39 research outputs found
Régulation de l'expression et de la fonction du CFTR par l'élastase du neutrophile et l'élastace B de Pseudomonas aeruginosa
No full textPARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF
Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2): results of a randomised, double-blind, placebo-controlled, phase 3 trial
No full textBACKGROUND: Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.METHODS: ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.FINDINGS: Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.INTERPRETATION: A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.FUNDING: Janssen Research & Development.</p
La différence entre micro- et macro-syntaxe est-elle marquée prosodiquement ? L'exemple des dispositifs clivés en "il y a SN qui/Ø V"
No full textInternational audienceDans cet article, nous discutons de l'hypothèse selon laquelle la différence entre les deux types morpho-syntaxiques de dispositifs clivés en « il y a » est marquée prosodiquement, i.e. nous nous posons la question de savoir si les tournures introduites (comme il y en a mon frère qui est venu à mon mariage) présentent des patrons mélodiques spécifiques par rapport à leurs homologues non introduites (comme il y a mon frère Ø il est venu à mon mariage). La distinction entre ces deux formes de dispositif clivé ayant été reversée dans l'opposition micro- vs macro-syntaxe par certains chercheurs du GARS [Cappeau & Deulofeu 2001], cela rend notre investigation d'autant plus intéressante. Elle devrait en effet permettre de faire avancer la réflexion générale sur le rôle joué par la prosodie à l'interface de la micro- et de la macro-syntaxe. Pour mener à bien notre recherche, nous avons relevé dans quelques corpus de français parlé une quinzaine d'occurrences pour chacun des deux types de dispositifs. Nous avons ensuite mené une analyse prosodique sur chacun d'eux, en cherchant à voir quelle relation entretenaient les groupes intonatifs qu'ils contiennent. Sur la base des travaux de nos prédécesseurs [Mertens 1987 ; Lacheret 2003 ; Simon 2004], nous avons rappelé qu'en français, les groupes intonatifs qui composent un énoncé pouvaient entretenir deux types de relation. Ou bien ils forment un paquet intonatif de rang supérieur (on dit dans ce cas qu'il y a dominance du second sur le premier) ; ou bien ils constituent des unités prosodiques autonomes l'une par rapport à l'autre (auquel cas on parle d'indépendance). A la suite de notre expertise, et contrairement à ce que l'on aurait pu attendre, on constate que ces deux types de patrons prosodiques ne sont pas associés aux deux types morphosyntaxiques identifiés. En d'autres termes, il semblerait qu'il n'y ait pas, à première vue, de processus prosodiques caractéristiques mobilisés pour coder des relations micro- ou macro-syntaxiques. Cette remarque, également formulée à leur façon par Choi-Jonin & Delais-Roussarie [2007], est discutée en conclusion, à la lumière d'une étude antérieure du même acabit, portant sur les couplages de constructions verbales
Prevalence and profile of cognitive impairment in adult glioma: a sensitivity analysis
No full textInternational audienceCognitive impairment has been reported in 27-83 % of adults with World Health Organization (WHO) grade I-III glioma. However, the few studies in this field used different methods for cognitive assessment. The objective of the present study was to establish the prevalence of cognitive impairment in patients with WHO grade I-III primary brain tumors and determine the effect sizes of a comprehensive battery of tests. This study used a comprehensive neuropsychological battery to examine 27 patients. To control for false positives, prevalence was estimated from the overall neuropsychological score. Size effects were determined using Cohen's d. Cognitive impairment was observed in 51.9 % (95 % CI 33-70.7 %) of the patients; the impairment affected action speed (38.5 %), cognitive (33 %) and behavioral (21.7 %) executive functions, oral expression (29.6 %), episodic memory (29.6 %) and visuoconstructive abilities (19.2 %). The largest effect sizes (d aeyenaEuroe1.645) were observed for the Digit Symbol Substitution test, global hypoactivity, free recall, Stroop time, the Boston Naming test (BNT), the Trail Making test B (TMTB), verbal fluency and the Rey-Osterrieth Complex Figure Test. Four of these scores (global hypoactivity, the Digit Symbol Substitution test, the TMTB perseveration, and the BNT) were combined to make a shortened battery (AUC 0.872; 95 % CI 0.795-0.949). The overall neuropsychological score was the sole factor associated with the functional outcome. Our results suggest that about half of survivors with a grade I-III primary brain tumor suffer from cognitive impairment. Tests with a large effect size should be included in future large-scale studies
Quand les cellules iNKT partent au charbon : nouvelles pistes thérapeutiques
No full textInternational audienc
Impact of preexisting anti-Ad26 humoral immunity on immunogenicity of the Ad26.COV2.S COVID-19 vaccine
No full textThis secondary analysis of the phase 3 ENSEMBLE trial (NCT04505722) assessed the impact of preexisting humoral immunity to adenovirus type 26 (Ad26) on the immunogenicity of Ad26.COV2.S-elicited SARS-CoV-2–specific antibody levels in 380 participants in Brazil, South Africa, and the United States. Among those vaccinated in Brazil and South Africa, 31% and 66%, respectively, had prevaccination serum-neutralizing activity against Ad26, with little preexisting immunity detected in the United States. Vaccine recipients in each country had similar post-vaccination spike-binding antibody levels, indicating that baseline immunity to Ad26 has no clear impact on vaccine-induced immune responses
Safety and immunogenicity of Ad26.COV2.S in adolescents: Phase 2 randomized clinical trial
No full textWe conducted a randomized, Phase 2 trial to assess the safety and humoral immunogenicity of reduced doses/dose volume of the standard dose of Ad26.COV2.S COVID-19 vaccine (5 × 1010 viral particles [vp]) in healthy adolescents aged 12–17 years. Participants were randomly assigned to receive Ad26.COV2.S at reduced dose levels of 0.625 × 1010 (0.5 mL), 1.25 × 1010 (0.5 mL) or 2.5 × 1010 (0.5 mL or low volume 0.25 mL) vp in a 1- or 2-dose (56-day interval) primary schedule. Adolescents who received a 1-dose primary schedule received a 2.5 × 1010 vp booster dose 6 months later. Safety and humoral immunogenicity were assessed up to 6 months post-last vaccination. All regimens were well tolerated, with no safety concerns identified. Local and systemic solicited AEs in adolescents were consistent with the known safety profile in adults. All 1- and 2-dose Ad26.COV2.S primary schedules elicited robust peak Spike-binding antibody responses and virus neutralizing titers against the reference strain, in participants with and without preexisting SARS-CoV-2 immunity. Immune responses were durable for at least 6 months. Spike-binding antibody responses were comparable to those elicited in young adults aged 18–25 years who received a standard dose of Ad26.COV2.S in Phase 3 efficacy studies Reduced doses/dose volume of Ad26.COV2.S had an acceptable safety profile and elicited robust humoral immune responses in adolescents aged 12–17 years. All 1- and 2-dose schedules elicited Spike-binding antibody responses that were comparable to an adult population in whom efficacy has been demonstrated using a higher vaccine dose. (clinicaltrials.gov NCT05007080)
Toll-like receptor 5 (TLR5), IL-1β secretion, and asparagine endopeptidase are critical factors for alveolar macrophage phagocytosis and bacterial killing.
No full textInternational audienceA deficit in early clearance of Pseudomonas aeruginosa (P. aeruginosa) is crucial in nosocomial pneumonia and in chronic lung infections. Few studies have addressed the role of Toll-like receptors (TLRs), which are early pathogen associated molecular pattern receptors, in pathogen uptake and clearance by alveolar macrophages (AMs). Here, we report that TLR5 engagement is crucial for bacterial clearance by AMs in vitro and in vivo because unflagellated P. aeruginosa or different mutants defective in TLR5 activation were resistant to AM phagocytosis and killing. In addition, the clearance of PAK (a wild-type P. aeruginosa strain) by primary AMs was causally associated with increased IL-1β release, which was dramatically reduced with PAK mutants or in WT PAK-infected primary TLR5(-/-) AMs, demonstrating the dependence of IL-1β production on TLR5. We showed that this IL-1β production was important in endosomal pH acidification and in inducing the killing of bacteria by AMs through asparagine endopeptidase (AEP), a key endosomal cysteine protease. In agreement, AMs from IL-1R1(-/-) and AEP(-/-) mice were unable to kill P. aeruginosa. Altogether, these findings demonstrate that TLR5 engagement plays a major role in P. aeruginosa internalization and in triggering IL-1β formation
