Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial

Background: S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke. Methods: RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov, NCT02877615. Findings: Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64–1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81–1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0–2 vs 3–6 or mRS 0–1 vs 2–6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2–8] in 150 mg S44819 group, 4 [2–7] in 300 mg S44819 group, and 4 [2–6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0–26·0] in 150 mg S44819 group, 23·0 [19·0–26·5] in 300 mg S44819 group, and 22·0 [17·0–26·0] in placebo group), time needed to complete parts A (50 s [IQR 42–68] in 150 mg S44819 group, 49 s [36–63] in 300 mg S44819 group, and 50 s [38–68] in placebo group) and B (107 s [81–144] in 150 mg S44819 group, 121 s [76–159] in 300 mg S44819 group, and 130 s [86–175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60–100] in 150 mg S44819 group, 90 [70–100] in 300 mg S44819 group, and 90 [70–100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths. Interpretation: There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans. Funding: Servier

Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats.

Maternal overnutrition has been implicated in affecting the offspring by programming metabolic disorders such as obesity and diabetes, by mechanisms that are not clearly understood. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring's hypothalamic Pomc gene, coding a key factor in the control of energy balance. Further, it aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition.Eight-week-old female Sprague-Dawley rats were fed HF diet or low-fat (LF) diet for 6 weeks before mating, and throughout gestation and lactation. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet.With maternal HF diet, offspring at weaning had rapid early weight gain, increased adiposity, and hyperleptinemia. The programmed adult offspring, subsequently fed LF diet, retained the increased body weight. Maternal HF diet combined with offspring HF diet caused more pronounced hyperphagia, fat mass, and insulin resistance. The ARC Pomc gene from programmed offspring at weaning showed hypermethylation in the enhancer (nPE1 and nPE2) regions and in the promoter sequence mediating leptin effects. Interestingly, hypermethylation at the Pomc promoter but not at the enhancer region persisted long term into adulthood in the programmed offspring. However, there were no additive effects on methylation levels in the regulatory regions of Pomc in programmed offspring fed a HF diet.Maternal overnutrition programs long-term epigenetic alterations in the offspring's hypothalamic Pomc promoter. This predisposes the offspring to metabolic disorders later in life

Work-family culture, work-family interference and well-being at work : iIs it possible to distinguish between a positive and a negative process?

Purpose – The purpose of this paper is to examine whether work-family (WF) interference functions as an explaining mechanism in the link between work-family culture and well-being, hereby distinguishing between a negative and a positive process. The negative, energy depleting process initiates from a hindrance work-family culture and ends up to burnout through the experience of work-family conflict. The positive, motivation generating process initiates from a supportive work-family culture and ends up to work engagement through work-family enrichment. Design/methodology/approach – The paper employs a quantitative study among employees from three different organizations (n=516). Findings – Work-family conflict fully mediates the relationship between a hindrance WF-culture and the exhaustion dimension of burnout and partially mediates the relationship between a hindrance WF-culture and the cynicism dimension of burnout. With regard to the mediational role of work-family enrichment the results also confirm the paper's hypothesis. Work-family enrichment partially mediates the relationship between a supportive WF-culture and work engagement. Interestingly, analyses of some alternative mediational paths reveal some additional findings. Specifically, a supportive work-family culture relates to work engagement through the perception of less work-family conflict. Moreover, a supportive culture is also related to less feelings of burnout through work-family enrichment. Originality/value – The study shows that it pays off to invest in a supportive work-family culture because such a culture contributes to work engagement and in the same time helps to prevent burnout

Clin Drug Investig

Background and Objectives Non-interventional studies are a valuable source of evidence that is complementary to traditional randomised, blinded and controlled clinical trials, for evaluating antidepressants in a real-world setting. The aim of the present study was to document the use of agomelatine in current medical practice and evaluate its effectiveness and safety in outpatients prescribed agomelatine to treat their current depressive episode. Methods This 12-month observational French study included patients initiating agomelatine treatment. The intensity and severity of depression were assessed using the 17-item Hamilton Depression Rating Scale (HAM-D17) total score and the Clinical Global Impression-Severity of Illness (CGI-S) scale. Patients’ quality of life and functioning were measured using the Quality of Life in Depression Scale and the Sheehan Disability Scale, respectively. The safety measures included emergent adverse events and biological samplings, with a focus on liver acceptability. Results A total of 1484 patients (70% of women; 49.6 ± 15.4 years of age) were enrolled in the study. Most patients (62.3%) were treated with agomelatine for at least 6 months and 28.8% were treated for at least 1 year. Mean HAM-D17 total score and mean CGI-S scores decreased by 13.6 ± 8.1 and 2.1 ± 1.5 points, respectively, from baseline to last visit on agomelatine. Rates of responders (i.e. with a decrease in HAM-D17 total score by at least 50%) and remitters (HAM-D total score < 7) at the last visit were 90.7% and 56.0%, respectively. The mean HAM-D total score decreased after agomelatine withdrawal (− 4.1 ± 6.7) until the last visit. The quality of life and daily functioning of patients improved, while the numbers of days lost and underproductive days decreased over the follow-up period. Safety findings were in accordance with the known information regarding agomelatine. Conclusion In the current medical practice, this study confirms the effectiveness and good tolerability of agomelatine administered for a treatment period in agreement with guideline recommendations

Mise au point d'un outil d'aide à la décision dans le domaine du risque sismique. Démarche expérimentale d'appropriation de la problématique des risques par les acteurs d'une collectivité urbaine (RP-50020-FR )

Référence : BRGM/RP-50020-FRRapport commandité par la Région Rhône-AlpesSynthèse Le risque naturel est une réalité pour de nombreuses collectivités et leurs services techniques ne l'ignorent pas. Toutefois les acteurs susceptibles d'y être confrontés, et d'en améliorer la prévention, tels que les entreprises, les populations ou les gouvernants ne l'ont pas toujours intégré. En effet, les problèmes sociaux, économiques ou politiques sont parfois plus préoccupants pour les responsables d'une collectivité qui laissent la prise en compte du risque naturel à la charge des responsables de la sécurité. Pourtant, un évènement sismique faible peut avoir des conséquences sociales ou économiques : des populations à faibles revenus peuvent être déplacées à la suite de rénovations entraînant une hausse de l'immobilier, de même que des entreprises peuvent être pénalisées par la perturbation de réseaux de télécommunication ou l'affectation de leurs salariés. Pour que le risque soit pris en compte par tous les acteurs d'une collectivité, il doit donc leur être présenté selon leur culture et doit être intégré dans le cadre de leurs préoccupations. Faut-il pour parler du risque, développer autant de discours qu'il y a d'acteurs ? Probablement non, car si les acteurs sont multiples ils appartiennent néanmoins tous à la collectivité et celle-ci n'a qu'une échelle de valeurs. C'est selon ce principe que la recherche a été menée. Réalisée dans le cadre du programme de recherche " Génie urbain et environnement ", financé par le contrat de plan Etat-Région Rhône Alpes 1994-1999, elle a pour objectif de définir une méthode permettant l'appropriation de la problématique du risque par les acteurs d'une collectivité territoriale. L'application pratique de cette recherche a été effectuée avec l'appui du district annécien. Cette recherche a nécessité l'association de compétences dans le domaine des risques, des aléas et des enjeux ainsi que dans celui de l'identification des Cohérences culturelles d'une collectivité. Elle est le résultat des travaux menés conjointement par le BRGM, l'Institut Cohérences, Nicaya et l'Université de Savoie. La recherche a porté sur l'appréhension de la problématique du risque par les différents acteurs, les conditions culturelles de l'appropriation active et sur les conditions du partage de la connaissance et de la compréhension. La mise en oeuvre des connaissances, à travers des décisions communes et la recherche collective de solutions n'a pas été abordée dans ce travail

Maternal perinatal undernutrition modifies lactose and serotranferrin in milk: relevance to the programming of metabolic diseases?

International audienc

Loss of skeletal muscle estrogen-related receptors leads to severe exercise intolerance

ObjectiveSkeletal muscle oxidative capacity is central to physical activity, exercise capacity and whole-body metabolism. The three estrogen-related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle remain unclear. The main aim of this study was to compare the relative contributions of ERRs to oxidative capacity in glycolytic and oxidative muscle, and to determine defects associated with loss of skeletal muscle ERR function.MethodsWe assessed ERR expression, generated mice lacking one or two ERRs specifically in skeletal muscle and compared the effects of ERR loss on the transcriptomes of EDL (predominantly glycolytic) and soleus (oxidative) muscles. We also determined the consequences of the loss of ERRs for exercise capacity and energy metabolism in mice with the most severe loss of ERR activity.ResultsERRs were induced in human skeletal muscle in response to an exercise bout. Mice lacking both ERRα and ERRγ (ERRα/γ dmKO) had the broadest and most dramatic disruption in skeletal muscle gene expression. The most affected pathway was "mitochondrial function", in particular Oxphos and TCA cycle genes, and transcriptional defects were more pronounced in the glycolytic EDL than the oxidative soleus. Mice lacking ERRβ and ERRγ, the two isoforms expressed highly in oxidative muscles, also exhibited defects in lipid and branch chain amino acid metabolism genes, specifically in the soleus. The pronounced disruption of oxidative metabolism in ERRα/γ dmKO mice led to pale muscles, decreased oxidative capacity, histochemical patterns reminiscent of minicore myopathies, and severe exercise intolerance, with the dmKO mice unable to switch to lipid utilization upon running. ERRα/γ dmKO mice showed no defects in whole-body glucose and energy homeostasis.ConclusionsOur findings define gene expression programs in skeletal muscle that depend on different combinations of ERRs, and establish a central role for ERRs in skeletal muscle oxidative metabolism and exercise capacity. Our data reveal a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, and show that ERR isoform-specific phenotypes are driven in part, but not exclusively, by their relative levels in different muscles