Biomonitoring of the genotoxic potential of aqueous extracts of soils and bottom ash resulting from municipal solid waste incineration, using the comet and micronucleus tests on amphibian (Xenopus laevis) larvae and bacterial assays (MutatoxR and Ames tests)

The management of contaminated soils and wastes is a matter of considerable human concern. The present study evaluates the genotoxic potential of aqueous extracts of two soils (leachates) and of bottom ash resulting from municipal solid waste incineration (MSWIBA percolate), using amphibian larvae (Xenopus laevis). Soil A was contaminated by residues of solvents and metals and Soil B by polycyclic aromatic hydrocarbons and metals. MSWIBA was predominantly contaminated by metals. Two genotoxic endpoints were analysed in circulating erythrocytes taken from larvae: clastogenic and/or aneugenic effects (micronucleus induction) after 12 days of exposure and DNA-strand-breaking potency (comet assay) after 1 and 12 days of exposure. In addition, in vitro bacterial assays (MutatoxR and Ames tests) were carried out and the results were compared with those of the amphibian test. Physicochemical analyses were also taken into account. Results obtained with the amphibians established the genotoxicity of the aqueous extracts and the comet assay revealed that they were genotoxic from the first day of exposure. The latter test could thus be considered as a genotoxicity-screening tool. Although genotoxicity persisted after 12 days’ exposure, DNA damage decreased overall between days 1 and 12 in the MSWIBA percolate, in contrast to the soil leachates. Bacterial tests detected genotoxicity only for the leachate of soil A (Mutatox). The results confirm the ecotoxicological relevance of the amphibian model and underscore the importance of bioassays, as a complement to physicochemical data, for risk evaluation

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Application d'une méthode électrochimique à l'étude de la fixation des E. Coli sur supports immergés

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Les substances pharmaceutiques dans l'environnement

Les molécules pharmaceutiques sont consommées en quantités importantes en médecines humaines et vétérinaires et, sont rejetées dans l'environnement via diverses voies. Aujourd'hui, grâce aux progrès des techniques analytiques, il est possible de quantifier dans l'environnement des substances pharmaceutiques. Celles-ci, et notamment les antibiotiques, sont effectivement présentes dans diverses matrices telles que les eaux usées urbaines, les boues de stations d'épuration, les effluents d'élevage, les sols amendés par ces produits, les eaux de surface, les eaux souterraines et les eaux potables. Une des interrogations est de savoir si ces molécules sont susceptibles d'entraîner des impacts biologiques sur les écosystèmes aquatiques et terrestres

How to set up a test battery ?

International audienc

Démarche optimale de sélection de batterie de bioessais pour l'évaluation écotoxicologique des milieux complexes. Synthèse bibliographique

National audienceThe use of a combination of biological tests (or battery) is now recognized to be relevant for characterizing the environment quality, in addition to chemical analyses. Thus, within the framework of this study, launched by Ademe, the selection of relevant bibliography was carried out in order to establish an inventory of the existing batteries of tests as well as an assessment of the possible statistical treatments used. Generally, two methods are mentioned to select the biological tests constitutive of a battery: a method a priori based on predefined criteria and, a method a posteriori based on results obtained on a broad series of samples. The majority of reviews deal with a posteriori selection. It also appears that the proposed test batteries are not dedicated to a particular application but, are used to evaluate the toxicity of the samples and/or to compare tests between them. As regards the statistical method found in the literature, it appears that these tools are often badly or under-employed. Commonly, the authors propose a posteriori step based on the application of a Principal Component Analysis (PCA) to determine the choice of the tests in the battery. Finally, an optimal framework including five steps was proposed for designing a battery of tests. This framework was not observed in the literature and should be studied more thoroughly in the future. In conclusion, this bibliographical review showed that few authors argue their choices concerning the development of the test batteries. Concerning the use of the batteries, it appeared that they are not dedicated to some scenarii such as agricultural valorisation. In addition, it is interesting to note that half of the selected batteries integrate a double approach direct and indirect.L'utilisation d'une combinaison de bioessais (ou batterie) est désormais reconnue comme pertinente pour la caractérisation de la qualité des milieux, en complément des analyses chimiques. Ainsi, dans le cadre de cette étude financée par l'Ademe, le recensement de la documentation pertinente a été réalisé afin d'établir un état des lieux des batteries d'essais existantes ainsi qu'un bilan des éventuels traitements statistiques utilisés. Généralement, deux méthodes sont mentionnées pour sélectionner les essais biologiques constitutifs d'une batterie : une méthode a priori se fondant sur des critères prédéfinis et une méthode a posteriori se fondant sur des résultats obtenus sur une large série d'échantillons. La plupart des travaux publiés à ce jour traitent de la sélection des tests a posteriori. Il apparaît également que les batteries d'essais proposées ne sont pas dédiées à une application particulière mais sont utilisées pour évaluer la toxicité des échantillons et/ou pour comparer des essais entre eux. En ce qui concerne les méthodes statistiques relevées dans la littérature, il apparaît que ces outils ont été souvent mal ou sous-employés. La plupart du temps, les auteurs proposent une démarche a posteriori fondée sur l'application d'une analyse en composantes principales (ACP) pour déterminer le choix des tests formant la batterie. Enfin, une démarche optimale en cinq étapes a été proposée pour l'élaboration de batteries d'essais. Cette démarche n'a pas été observée dans la littérature et mériterait d'être étudiée d'une façon plus approfondie, dans un proche avenir. En conclusion, cette revue bibliographique a fait ressortir que peu d'auteurs fournissent un argumentaire en ce qui concerne l'élaboration des batteries d'essais qu'ils ont mis en oeuvre. Concernant le type d'utilisation des batteries, il est apparu qu'elles n'étaient pas dédiées à certains scénarii comme la valorisation agricole. Par ailleurs, il est intéressant de noter que la moitié des batteries sélectionnées intègre une double approche directe et indirecte