Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

L'interjection modalisation, axiologisation et grammaticalisation. Le cas des interjections roumaines zau et vai

Mariana Tutescu: The interjection modality, axiological investment and grammaticalization. The case of the Romanian interjections ZAU et VAI Interjection is conceived in this paper as an epistemic modaliser whose function on the utterance level is that of an évaluation marker. The interjection as a linguistic sign is at the same time an index, an icon and a symbol. Describing the uses of the Romanian interjections VAI Deus lat, the author conjectures that thèse interjectional modalisers undergo a grammaticalization based upon generalized delocutivity and axiological investment. The argument focusses on the grammaticalization of VAI, whose graduai conversion from exophrastic to endophrastic use relies on seven steps.Tutescu Mariana. L'interjection modalisation, axiologisation et grammaticalisation. Le cas des interjections roumaines zau et vai. In: Langages, 40e année, n°161. 2006. L'interjection : jeux et enjeux, sous la direction de Claude Buridant. pp. 37-46

Le Temps verbal, facteur de cohérence textuelle (logique combinatoire destemps dans la formation du texte)

NICE-BU Lettres Arts Sci.Hum. (060882104) / SudocSudocFranceF

Le Concept d''agrammaticalité" et la structuration du français

La problématique de l'énoncé déviant concerne les fondements épistémologiques de la science linguistique et des différents modèles de description de la langue. L'objectif de ce travail consiste à mettre en évidence ces rapports, à travers une étude systématique du rôle que remplit la séquence agrammaticale dans l'approche linguistique. La méthode de la falsification utilisée dans toute la linguistique moderne prouve l'immense valeur heuristique dont s'investit la phrase astérisquée. Après un historique de la question de la déviance dans la grammaire française, on examinera le mode d'introduction et d'élaboration du procédé d'agrammaticalisation dans le cadre génératif-transformationnel. On balise aussi le champ des paramètres impliqués dans le jugement linguistique, tels que le sujet locuteur, l'intuition, le statut du linguiste, la valeur des exemples dans la théorie linguistique. On aboutit dans la troisième partie de l'exposé à une définition du concept d'agrammaticalité par rapport à un certain modèle de structuration de la langue française. Nous énoncerons ainsi des principes généraux qui témoignent de notre conception sur la forme que devrait avoir une grammaire adéquate de la langue, et nous mettrons l'accent sur la contribution essentielle de la notion d'agrammaticalité à ce type de grammaire. Une annexe constituée d'une typologie des énoncés agrammaticaux complétera notre argumentation.STRASBOURG-B.N.U.S. (674821001) / SudocSudocFranceF