using real-time quaking-induced conversion. This substrate enables (i) rapid and robust amplification of the most common human prion strains and (ii) clear and direct discrimination between variant CJD and all tested sporadic CJD subtypes, based on statistical analyses of lag times of the prion amplification reactions. These findings represent a significant step toward the development of ante-mortem tools for prion strain typing in affected patients
Thrombectomy With Low ASPECTS: The Roles of Infarct Volume and Postacute Neurological Status
No full textInternational audienceBACKGROUND: Recent randomized trials demonstrated the beneficial effect of endovascular therapy in patients with low Alberta Stroke Program Early CT Score. Despite large follow-up infarct volumes, a significantly increased rate of good functional outcomes was observed, challenging the role of infarct volume as a predictive imaging marker. This analysis evaluates the extent to which the effects of endovascular thrombectomy on functional outcomes are explained by (1) follow-up infarct volume and (2) early neurological status in patients with stroke with low Alberta Stroke Program Early CT Score. METHODS: TENSION (Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time Window) was a randomized trial conducted from February 2018 to January 2023 across 41 stroke centers. Two hundred fifty-three patients with ischemic stroke due to anterior circulation large vessel occlusion and Alberta Stroke Program Early CT Score of 3 to 5 were randomized to endovascular thrombectomy plus medical treatment or medical treatment alone. All patients with the availability of relevant data points were included in this secondary as-treated analysis. The primary outcome was the 90-day modified Rankin Scale score. Confounder-adjusted mediation analysis was performed to quantify the proportion of the treatment effect on a 90-day modified Rankin Scale score explained by (1) 24-hour follow-up infarct volume and (2) 24-hour National Institutes of Health Stroke Scale scores. RESULTS: One hundred eighty-eight patients were included; thereof, 87 (46%) were female patients. Median age was 72 (interquartile range, 63–79) years. The endovascular thrombectomy cohort had a 20.5 (95% CI, 8.3–33.7) percentage points higher probability of achieving independent ambulation (modified Rankin Scale, 0–3) and a 24.2 (95% CI, 13.4–35.8) percentage points lower mortality at 90 days compared with medical treatment alone. The reduction in 24-hour follow-up infarct volume explained 30% of the treatment effect on functional outcomes, while the 24-hour National Institutes of Health Stroke Scale score explained 61%. CONCLUSIONS: In patients with low Alberta Stroke Program Early CT Score, infarct volume demonstrated limited explanatory power for functional outcomes compared with the early neurological status, which may more effectively reflect factors such as the involvement of specific brain regions, disruption of structural networks, and selective neuronal loss
Efficacy and safety of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy versus Roux-en-Y gastric bypass in France (SADISLEEVE): results of a randomised, open-label, superiority trial at 2 years of follow-up
No full textInternational audienceAbstract Background hPG 80 (circulating progastrin), initially recognized for its oncogenic properties due to its direct link to the Wnt signaling pathway, is secreted by cancer cells and detectable in the blood of cancer patients. The ONCOPRO centralized case-control study (NCT03787056) was designed to prospectively evaluate the diagnostic utility of hPG 80 in patients with 16 different types of cancer. Methods hPG 80 levels were measured in 421 patients with 16 newly diagnosed cancers (median age 65.6 years old) using the DxPG80.Lab kit (Biodena Care). The diagnostic performance of hPG 80 (the primary endpoint) was assessed by comparing baseline hPG 80 levels in cancer patients with those of 330 asymptomatic aged-matched healthy subjects from the general population. Results Between 2018 and 2022, a total of 506 cancer patients were enrolled in the study, with 421 assessable across 16 distinct cancer cohorts. hPG 80 concentrations were significantly higher in cancer patients compared to the healthy population (median 3.8 [IQR: 1.0-11.1] vs. 1.9 [IQR: 0.6–4.2] pM, P 7.73 pM in patients aged > 58 years old) and hepatocellular carcinoma HCC (ROC AUC 0.75, 95% CI [0.66-083]; specificity = 88% for hPG 80 > 7.73 pM in patients aged > 58 years old). Conclusions This large prospective study confirms that cancer patients have significantly higher hPG 80 blood concentration compared to the healthy population. Incorporating this straightforward ELISA assay into screening programs is warranted. Trial registration NCT03787056
Neoadjuvant immune checkpoint inhibitors for patients with resectable stage III/IV melanoma: A nationwide real-life study in France (NEOMEL)
No full textInternational audienceDespite the clear therapeutic benefits of neoadjuvant treatment (NT) with immune checkpoint inhibitors (ICIs) in clinical trials, the efficacy of NT ICIs (NT-ICI) and the optimal regimen for patients (pts) with resectable metastatic melanoma (RMM) remain to be confirmed in real life. Objective To assess the efficacy and safety of NT-ICI among pts with RMM in real life. Methods NEOMEL is a French retrospective multicentric cohort study. Dermato-oncologists from the French group of skin cancers included pts treated with NT-ICI for RMM (AJCC 8th stage III or IV) between July 2016 and April 2024. Pts were treated either with NT anti-programmed cell death protein-1 (anti-PD-1) monotherapy or with the combination of anti–cytotoxic T lymphocyte-associated protein-4 (anti-CTLA-4) plus anti-PD-1 (1-mg/kg ipilimumab (IPI) and 3-mg/kg nivolumab (NIVO); or 3-mg/kg IPI and 1-mg/kg NIVO). The primary endpoint was the pathological complete response (pCR) rate. The secondary endpoints were pathological response according to the International Neoadjuvant Melanoma Consortium criteria, radiological response, the occurrence of immune-related adverse events (irAEs) including those of ≥ grade 3 and outcomes with recurrence-free survivals (RFS) and event-free survivals (EFS). Results Among the 174 included pts, 149 (86%) underwent surgery. NT-ICI achieved a high pCR rate of 43% (95% CI, 34.9-51.3), including 44.7% (95% CI, 35.4–54.3) with NT-anti-PD-1 and 37.1% (95% CI, 21.5–55.1) with NT-IPI-NIVO (p=0.427). The major (complete + near-complete) pathological response rate was 53.2%. Radiological responses were observed in 49.9% of pts, including 12 complete responses (12.1%), of which 91.7% (n=11) corresponded to pCR. Severe immune-related adverse events (irAEs) occurred more frequently with NT-IPI-NIVO (24.4%) compared to NT-anti-PD-1 (3.1%) (p<0.001). The median RFS was 29.61 months (95% CI, 27.70-not reached [NR]) with significantly higher RFS in pts with pCR than no-pCR (HR, 0.218 [95% CI, 0.082–0.583], p=0.0009). The median EFS was 35.7 months 2 (95% CI, 28-NR). Conclusion In this retrospective real-life study, NT-ICI confirms its efficacy in RMM pts, achieving high pathological response rates. However, dual checkpoint inhibition with IPI-NIVO was associated with a higher risk of severe irAEs. These findings underscore the relevance of NT-ICI for RMM in clinical practice and required further confirmation
Left ventricular ejection fraction and benefit of tricuspid valve interventions – insights from the international TRIGISTRY
No full textInternational audienceAims The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across LVEF categories. Methods and results Patients with severe isolated TR from the TRIGISTRY, a multicentre international registry, were categorized based on LVEF (preserved ejection fraction [pEF]: ≥50%, mildly reduced ejection fraction [mrEF]: 41–49%, and reduced ejection fraction [rEF]: ≤40%). We assessed the impact of treatment modality and procedural success (mild‐to‐moderate or lower residual TR) on 2‐year survival within each LVEF category. Among 2384 patients, 1383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery ( p < 0.0005) and TTVI ( p < 0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF ( p = 0.28 for both), nor in those with rEF ( p = 0.76 and p = 0.22, respectively). Similar results were obtained when surgical and transcatheter interventions were grouped ( p < 0.0001, p = 0.17 and p = 0.29 in patients with pEF, mrEF and rEF, respectively). Patients with residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories ( p = 0.47, p = 0.33 and p = 0.008 in pEF, mrEF and rEF, respectively). Conclusions Transcatheter tricuspid valve intervention, whether surgical or transcatheter‐based, was associated with improved survival in patients with pEF but not in those with mrEF or rEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering TTVI in individuals with rEF
Pharmacokinetics of Subcutaneous and Intravenous Ceftriaxone in an Older Population: The PhASAge Study.
No full textInternational audienceBackground: Ceftriaxone is frequently administered subcutaneously in France, especially in older patients, although this practice is currently off-label. This work aims to describe the pharmacokinetics (PK) and pharmacodynamics (PD) and tolerance of ceftriaxone administered by intravenous and subcutaneous routes in older patients.Methods: Patients aged ≥65 years receiving intravenous or subcutaneous ceftriaxone 1 g every 24 hours were included. Steady-state plasma concentrations of ceftriaxone were measured. Based on intravenous and subcutaneous ceftriaxone concentrations and 24-hour area under the concentration-time curve (AUC), a population PK model was developed for probability of target attainment (PTA) analysis. Local and systemic adverse events (AEs) were collected.Results: Data from 47 patients (24 in subcutaneous and 23 in intravenous groups) were analyzed. No between-group difference was observed in demographic and biological characteristics, ceftriaxone trough concentrations, or AUC. Bioavailability of subcutaneous ceftriaxone was estimated at 99% by population modeling. The PTA associated with subcutaneous administration were similar to or slightly better than that of the intravenous route. A dosing regimen of 1 or 2 g every 24 hours was associated with acceptable PTA and a low risk of overexposure in patients with normal or moderately altered renal function. Tolerance was assessed on 149 infusions (67 intravenous and 82 subcutaneous). One local AE (1.5%) was reported in the intravenous group versus 11 local AEs (mainly edema) in the subcutaneous group (13%), all transient and nonsevere.Conclusions: Subcutaneous administration of ceftriaxone was associated with PK/PD and dosage requirements comparable to those of intravenous administration, supporting the use of subcutaneous ceftriaxone in older patients
Fusing Echocardiography Images and Medical Records for Continuous Patient Stratification
No full textInternational audienceDeep learning enables automatic and robust extraction of cardiac function descriptors from echocardiographic sequences, such as ejection fraction (EF) or strain. These descriptors provide fine-grained information that physicians consider, in conjunction with more global variables from the clinical record, to assess patients’ condition. Drawing on novel Transformer models applied to tabular data, we propose a method that considers all descriptors extracted from medical records and echocardiograms to learn the representation of a cardiovascular pathology with a difficult-to-characterize continuum, namely hypertension. Our method first projects each variable into its own representation space using modality-specific approaches. These standardized representations of multimodal data are then fed to a Transformer encoder, which learns to merge them into a comprehensive representation of the patient through the task of predicting a clinical rating. This stratification task is formulated as an ordinal classification to enforce a pathological continuum in the representation space. We observe the major trends along this continuum on a cohort of 239 hypertensive patients, providing unprecedented details in the description of hypertension’s impact on various cardiac function descriptors. Our analysis shows that: 1) the XTab foundation model’s architecture allows to reach high performance (96.8% AUROC) even with limited data (less than 200 training samples); 2) stratification across the population is reproducible between trainings [within 5.7% of mean absolute error (MAE)]; and 3) patterns emerge in descriptors, some of which align with established physiological knowledge about hypertension, while others could pave the way for a more comprehensive understanding of this pathology. The code is available at https://github.com/creatis-myriad/didacti
Beyond overweight, visceral adiposity is associated with estimation of cardiovascular risk in patients living with type 1 diabetes: findings from the SFDT1 cohort
No full textConflicts of interests: EBP reports receiving lecture honorariums from Astra Zeneca and Sanofi, and has been an employee of Boehringer Ingelheim since February 2024International audienceIntroduction & Objectives As in the general population, people living with type 1 diabetes (PWT1D) are faced with overweight and obesity, which contribute to cardiovascular (CV) risk. However, the role of visceral adiposity, due to its adverse metabolic profile, should also be addressed in PWT1D. We aimed to assess the 10-year CV risk of PWT1D according to body mass index (BMI) and waist-to-height ratio (WHtR), a parameter for estimating visceral adiposity. MethodsIn this cross-sectional study, PWT1D in primary CV prevention from the SFDT1 cohort were categorized by BMI status, either normal (18.5-24.9 kg/m 2 ) or overweight/obesity (≥ 25 kg/m 2 ), and by WHtR according to the validated threshold of 0.5. The 10-year CV risk was estimated using the Steno Type 1 Risk Engine and classified into three categories: low (< 10%), intermediate (10-20%) and high (> 20%). The distribution of CV risk was assessed using density plots. In multivariable analysis, the association between BMI, WHtR, and high estimated 10-year CV risk was studied using spline regression models with sex stratification. Thresholds were determined by the Receiver Operating Characteristic (ROC) curve. ResultsThe study included 1,482 patients; 49.9% had a normal BMI, and 50.1% a BMI ≥ 25 kg/m 2 . The proportion of patients with high CV risk was higher in PWT1D with overweight/obesity (12% vs. 7%) and in those with WHtR ≥ 0.5 (13% vs. 4%). BMI was significantly associated with high CV risk in men (p = 0.001) but a non-significant trend was found in women (p = 0.053). WHtR was significantly associated with high CV risk in both men (p < 0.001) and women (p = 0.046). The BMI threshold associated with high CV risk was 24.9 kg/m 2 for men, and the WHtR threshold was 0.5 for both men and women. ConclusionIn PWT1D in condition of primary CV prevention, visceral adiposity, assessed by WHtR, is a more robust marker of estimated 10-year CV risk than overweight/obesity status in both men and women.</div
