Preparation, characterisation and biological evaluation of new N-phenyl amidobenzenesulfonates and N-phenyl ureidobenzenesulfonates inducing DNA double-strand breaks. Part 3. Modulation of ring A

N-Phenyl ureidobenzenesulfonates (PUB-SOs) are a new class of anticancer agents blocking the cell cycle progression in S-phase, inducing replicative stress and DNA double-strand breaks (DSBs). In this study, we evaluate the effect of modifying the nature and the position of different substituents on ring A of PUB-SOs on the antiproliferative activity, pharmacological activity as well as on calculated physicochemical, pharmacokinetics and drug-likeness properties. Modification of the urea group by an amide group led to new PUB-SO analogs designated as N-phenyl amidobenzenesulfonates (PAB-SOs). The 2-chloroethyl moiety on ring A was also substituted by different alkyl, cycloalkyl and chloroalkyl groups. The new PAB-SOs and PUB-SOs blocking the cell cycle progression in S-phase exhibit antiproliferative activity in the submicromolar to low micromolar range (0.14–27 μM) on four human cancer cell lines, namely HT-1080, HT-29, M21 and MCF7. Moreover, selected PUB-SO and PAB-SO derivatives induced the phosphorylation of H2AX in M21 cells and do not exhibit or only slightly alkylating activity as confirmed by the 4-(4-nitrobenzyl)pyridine (NBP) assay. Finally, our results show that structure modifications weakly affect the calculated physicochemical, pharmacokinetics and drug-likeness properties of PAB-SOs and PUB-SOs. Therefore, PAB-SOs and PUB-SOs are promising anticancer agents inducing replicative stress and DNA damage via a mechanism of action unrelated to DNA alkylation

Optimal Reissue Policies for Reducing Tail Latency

Interactive services send redundant requests to multiple different replicas to meet stringent tail latency requirements. These addi- tional (reissue) requests mitigate the impact of non-deterministic delays within the system and thus increase the probability of re- ceiving an on-time response. There are two existing approaches of using reissue requests to reduce tail latency. (1) Reissue requests immediately to one or more replicas, which multiplies the load and runs the risk of overloading the system. (2) Reissue requests if not completed after a fixed delay. The delay helps to bound the number of extra reissue requests, but it also reduces the chance for those requests to respond before a tail latency target. We introduce a new family of reissue policies, Single-Time / Random ( SingleR ), that reissue requests after a delay d with probability q . SingleR employs randomness to bound the reissue rate, while allowing requests to be reissued early enough so they have sufficient time to respond, exploiting the benefits of both immediate and delayed reissue of prior work. We formally prove, within a simplified analytical model, that SingleR is optimal even when compared to more complex policies that reissue multiple times. To use SingleR for interactive services, we provide efficient algorithms for calculating optimal reissue delay and probability from response time logs through data-driven approach. We apply itera- tive adaptation for systems with load-dependent queuing delays. The key advantage of this data-driven approach is its wide applica- bility and effectiveness to systems with various design choices and workload properties. We evaluated SingleR policies thoroughly. We use simulation to illustrate its internals and demonstrate its robustness to a wide range of workloads. We conduct system experiments on the Re- dis key-value store and Lucene search server. The results show that for utilizations ranging from 40 - 60% , SingleR reduces the 99 th-percentile latency of Redis by 30 - 70% by reissuing only 2% of requests, and the 99 th-percentile latency of Lucene by 15 - 25% by reissuing 1% only

Etude expérimentale et numérique d'un écoulement diphasique gaz-particules

Dans ce travail, une étude numérique et expérimentale est réalisée dans un jet diphasique turbulent (gaz-particules) issu d'un brûleur coaxial. Le modèle numérique repose sur une approche eulérienne-lagrangienne permettant une description fine des mécanismes d'interactions entre les deux phases. La technique d'Anémométrie à Phase Doppler (PDA) est utilisée pour mesurer la taille et la vitesse simultanément de particules solide sphériques de diamètre du 102 µm jusqu'à 212 µm

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Techniques d’imagerie pour la mesure en mécanique des fluides

International audienceImaging is a technique used in various fields related to fluid mechanics. It allows the measurement of geometric parameters such as size and shape, as well as scalar field variables like temperature, pH, and mixture.This article provides an overview digital imaging and its application in fluid mechanics. It presents the main experimental setups used and their implementation. The aspects of signal processing and information management, crucial in this context, are also addressed. Finally, the article illustrates the potential of the technique through several examples of applications emphasizing coupling and ultra-fast imaging.L'imagerie est une technique utilisée dans de nombreux domaines liés à la mécanique des fluides. Elle permet de mesurer des paramètres géométriques (taille, forme…), ainsi que des champs de grandeurs scalaires (température, pH, mélange…).Cet article propose une vue d’ensemble de l’imagerie et de son application en mécanique des fluides. Il présente les principaux montages expérimentaux utilisés, ainsi que leur mise en œuvre. Les aspects traitement du signal et gestion de l'information, essentiels dans ce cas, sont également abordés. Enfin, l'article illustre le potentiel de la technique via plusieurs exemples d'applications mettant l'accent sur le couplage et l'imagerie ultrarapide

18F-FDG PET/CT in anti-NMDA receptor encephalitis: Typical pattern and follow-up

International audienceWe report the case of a 28-year-old woman presenting behavior disorders of subacute onset. She was referred in our institution for a suspicion of limbic encephalitis. 18F-FDG PET/CT did not show any mesiotemporal abnormality but depicted a decreased uptake of bilateral parietal and occipital lobes. This atypical pattern was compatible with an anti-N-methyl-D-aspartate receptor encephalitis that was later confirmed