South Gloucestershire and Stroud College, also known as SGS College, is a college of further education and higher education based in South Gloucestershire and Stroud, England. It was established in February 2012 following the merger of Filton College and Stroud College. The college is made up of six campuses located in and around Bristol, North Bristol, South Gloucestershire and Stroud. In 2021, the college launched University Centre WISE | West of England Institute of Specialist Education after being awarded university centre status by the Department for Education.
Xanthomonas spp. are increasingly recognized as a global threat to agriculture, impacting a broad range of economically important crops. We report the whole-genome sequences of six Xanthomonas strains isolated from tomato and pepper plants in Turkey that were experiencing symptoms of bacterial spot disease. Phylogenomic analysis with representative Xanthomonas genomes from each species revealed that three of these strains belonged to Xanthomonas perforans, two to Xanthomonas euvesicatoria and one to Xanthomonas campestris. We then analysed the phylogenomic relatedness of these strains with other strains from these respective species and characterized their type III secreted effector content. These genomic data represent a valuable resource for understanding the genetic diversity and local epidemiology of bacterial spot disease in Turkey.
IntroductionWhile numerous healthy volunteers contribute to clinical trials on a yearly basis, the aspect of including these participants in the drug development process, like the patient-centric approaches, are not well known. To gain broader insights in the aspect of healthy participant engagement, preferences, and motivation, we performed a European wide survey. Additionally, a literature search on the topic of healthy participant engagement was performed.MethodsAn online questionnaire containing 61 questions on demographics, motivation, informed consent, engagement, transparency, and preferences was created, combining five-point Likert and open text field answers. The questionnaire was translated in several European languages and shared among early phase clinical trial units within Europe. Additionally, a literature search was performed on healthy participant engagement.ResultsA total of 4,349 completed questionnaires were eligible for analysis. Countries with adequate number of responses were Belgium, France, Netherlands, Germany, Hungary and United Kingdom. Altruistic motivation was the primary reason for participation. The Informed Consent Form (ICF) paragraphs on risk, schedule of assessments and restriction was better read than the financial aspects, ethics and data protection, with variations between gender, age, experience and country. Only 71.2% of the responders finds an ICF written in correct lay language and 44.6% is willing to assist in ICF review on adequate lay language. In the literature search, no articles described healthy participant engagement.DiscussionThe benefit of including patients in the drug development process has been proven in multiple publications and is a movement that is being advocated more frequently. Healthy participant engagement is not known yet, while similar benefits can be suggested. As altruistic reasons are the main motivation for participation, engaging participant in the clinical trials might enhance their motivation. Together with all stakeholders, description of methods for healthy participant engagement should be initiated to increase willingness to contribute to clinical trials.
BACKGROUND:Fexinidazole, a nitroimidazole antiparasitic, has been approved to treat human African trypanosomiasis (HAT) worldwide. In vitro studies have shown that fexinidazole inhibits and weakly induces CYP3A4/5. In silico predictions indicated that fexinidazole, which has a significant intestinal and liver first-pass metabolism, could increase the exposure of a sensitive probe substrate of CYP3A4 by two-fold. Therefore, this study investigated the potential clinical drug-drug interactions (DDIs) of fexinidazole with CYP3A4 substrates. OBJECTIVE:To assess the effect of fexinidazole on the pharmacokinetics of midazolam, a well-recognised sensitive CYP3A4 substrate (and its metabolites 1-hydroxy-midazolam and N-glucuronide-midazolam) in humans and to elucidate the underlying mechanism of the in vivo DDI. METHODS:This was a phase I, open-label, single-centre, non-randomised, single-sequence, two-period, two-treatment crossover study. The study population consisted of 12 healthy male and female participants. The two treatment periods included Period 1, wherein a single midazolam dose was administered on Day 1, and Period 2, wherein fexinidazole was administered once daily from Day 1 to Day 5, with a single midazolam dose co-administered on Day 4. Key pharmacokinetic parameters of midazolam and its main metabolites, including the maximum plasma concentration (Cmax), area under the curve (AUC), and elimination half-life (t1/2z), were evaluated. Additionally, in vitro assessments (protein-binding and CYP enzyme induction studies) were conducted to investigate potential mechanisms contributing to the observed interaction. RESULTS:Contrary to the in vitro predictions, fexinidazole significantly reduced midazolam exposure in vivo, resulting in a reduction of 39% in Cmax, 57% in AUC, and 33% in t1/2z, without significant changes in tmax. Mechanistic studies ruled out reduced absorption and plasma protein displacement as potential causes. At clinically relevant concentrations, fexinidazole and M1 exhibited weak induction potential on CYP3A4/5 and no significant induction on other enzymes. Further, in vivo investigations on midazolam metabolites confirmed that CYP3A4/5 induction by fexinidazole was the primary mechanism, increasing the first-pass metabolism and clearance of midazolam. The metabolic ratios of 1-hydroxy-midazolam and N-glucuronide-midazolam were increased by 1.63-fold and 1.24-fold, respectively. Steady-state exposures of fexinidazole and its metabolites M1 and M2 were consistent with those previously assessed in other clinical studies. CONCLUSION:While in vitro studies showed weak induction by fexinidazole and its metabolite M1, the clinical pharmacokinetic data provided stronger evidence, supporting the conclusion that fexinidazole is a moderate inducer of CYP3A4/5 in vivo. Thus, it is suggested to update the product information by including the potential for CYP3A4/5 induction in vitro, removing the risk of CYP3A4 inhibition in vivo, and adding clinical interaction data highlighting the risk of induction on drugs predominantly metabolised by CYP3A4/5. TRIAL REGISTRATION:EudraCT No.: 2021-004533-36.
The Variable Size and Cost Bin Packing Problem (VSCBPP) focuses on minimizing the overall cost of containers used to pack a specified set of items. This problem has significant applications across various fields, including energy, cargo transport, and informatics, among others. Most research conducted on this problem has concentrated on enhancing solution methodologies. Recently, some studies have investigated the use of fuzzy approaches to VSCBPP, which allow for the relaxation of certain constraints. In this paper, we introduce a metaheuristic method for solving the fuzzy version of VSCBPP, facilitating the simultaneous relaxation of two constraints: the overloading of containers and the exclusion of specific items from the packing process. Consequently, this two-dimensional fuzzy relaxation of the VSCBPP enables us to derive a range of solutions that present varying trade-offs between cost and the satisfaction levels of the original constraints. We employ mechanisms from the multi-objective metaheuristic approach to maximize the degrees of relaxation while minimizing the original cost function. To demonstrate the efficacy of our proposed solution, we utilized two well-known multi-objective evolutionary P-metaheuristics (Multi-Objective Genetic Algorithm and NSGA-II) and two S-metaheuristics (Multi-Objective Local Search and Ulungu Multi-Objective Simulated Annealing) specifically tailored for the fuzzy version of the VSCBPP. Computational experiments were conducted on 39 instances to validate the effectiveness of this approach.
