Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), ...new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.
This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12.
Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends.
Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation.
ClinicalTrials.gov NCT00831922.
In France, there is no religious education in state schools. 'Convictional education' appeared by drawing its perimeter around three educational subjects: philosophy, teaching about religions, and ...moral and civic education. Today, the French school is facing new challenges in a highly secularised society on which religion is laying new claims. As an institution, it is not neutral insofar as it proceeds from a political philosophy that evolved from the French Revolution. It is within the operative framework of this philosophy and with specific teaching practices that it intends to combine unity and plurality within itself.
Clinical joint examination (CJE) is less time-consuming than ultrasound (US) in rheumatoid arthritis (RA). Low concordance between CJE and US would indicate that the 2 tests provide different types ...of information. Knowledge of factors associated with CJE/US concordance would help to select patients and joints for US. Our objective was to identify factors associated with CJE/US concordance.
Seventy-six patients with RA requiring tumor necrosis factor-α (TNF-α) antagonist therapy were included in a prospective, multicenter cohort. In each patient, 38 joints were evaluated. Synovitis was scored using CJE, B-mode US (B-US), and power Doppler US (PDUS). Joints whose kappa coefficient (κ) for agreement CJE/US was < 0.1 were considered discordant. Multivariate analysis was performed to identify factors independently associated with CJE/US concordance, defined as factors yielding p < 0.05 and OR > 2.
Concordance before TNF-α antagonist therapy varied across joints for CJE/US (κ = -0.08 to 0.51) and B-US/PDUS (κ = 0.30 to 0.67). CJE/US concordance was low at the metatarsophalangeal joints and shoulders (κ < 0.1). Before TNF-α antagonist therapy, a low 28-joint Disease Activity Score (DAS28) was associated with good CJE/B-US concordance, and no factors were associated with CJE/PDUS concordance. After TNF-α antagonist therapy, only the joint site was associated with CJE/B-US concordance; joint site and short disease duration were associated with CJE/PDUS concordance.
Concordance between CJE and US is poor overall. US adds information to CJE, most notably at the metatarsophalangeal joints and shoulders. Usefulness is decreased for B-US when DAS28 is low and for PDUS when disease duration is short.
République and laïcité Gaudin, Philippe
Philosophy & social criticism,
05/2016, Letnik:
42, Številka:
4-5
Journal Article
Recenzirano
How should one define the republican democratic and ‘laïque’ spirit in both the most concise and effective manner, as well as that most suited to the French case? The republican spirit resides ...without doubt in refusing submission to any single individual whoever that individual may be. The democratic spirit does not consist of decreeing the sovereignty of the people, but in developing formal modalities of political life allowing the people not to be divested of it. The ‘laïque’ spirit rejects all distinctions concerning the nature and rights of citizens; it also equally rejects religious laws being imposed over political law.
République and laïcité Gaudin, Philippe
Philosophy & social criticism,
05/2016, Letnik:
42, Številka:
4-5
Journal Article
Recenzirano
How should one define the republican democratic and 'laïque' spirit in both the most concise and effective manner, as well as that most suited to the French case? The republican spirit resides ...without doubt in refusing submission to any single individual whoever that individual may be. The democratic spirit does not consist of decreeing the sovereignty of the people, but in developing formal modalities of political life allowing the people not to be divested of it. The 'laïque' spirit rejects all distinctions concerning the nature and rights of citizens; it also equally rejects religious laws being imposed over political law.
Objective
To evaluate and improve the reliability of power Doppler ultrasonography (PDUS) for detecting and scoring enthesitis in patients with spondylarthitis, using a 3‐step procedure.
Methods
In ...the first step, we evaluated the reliability of 5 sonographers by bilaterally scanning 5 entheses twice in 5 patients. In the second step, starting from disagreements observed during the first step, we established consensus guidelines. The sonographers' implementation was further evaluated in 2 reliability exercises: one on 60 PDUS enthesitis images and the other by scanning 5 new patients. In the third step, we performed a final reliability evaluation of 5 additional patients after 1 year. Kappa coefficients (κ) as well as variance component analysis (VCA) and generalizability theory (GT) were used to assess reliability.
Results
The initial intra‐ and interobserver reliability were poor, especially for detecting and scoring Doppler signal. VCA and GT showed that most variability was accounted for by interaction between sonographer and enthesis. Implementation of consensus guidelines was associated with a significant improvement in Doppler reliability between the first and second steps (mean interobserver κ increased from 0.13 to 0.51 for binary Doppler scoring in patients; P < 0.005), which persisted in the third step (mean interobserver κ = 0.57). The high GT coefficients reached in the last steps supported such improvement.
Conclusion
The 3‐step procedure used in this study to standardize PDUS technique was associated with a significant improvement in interobserver reliability for detecting enthesitis in spondylarthritis patients. Such an approach can be useful to standardize PDUS assessment of musculoskeletal disorders.
Für die Vereinbarkeit des Respekts der Überzeugungen von Schüler/-innen und Familien mit dem Philosophieunterricht stellen sich heute neue Probleme – dies aufgrund der starken Zunahme von ...Schüler/-innen auf der Sekundarstufe, der Säkularisierung und der religiösen Pluralität in Frankreich, wie auch in anderen europäischen Ländern. Auch wenn „Religion“ ein Konzept ist, das schon lange „Teil des Lehrplans für Philosophie“ ist, so müssten die Gründe der Vorbehalte der Philosophielehrpersonen gegenüber des religionskundlichen Unterrichts genauer analysiert werden. Eine einfache Analyse der offiziell anerkannten Philosophielehrpläne sowie der Liste der offiziell anerkannten Autor/-innen zeigt, wie stark Religionsthemen in der Philosophie präsent sind. Anders gesagt: Die Lehrpersonen können, unabhängig von ihren philosophischen Grundeinstellungen, nicht länger darauf verzichten, ihre Schülerinnen und Schüler in die kulturellen Hintergründe der Religionen einzuführen, die diese heutzutage oft nicht haben.
Water warming induced by human activities can impact fish larvae survival, notably because it influences larval development and prey abundances. Amphidromous gobies of the subfamily Sicydiinae are ...particularly sensitive to this threat as the newly hatched free embryos are poorly developed and the first feeding opportunity only occurs after they reach the ocean. Here, we studied how water temperature (21, 23, 25, 29 and 31°C) impacts early development stages of Sicyopterus lagocephalus in both freshwater and marine aquaria (salinity 35). We monitored survival time, larval condition and the occurrence of critical developmental events such as mouth opening, yolk sac and oil globule resorption. In freshwater, the survival exceeded 150 hours at 21°C, while it dropped below 50 hours at 31°C. In seawater, the larval development of unfed larvae was significantly affected by temperature, survival time being greatly reduced in warmer waters. Accounting for the observed duration between mouth opening and the resorption of the oil globule, we estimated that larvae need to find suitable prey in seawater within a short time: around 30 hours during the peak of reproduction in summer. Otherwise, their endogenous reserves become depleted and their condition degrades. This study emphasises the sensitivity of free embryos to stream flow alterations, which contributes to the increase in water temperature and to the slowing down of larvae drift to the ocean. We conclude that once in seawater the temperature and feeding conditions experienced by amphidromous larvae are critical for survival.
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