ABSTRACT:The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL)-2014 trial evaluated an intensive, age-adapted protocol for adults aged 18 to 59 years with Philadelphia chromosome negative acute lymphoblastic leukemia. The trial was motivated by findings from the previous GRAALL-2005 study, which reported excessive toxicity from pediatric-inspired therapy in older patients and no added benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT) among those with an early favorable response to treatment. Thus, the GRAALL-2014 protocol aimed to reduce treatment-related toxicity in patients aged ≥45 years and to limit allo-HSCT to patients with poor measurable residual disease (MRD) responses. A total of 743 patients were included, and outcomes were compared with those of GRAALL-2005 trial. The GRAALL-2014 study demonstrated reduced early mortality and higher complete remission rates in patients aged ≥45 years. MRD-guided transplantation decisions reduced allo-HSCT indications by ∼50%. Although older patients experienced a higher cumulative incidence of relapse, no significant difference in disease-free survival (DFS) was observed compared with historical cohorts across age subgroups. The overall 4-year DFS was 57.1% (95% confidence interval [CI], 53.4-61.1). Notably, 4-year overall survival improved significantly, from 65.5% (95% CI, 61.7-69.8) to 71.7% (95% CI, 67.7-76.0) in younger patients (P = .031) and from 49.6% (95% CI, 43.5-56.5) to 59.5% (95% CI, 53.5-66.3) in older patients (P = .011). These findings highlight the value of individualized treatment strategies that balance efficacy and safety. Future studies should investigate the integration of immunotherapy to further reduce treatment intensity and improve outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02617004 and #NCT02619630.
Background:Wearable digital health technologies offer a unique opportunity to assess gait at the stride level in real-world settings. Walking impairment is a major cause of disability in multiple sclerosis (MS), yet current clinical metrics lack sensitivity to early and progressive changes in mobility. Methods:We conducted two studies (NCT04888689/NCT04882891) using a wearable device to develop and validate digital mobility outcome measures based on individual strides in patients with MS. First, we assessed technical performance in a controlled, single-center environment between September 12 and September 18, 2021. We then conducted a 12-month longitudinal study under daily living conditions across six sites between March 2021 and January 2024. The evaluated metrics included stride velocity 95th centile, walking distance 90th centile, and strides per hour. Findings:The controlled and longitudinal studies included 21 and 78 participants, respectively. The device demonstrated high stride detection accuracy (precision: 0·99) and a mean absolute error in stride velocity of 0·019 m/s. In the longitudinal study, stride velocity 95th percentile showed excellent reliability (ICC (2,1) = 0·97, SEM = 0·06) and strong agreement with Expanded Disability Status Scale (Spearman's rho = 0·65, p < 0·001) and Timed 25-Foot Walk (Spearman's rho = -0·71, p < 0·001), sensitivity to 12-month progression in both relapsing-remitting and progressive MS (p = 0·049 and p = 0·006, respectively), outperforming the Expanded Disability Status Scale. Walking distance 90th percentile and strides per hour were reliable and valid but less sensitive to progression. Interpretation:Stride velocity 95th percentile derived from real-world, stride-level data, provides a valid, reliable, and sensitive digital outcome for detecting MS progression. It may serve as an early indicator of progression and support the accelerated evaluation of treatments targeting progression. Funding:This study was funded by F. Hoffmann-La Roche Ltd.
Introduction Outre des symptômes moteurs caractéristiques, la maladie de Parkinson (MP) entraîne divers troubles langagiers dont la nature reste encore controversée. Objectifs Contrairement aux études existantes ciblant un domaine langagier spécifique, cette étude vise à dresser une analyse détaillée des compétences langagières de patients parkinsoniens non déments. Méthodes Cinquante patients avec MP non déments (30 hommes), âgés de 54 à 85 ans, et un groupe de 100 sujets contrôles sains, appariés au niveau de l’âge, du genre et du niveau d’études ont été recrutés. Quatorze tâches langagières ont exploré les aspects lexicaux, sémantiques, morphosyntaxiques et pragmatiques du langage oral. Résultats Au niveau lexical, un déficit en dénomination pour les noms et les verbes, ainsi qu’une altération de la fluence d’action sont observés. La catégorisation sémantique est déficitaire. Des altérations syntaxiques sont observées au niveau du traitement des phrases et du discours. Des difficultés pragmatiques sont également identifiées. Une analyse de cluster indique des performances relativement homogènes entre domaines langagiers, avec une séparation en trois clusters selon le niveau d’altération langagière globale. Discussion Ces résultats rencontrent partiellement les études antérieures concernant les difficultés d’accès lexical, de traitement syntaxique et de pragmatique. Cette étude montre cependant une altération simultanée des différents niveaux langagiers suivant la progression de la maladie en l’absence de tableau démentiel. Conclusion Il est recommandé de mener une investigation approfondie des capacités langagières chez les patients parkinsoniens non déments, en raison de la nature multiple et progressive de leurs déficits langagiers.
OBJECTIVES:The course of chronic obstructive pulmonary disease (COPD) features episodic exacerbation, contributing to severity. The present study assessed associations between COPD, dysphonia and dysphagia. Laryngeal aspiration is a risk factor for repeated exacerbation of COPD. Certain risk factors are common to COPD and laryngeal pathology; dyspnea impairs phonation and swallowing. MATERIAL AND METHODS:This prospective study included 29 patients with group E COPD outside of exacerbation episodes, and free of neurodegenerative disease and history of head and neck cancer. Phonation and swallowing were assessed concomitantly. ENDPOINTS:The main study endpoint was the prevalence of phonation and swallowing disorders in severe COPD. The secondary objective was to determine whether vocal disorder is a marker of dysphagia in patients at risk of respiratory infection. RESULTS:Prevalence of dysphonia and dysphagia was high on objective assessment but underestimated in self-reports. More than 50% of patients showed deficits in at least 1 mechanism of swallowing, and notably delayed triggering of the pharyngeal reflex. Only the s/z ratio was significantly associated with dysphagia. CONCLUSION:Dysphagia and dysphonia are frequent and underestimated in severe COPD. The present study argues for systematic objective screening of swallowing disorder, even in the absence of complaint or dysphonia.
Importance:Controversies persist about management of the ductus arteriosus by nonsteroidal anti-inflammatory drugs in extremely preterm infants. Acetaminophen (paracetamol) appears to be a promising alternative with possibly fewer adverse effects. Objective:To evaluate whether prophylactic intravenous acetaminophen started within 12 hours of birth increases survival without neonatal severe morbidities at 36 weeks' postmenstrual age. Design, Setting, and Participants:A double-blind, randomized, placebo-controlled clinical trial was conducted among preterm infants born between 23 weeks 0 days and 28 weeks 6 days of gestation in 43 neonatal intensive care units of 14 European countries between October 2020 (October 2021 for infants born at 23-26 weeks' gestation, after the phase 2 study identified the optimal dose of acetaminophen) and April 2024. Data analysis was conducted from January to June 2025. Intervention:In the acetaminophen group, patients born at 27 to 28 weeks' gestation received a 20-mg/kg loading dose of acetaminophen followed by 7.5 mg/kg every 6 hours for 5 days, and patients born at 23 to 26 weeks' gestation received a 25-mg/kg loading dose of acetaminophen followed by 10 mg/kg every 6 hours for 5 days. In the placebo group, isotonic sodium chloride was administered. Main Outcomes and Measures:The primary outcome was survival without neonatal morbidity evaluated at 36 weeks' postmenstrual age. The secondary exploratory outcome was ductus arteriosus closure, assessed by echocardiography on day 7. Results:A total of 778 patients (median [IQR] gestational age, 26 [25-27] weeks; 375 [48.2%] female) were included in the study, with 391 in the acetaminophen group and 387 in the placebo group. Survival without severe morbidities at 36 weeks' postmenstrual age occurred in 259 infants (66.2%) in the acetaminophen group and 246 (63.6%) in the placebo group (absolute risk difference [ARD], 2.7 [95% CI, -4.0 to 9.3] percentage points; relative risk [RR], 1.04 [95% CI, 0.94 to 1.16]). The ductus arteriosus was considered closed on day 7 in 264 of 371 infants (71.2%) assigned to acetaminophen and 191 of 366 infants (52.2%) assigned to placebo (ARD, 19.0 [95% CI, 12.0 to 25.7] percentage points; RR, 1.36 [95% CI, 1.21 to 1.53]). In the safety analysis, adverse events were not different except for a higher cholestasis rate in the acetaminophen group (25 of 392 infants [6.4%]) vs the placebo group (10 of 386 infants [2.6%]) (ARD, 3.8 [95% CI, 0.9 to 6.9]) percentage points. Conclusions and Relevance:This study found that prophylactic acetaminophen treatment for patent ductus arteriosus did not increase survival without neonatal morbidities. Trial Registration:ClinicalTrials.gov Identifier: NCT04459117.
