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العلوم
يعد هذا الكتاب العلوم وهو مخصص للأطفال تستهدف الطفولة المبكرة وتعمل على استثمار الطفل في بناء المهارات المختلفة المرتبطة بالخيال والابتكار وقوة الشخصية والبحث عن حلول إبداعية ويستمد الطفل من خلالها الكثير من العلم والمعرفة والمعلومات ويعد من المنهج السلوكي التربوي رائع يعلم الطفل كيف يستخلص من مشكلاته وكيف يبني شخصيته بشكل مميز.
Book
Improving cost-efficiency of faecal genotyping: New tools for elephant species
Despite the critical need for non-invasive tools to improve monitoring of wildlife populations, especially for endangered and elusive species, faecal genetic sampling has not been adopted as regular practice, largely because of the associated technical challenges and cost. Substantial work needs to be undertaken to refine sample collection and preparation methods in order to improve sample set quality and provide cost-efficient tools that can effectively support wildlife management. In this study, we collected an extensive set of forest elephant (Loxodonta cyclotis) faecal samples throughout Gabon, Central Africa, and prepared them for genotyping using 107 single-nucleotide polymorphism assays. We developed a new quantitative polymerase chain reaction (PCR) assay targeting a 130-bp nuclear DNA fragment and demonstrated its suitability for degraded samples in all three elephant species. Using this assay to compare the efficacy of two sampling methods for faecal DNA recovery, we found that sampling the whole surface of a dung pile with a swab stored in a small tube of lysis buffer was a convenient method producing high extraction success and DNA yield. We modelled the influence of faecal quality and storage time on DNA concentration in order to provide recommendations for optimized collection and storage. The maximum storage time to ensure 75% success was two months for samples collected within 24 hours after defecation and extended to four months for samples collected within one hour. Lastly, the real-time quantitative PCR assay allowed us to predict genotyping success and pre-screen DNA samples, thus further increasing the cost-efficiency of our approach. We recommend combining the validation of an efficient sampling method, the build of in-country DNA extraction capacity for reduced storage time and the development of species-specific quantitative PCR assays in order to increase the cost-efficiency of routine non-invasive DNA analyses and expand the use of next-generation markers to non-invasive samples.
Journal Article
Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation
In this phase 2 study, single oral doses of gepotidacin were ≥95% effective for bacterial eradication in culture-proven uncomplicated urogenital gonorrhea. New antibiotics for drug-resistant Neisseria gonorrhoeae are urgently needed. With additional evaluation, gepotidacin may provide an alternative therapeutic option.
Abstract
Background
In this phase 2 study, we evaluated the efficacy and safety of oral gepotidacin, a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor, for the treatment of uncomplicated urogenital gonorrhea.
Methods
Adult participants with suspected urogenital gonorrhea were enrolled and completed baseline (day 1) and test-of-cure (days 4-8) visits. Pretreatment and posttreatment urogenital swabs were collected for Neisseria gonorrhoeae (NG) culture and susceptibility testing. Pharyngeal and rectal swab specimens were collected if there were known exposures. Participants were stratified by gender and randomized 1:1 to receive a 1500-mg or 3000-mg single oral dose of gepotidacin.
Results
The microbiologically evaluable population consisted of 69 participants, with NG isolated from 69 (100%) urogenital, 2 (3%) pharyngeal, and 3 (4%) rectal specimens. Microbiological eradication of NG was achieved by 97%, 95%, and 96% of participants (lower 1-sided exact 95% confidence interval bound, 85.1%, 84.7%, and 89.1%, respectively) for the 1500-mg, 3000-mg, and combined dose groups, respectively. Microbiological cure was achieved in 66/69 (96%) urogenital infections. All 3 failures were NG isolates that demonstrated the highest observed gepotidacin minimum inhibitory concentration of 1 µg/mL and a common gene mutation. At the pharyngeal and rectal sites, 1/2 and 3/3 NG isolates, respectively, demonstrated microbiological cure. There were no treatment-limiting adverse events for either dose.
Conclusions
This study demonstrated that single, oral doses of gepotidacin were ≥95% effective for bacterial eradication of NG in adult participants with uncomplicated urogenital gonorrhea.
Clinical Trials Registration
NCT02294682.
Journal Article
COVID-19 has revealed a pandemic of inequality
Pervasive inequality in the Americas has fueled the COVID-19 pandemic and must be tackled.
Journal Article
Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea
BackgroundGepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is active against most strains of Neisseria gonorrhoeae (N. gonorrhoeae). Phase II data suggested higher exposures were needed for efficacy and to suppress resistance development. A translational approach using in vitro pharmacokinetic/pharmacodynamic (PK/PD) and clinical data was used to select a gepotidacin dose for a phase III study. In this narrative review of previously shown data, we summarise how a translational approach based on in vitro PK/PD and population PK modelling and simulation data was undertaken to select a dosing regimen for the ongoing phase III gepotidacin study in participants with uncomplicated urogenital gonorrhoea.MethodsFor dose selection, prior in vitro minimum inhibitory concentrations (MICs) and PK/PD data were available. PK modelling was conducted to determine a dose that would limit plasma concentrations to less than 14 µg/mL (as concentrations above this are associated with QT prolongation and effects associated with acetylcholinesterase inhibition) while maintaining ≥90% probability of target attainment (PTA) for efficacy and resistance suppression against N. gonorrhoeae isolates with gepotidacin MICs ≤1 µg/mL.ResultsTwo 3000 mg gepotidacin doses, administered 10–12 hours apart, resulted in PTA of ≥97.5% and ≥91.7% for gepotidacin MICs ≤1 µg/mL for the ratio of the area under the free drug plasma concentration–time curve over 24 hours to the MIC (fAUC0–24/MIC) efficacy, and resistance suppression targets of 40 and 46, respectively, but limited the occurrence of maximum plasma concentrations ≥14 µg/mL.ConclusionsTwo gepotidacin 3000 mg oral doses 10–12 hours apart provide ~2-fold higher systemic exposures, increase efficacy for higher gepotidacin MIC N. gonorrhoeae isolates, reduce resistance potential and limit plasma concentrations of potential safety concern, compared with higher doses.
Journal Article
High Resolution STEM Images of the Human Tooth Enamel Crystals
High-resolution scanning transmission electron microscopy (STEM) images of human tooth enamel crystals, mainly in the high-angle annular dark-field (STEM-HAADF) mode, are presented in this work along the [1000], [10-11]. and [1-210] directions. These images allow knowing some structural details at the nanometric level of the human tooth enamel crystals and of the central dark line (CDL) observed at their centers. The transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) images of the CDL showed the Fresnel contrast. In the STEM bright-field (STEM-BF) and annular-dark-field (STEM-ADF) images, the CDL was observed as an unstrain hydroxyapatite (HAP)-like zone but surrounded by a strained zone. In the STEM-HAADF images, the CDL appeared with a weak contrast, and its contrasts’ thickness was registered between 3 and 8 Å. The arrangement obtained in the STEM-HAADF images by identifying the bright points with the Ca atoms produced the superposition of the HAP atomic sites, mainly along the [0001] direction. The findings provide further information on the structure details at the center of enamel crystals, which favors the anisotropic carious dissolution at the CDL.
Journal Article
Aberration-Corrected Transmission Electron Microscopic Study of the Central Dark Line Defect in Human Tooth Enamel Crystals
Angstrom resolution images of human tooth enamel (HTE) crystallites were obtained using aberration-corrected high-resolution transmission electron microscopy and atomic-resolution scanning transmission electron microscopy in the modes of bright field, annular dark field, and high-angle annular dark-field. Images show that the central dark line (CDL) defect observed around the center of the HTE crystals is a site for caries formation in the HTE and has a thickness of ~0.2 nm. Results also suggest that the CDL goes through one of the OH− planes.
Journal Article
Microbiome recovery in adult females with uncomplicated urinary tract infections in a randomised phase 2A trial of the novel antibiotic gepotidacin (GSK2140944)
Background
With increasing concerns about the impact of frequent antibiotic usage on the human microbiome, it is important to characterize the potential for such effects in early antibiotic drug development clinical trials. In a randomised Phase 2a clinical trial study that evaluated the pharmacokinetics of repeated oral doses of gepotidacin, a first-in-chemical-class triazaacenaphthylene antibiotic with a distinct mechanism of action, in adult females with uncomplicated urinary tract infections for gepotidacin (GSK2140944) we evaluated the potential changes in microbiome composition across multiple time points and body-sites (
ClinicalTrials.gov
: NCT03568942).
Results
Samples of gastrointestinal tract (GIT), pharyngeal cavity and vaginal microbiota were collected with consent from 22 patients at three time points relative to the gepotidacin dosing regimen; Day 1 (pre-dose), Day 5 (end of dosing) and Follow-up (Day 28 ± 3 days). Microbiota composition was determined by DNA sequencing of 16S rRNA gene variable region 4 amplicons. By Day 5, significant changes were observed in the microbiome diversity relative to pre-dose across the tested body-sites. However, by the Follow-up visit, microbiome diversity changes were reverted to compositions comparable to Day 1. The greatest range of microbiome changes by body-site were GIT followed by the pharyngeal cavity then vagina. In Follow-up visit samples we found no statistically significant occurrences of pathogenic taxa.
Conclusion
Our findings suggest that gepotidacin alteration of the human microbiome after 5 days of dosing is temporary and rebound to pre-dosing states is evident within the first month post-treatment. We recommend that future antibiotic drug trials include similar exploratory investigations into the duration and context of microbiome modification and recovery.
Trial registration
NCT03568942
. Registered 26 June 2018.
Journal Article
Pharmacokinetics, safety, and tolerability of gepotidacin administered as single or repeat ascending doses, in healthy adults and elderly subjects
Gepotidacin, a novel, first‐in‐class triazaacenaphthylene antibiotic, inhibits bacterial DNA replication by a distinct mechanism of action. We report the pharmacokinetics (PKs), safety, and tolerability of gepotidacin following single or multiple ascending doses. Studies 1 and 2 were randomized, single‐blind, placebo‐controlled trials in healthy adults aged 18–60 years, who received single (study 1 [NCT02202187]; 100–3000 mg) or repeat (study 2 [NCT01706315]; 400 mg twice daily to 2000 mg thrice daily) ascending doses of gepotidacin. Study 3 (NCT02045849) was an open‐label, three‐part, study in healthy adults; here, we report on part 3, a two‐period, repeat‐dose, crossover study. Healthy elderly participants received repeat 1500 mg gepotidacin twice daily with or without a moderate‐fat meal. Primary end points were PKs (studies 1 and 2) and safety (studies 1 and 3 part 3). Gepotidacin PK parameters were comparable across all ages and were dose proportional. In all studies, gepotidacin was readily absorbed with median time to maximum concentration observed ranging from 1.0 to 4.0 h across all doses. Median apparent terminal phase half‐life was consistent across studies and doses (range: 5.97–19.2 h). Steady‐state was achieved following repeated dosing for 3–5 days; gepotidacin PK parameters were time invariant after repeated oral dosing. A moderate‐fat meal did not affect gepotidacin PK parameters. Gepotidacin was generally well‐tolerated, with no drug‐related serious adverse events reported. Collectively, these PK and safety data across a wide range of doses in healthy participants aged greater than or equal to 18 years support the development of gepotidacin in further clinical studies.
Journal Article