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Oncogenomic profiling in infant–toddler T‐ALL identifies NKX2 family genes as drivers linked to favorable outcomes
No full textInternational audienceT‐cell acute lymphoblastic leukemia (T‐ALL) is a rare and aggressive hematological malignancy primarily affecting adolescents and young adults and is scarce in infants and toddlers under age 3. Unlike B‐ALL, T‐ALL in this young population remains poorly characterized due to limited data and lacks evidence‐based guidelines to help clinicians determine the optimal treatment approach. In this study, we conducted a comprehensive genetic analysis of infant/toddler T‐ALL cases from a French national cohort, utilizing high‐throughput targeted sequencing, optical genome mapping, and RNA sequencing. Genetic analysis revealed the absence of TLX1/3 dysregulation. Instead, we identified a significant prevalence of NKX2 rearrangements ( n = 9, 33%), co‐occurring with MYB alterations ( n = 5/9) or chromothripsis‐like events ( n = 3/9). Additional findings included TAL1/‐like anomalies (30%), STAG2::LMO2 (15%), ETS rearrangements (15%), and rarely, KMT2A rearrangements (7%). Comparative analyses with 245 patients aged 3–18 years, enrolled in the pediatric FRALLE2000T French protocol, underscored the distinct clinical and genetic profiles of infants/toddlers. Despite presenting with higher rates of hyperleukocytosis and slower responses to treatment, they demonstrated comparable survival outcomes to older pediatric patients, with a 5‐year overall survival (OS) rate of 75.4% (95% confidence interval [CI]: 60.0%–94.8%) versus 75.2% (95% CI: 69.8%–81.1%), p = 0.86. Notably, alterations in NKX2 , KMT2A , and STAG2::LMO2 delineated oncogenic subgroups exhibiting a remarkable 100% OS rate, while patients with TAL1 or ETS dysregulation experienced less favorable outcomes. This was further supported by analyses of data from the COG AALL0434 trial, enhancing our understanding of T‐ALL in infants/toddlers. Large‐scale collaborative studies remain essential to confirm these findings and refine treatment strategies
REM sleep microstructure alterations in REM sleep behavior disorder: beyond muscle tone
No full textInternational audienceStudy objectives: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by dream enactment behaviors and loss of atonia during REM sleep. It is considered a prodromal stage of alpha-synucleinopathies and may result from dysfunction of brainstem structures regulating muscle tone in REM sleep. Whether other REM sleep features are affected remains unclear. Here, we investigated alterations in REM sleep microstructure, including phasic REM sleep, sawtooth waves (STW), and non-REM/REM transitions, in iRBD and RBD associated with Parkinson's disease (PD + RBD). Methods: We retrospectively included 20 patients with iRBD (85% male, 66.5[63-68]years), 20 patients with PD + RBD (75% male, 62.5[57.5-65]years) and 20 controls (75% male, 67[61-70]years). REM sleep without atonia (RSWA), bursts of REMs and STW bursts were manually scored. Phasic REM sleep proportion (derived from REMs), STW density/duration/frequency and the duration of NREM/REM transitions were compared between groups with a general linear mixed-effects model. Results: Phasic REM sleep proportion was higher in the iRBD group (26.5[21-33]%) than in control (16.4[12.5-22.3]%, p-corrected = 0.005) and PD + RBD (17.6[13.9-21.7]%, p-corrected = 0.005) ones. Non-REM/REM transitions showed a duration gradient, increasing from controls (119.0[58.5-186.1]sec) to iRBD (212.1[68.5-391.4]sec, p-corrected = 0.0038) and PD + RBD (375.8[217.6-514.6]sec, p-corrected<0.001) patients. STW density and duration were reduced in the PD + RBD group (1.33[1.1-1.54]/min; 2.13[1.70-2.69]sec) vs controls (1.74[1.52-2.05]/min, p-corrected = 0.005; 2.98[2.18-4.11], p-corrected<0.001), whereas altered STW spectral content was observed in both patient’s groups with a power shift toward higher frequencies (both p<001 vs controls). Conclusions: These results reinforce the hypothesis that REM sleep dysregulation in RBD extends to REM-specific electrophysiological features beyond loss of muscle atonia and dream enactments
Clinical Presentation and Mid-Term Results of Mitral Valve Surgery for Calcified Mitral Valve Disease - The MITRACURE registry
No full textInternational audienceBackgroundCalcified mitral valve disease (CMVD) is an increasingly recognized condition associated with specific management challenges. MITRACURE, a large multicenter observational registry conducted in France and Canada, provides real-world insights into the characteristics and outcomes of patients with CMVD undergoing MV surgery.MethodsAmong the 3,522 patients included in MITRACURE, patients identified with CMVD were matched 4:1 for age, sex, and concomitant procedures with patients with myxomatous MV disease.ResultsSixty patients (2%) with CMVD were matched to 240 with myxomatous MV disease. Compared to the myxomatous cohort, CMVD patients had a greater burden of cardiovascular risk-factors, more comorbidities, and a more advanced presentation, with 70% vs. 52% in NYHA class III–IV (P=0.01). In-hospital mortality and major complication rates (composite of death, cardiogenic shock/low cardiac output requiring inotropes, acute renal failure requiring dialysis, and stroke or transient ischemic attack) were significantly higher in CMVD than myxomatous patients (20% vs. 4%, and 38% vs. 20%, both P<0.01). Median EuroSCORE II was slightly higher in CMVD patients (3.5 [IQR 2.2-5.7]) compared with those with myxomatous disease (2.6 [IQR 1.5-4.2], P<0.01). However, the observed mortality in the CMVD group was three to four times higher than predicted, whereas in the myxomatous group it was consistent with predicted values.ConclusionCMVD defines a high-risk surgical population with substantial baseline cardiovascular morbidity and markedly elevated postoperative mortality and complication rates that were substantially underestimated by EuroSCORE II emphasizing the need for refined risk prediction models and individualized management strategies in this subset of patients
Opportunistic CT-based osteoporosis screening of the hip: a systematic review of diagnostic accuracy
No full textInternational audienceIntroductionOsteoporosis is a major public health concern characterized by diminished bone mass and an increased fracture risk, yet its timely diagnosis remains challenging due to underutilization of Dual-energy X-ray Absorptiometry (DXA). Opportunistic screening using Computed Tomography (CT) images obtained for other indications offers a promising alternative for identifying patients at risk of fractures. This systematic review aims to evaluate the diagnostic accuracy of opportunistic osteoporosis screening using hip, pelvic, and abdominal CT scans, with a focus on measurements at the proximal femur.Materials and methodsA systematic review was conducted to evaluate the use of opportunistic CT imaging of the hip for osteoporosis screening, following a search of PubMed, EMBASE, and MEDLINE databases up to January 2024 using PRISMA guidelines. All studies evaluating the diagnostic accuracy of CTs including the hip to diagnose osteopenia/osteoporosis were included. The outcomes assessed were: the correlation between CT-derived Hounsfield Units (HU) and DXA-derived Bone Mineral Density (BMD), and the diagnostic accuracy of CT-derived metrics to diagnose osteopenia/osteoporosis.ResultsThe systematic review included 16 studies with 6,772 patients (mean age 43.5–81.9 years), predominantly females (73%). Correlations between CT-derived HU values and DXA-derived BMD were strong across studies, with correlation coefficients up to 0.947. Diagnostic performance for osteoporosis was generally superior to that for osteopenia, with AUC values up to 0.987 and variability in cut-off values (e.g., 54–425 HU for the hip), highlighting significant differences across regions of interest and methodologies.ConclusionThis review shows opportunistic hip CT has promise for osteoporosis detection, with strong correlations to DXA and high reported accuracy. However, wide variability in HU thresholds and lack of standardized protocols mean current evidence is insufficient for clinical implementation. Until acquisition methods and calibration are standardized and validated, opportunistic CT should not replace DXA but remains a potential complementary tool
Efficacy and safety of balneotherapy in rheumatology: a systematic review and meta-analysis
No full textInternational audienceObjective The efficacy of balneotherapy in rheumatology remains unclear. We aimed to estimate its benefits and risks in rheumatology. Methods We conducted a systematic review of randomised trials assessing any European balneotherapy for a rheumatological indication in adults versus any control, on clinical outcomes. We searched PubMed, Cochrane Library, Embase and https://clinicaltrials.gov/ (up to 28 November 2023). We used the Cochrane risk of bias tool version 2, funnel plot and asymmetry tests. We used a random effects model with an inverse-variance weighting method for standardised mean difference (SMD) and risk ratio (RR). We used the Grading of Recommendations Assessment, Development and Evaluation approach for two primary outcomes, pain and quality of life (QoL) at 3 months, and two safety outcomes, withdrawal and any adverse event (AE). Results We included 29 trials in mechanical disorders, 9 in inflammatory diseases and 4 in fibromyalgia. The synthesis suggested a decrease in pain of a very low level of certainty (SMD: −0.72 (95% CI (−1.00; −0.44)), very serious risk of bias and of inconsistency, publication bias strongly suspected); an increase in QoL of a very low level of certainty (SMD: 0.56 (95% CI (0.37; 0.75)), very serious risk of bias and serious risk of inconsistency); inconclusive results regarding the risk of withdrawal (RR: 0.75 (95% CI (0.46; 1.20)), very serious risk of bias and serious risk of imprecision) and of AE (RR: 0.80 (95% CI (0.43; 1.50)), serious risk of bias and of inconsistency and very serious risk of imprecision). Conclusion The certainty of the effect of balneotherapy in rheumatology was very low. PROSPERO registration number CRD42023448206
An in-vivo approach to quantify intra-MRI head motion tracking accuracy: comparison of markerless optical tracking versus fat-navigators
No full textPurpose Head-motion tracking and correction remains a key area of research in MRI, but the lack of rigorous and standardized evaluation approaches hinders their optimization and comparison. We introduce an in-vivo framework for assessing the accuracy of intra-MRI head motion tracking, and demonstrates its effectiveness by comparing two methods based on a markerless optical system (MOS) and a fat signal navigator (FatNav). Methods Six participants underwent 3T brain MRI using a T1-weighted (T1w) pulse-sequence with a fat- navigator module. Participants performed head-rotations of 2° or 4°, each visually guided by MOS feedback around a single primary axis (X or Z). MOS and FatNav estimations were evaluated against rigid-registration of T1w-images, as gold-standard, across seven different head positions. Results The proposed approach revealed that MOS outperforms FatNav in estimating translation and large head rotations (2-4°), while FatNav shows better accuracy for subtle rotations. Image quality assessments following correction for three head rotations (rightward, upward, and leftward) confirmed that MOS outperformed FatNav in restoring image fidelity, as evidenced by the higher Structural Similarity Index, Peak Signal-to-Noise Ratio, and Focus Measure. Unlike the traditional image quality- based comparisons, the proposed framework demonstrated sensitivity to subtle improvements in FatNav performance, achieved by applying a neck mask to the fat-navigator images. Conclusion The proposed framework enabled a precise in-vivo evaluation and comparison of MOS and FatNav for head-motions estimation. It was sufficiently sensitive to reveal a slight improvement in FatNav performance when neck was masked in fat-navigator images. In parallel, the conventional image quality-based approach confirmed the superior performance of MOS in restoring T1W image quality, though it did not capture the improvement achieved by FatNav with neck-masking. Together, these two complementary approaches provide a comprehensive assessment of both head-motions estimation and correction in MRI
Interleukins 15 and 18 synergistically prime the antitumor function of natural killer cells through noncanonical activation of mTORC1
No full textInternational audienceThe multiprotein complex mTORC1 is essential for the increase in protein synthesis and bioenergetic metabolism that supports the proliferation of many cell types, including natural killer (NK) cells, which are important innate effectors of the antitumoral response. Here, we investigated the mechanisms of mTORC1 activation in NK cells by interleukin-15 (IL-15) and IL-18, which promote NK cell function and are components of a cytokine cocktail used to preactivate NK cells for cancer immunotherapy. Through genetic and pharmacological approaches, we showed that IL-15 activated mTORC1 through the PI3K/Akt/ERK pathway, whereas IL-18 signaled through the p38 effectors MK2 and MK3 in both murine and human primary NK cells. Both pathways synergized to promote NK cell proliferation and effector functions in an mTORC1-dependent manner. Moreover, both pathways operated independently of the inhibitor TSC and the activator Rheb, revealing a noncanonical mode of mTORC1 activation by cytokines. Treating mice with IL-15 and IL-18 in combination led to increased NK cell numbers and improved antitumoral activity, suggesting that this cytokine combination could be exploited to enhance NK cell potential in therapeutic settings
Glycated human serum albumin: Computational studies of drug binding through molecular docking and binding affinity prediction
No full textInternational audienceHuman serum albumin (HSA) plays a major role in the transport of endogenous and exogenous compounds such as many drugs and thus in the distribution of these essential molecules towards tissues and organs. The glycation of HSA can easily be formed either in normal or diabetic conditions, perturbating the function of this key protein. In this work, we developed a method aiming at estimating the relative binding affinities for glycated and normal HSA at the Sudlow site I which is the most sensitive to protein glycation due to Lys195 glycation. This method involves molecular docking and affinity prediction and was exemplified for several common drugs with available structure in complex with HSA and extended to three other drugs involved in the treatment of diabetes without structural data.</div
Lung virome convergence precedes hospital-acquired pneumonia in intubated critically ill patients
No full textInternational audienceHospital-acquired pneumonia (HAP) is one of the most common nosocomial infections, leading to significant morbidity and mortality in critically ill patients. HAP is previously associated with dysbiosis of the microbiota. However, the composition of the lung virome and its role in HAP pathogenesis remain unclear. Here, we longitudinally analyze the endotracheal virome in 87 critically ill patients, including 48 with HAP. Within the virome dominated by Caudoviricetes, a decrease in viral beta-diversity toward a bacteriophage-dominated signature and a distinct viral-bacterial interactome is observed 5-4 days before HAP onset. Lung virome composition, viral convergence before HAP onset, and conservation of 18% of the bacteriophage signature are validated in an external cohort of 40 patients. In silico causal inference further identifies bacteriophages associated with Streptococcus and Prevotella as a key regulator of HAP onset. These findings suggest an uncovered pathophysiological mechanism of HAP with virome involvement in lung microbiota dysbiosis. The discovery and validation studies are registered at ClinicalTrials.gov (NCT02003196 and NCT04793568)