Towards a fair and transparent research participant compensation and reimbursement framework in Viet Nam

Background: Providing compensation for participants in clinical research is well established and whilst international guidelines exist, defining a context specific and fair compensation for participants in low resource settings is challenging due to ethical concerns and the lack of practical, national compensation and reimbursement frameworks. Methods: We reviewed OUCRU (Oxford University Clinical Research Unit) internal reimbursement documentation over a ten-year period and conducted a scoping literature review to expand our knowledge of compensation and reimbursement practices including ethical concerns. We developed a preliminary reimbursement framework that was presented to Community Advisory Boards (CAB) and clinical investigators to assess its applicability, fairness, and transparency. Results: The main topics discussed at the workshops centered on fairness and whether the reimbursements could be perceived as financial incentives. Other decisive factors in the decision making process were altruism and the loss of caregivers’ earnings. Investigators raised the issue of additional burdens, whereas the CAB members were focused on non-monetary elements such as the healthcare quality the patients would receive. All elements discussed were reviewed and where possible, incorporated into the final framework. Conclusion: Our new reimbursement framework provides a consistent, fair and transparent decision-making process and will be implemented across all future OUCRU clinical research in Viet Nam

Pharmacokinetic/pharmacodynamic integration and modelling of florfenicol for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida

Pharmacokinetic-pharmacodynamic (PK/PD) integration and modelling were used to predict dosage schedules for florfenicol for two pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida. Pharmacokinetic data were pooled for two bioequivalent products, pioneer and generic formulations, administered intramuscularly to pigs at a dose rate of 15 mg/kg. Antibacterial potency was determined in vitro as minimum inhibitory concentration (MIC) and Mutant Prevention Concentration in broth and pig serum, for six isolates of each organism. For both organisms and for both serum and broth MICs, average concentration:MIC ratios over 48 h were similar and exceeded 2.5:1 and times greater than MIC exceeded 35 h. From in vitro time-kill curves, PK/PD modelling established serum breakpoint values for the index AUC24h/MIC for three levels of inhibition of growth, bacteriostasis and 3 and 4log10 reductions in bacterial count; means were 25.7, 40.2 and 47.0 h, respectively, for P. multocida and 24.6, 43.8 and 58.6 h for A. pleuropneumoniae. Using these PK and PD data, together with literature MIC distributions, doses for each pathogen were predicted for: (1) bacteriostatic and bactericidal levels of kill; (2) for 50 and 90% target attainment rates (TAR); and (3) for single dosing and daily dosing at steady state. Monte Carlo simulations for 90% TAR predicted single doses to achieve bacteriostatic and bactericidal actions over 48 h of 14.4 and 22.2 mg/kg (P. multocida) and 44.7 and 86.6 mg/kg (A. pleuropneumoniae). For daily doses at steady state, and 90% TAR bacteriostatic and bactericidal actions, dosages of 6.2 and 9.6 mg/kg (P. multocida) and 18.2 and 35.2 mg/kg (A. pleuropneumoniae) were required. PK/PD integration and modelling approaches to dose determination indicate the possibility of tailoring dose to a range of end-points

Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa.

Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains.IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection

Sex steroids induce membrane stress responses and virulence properties in pseudomonas aeruginosa

© 2020 Vidaillac et al. Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa. This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains. IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection

Unravelling of a mechanism of resistance to colistin in Klebsiella pneumoniae using atomic force microscopy

International audienceObjectives: In this study we focused on the mechanism of colistin resistance in Klebsiella pneumoniae.Methods: We used two strains of K. pneumoniae: a colistin-susceptible strain (K. pneumoniae ATCC 700603, KpATCC) and its colistin-resistant derivative (KpATCCm, MIC of colistin 16 mg/L). We performed a genotypic analysis based on the expression of genes involved in LPS synthesis and L-Ara4N moiety addition. We also explored the status of the mgrB gene. Then, a phenotypic analysis was performed using atomic force microscopy (AFM). The Young modulus was extracted from force curves fitted using the Hertz model, and stiffness values were extracted from force curves fitted using the Hooke model.Results: We failed to observe any variation in the expression of genes implicated in LPS synthesis or L-Ara4N moiety addition in KpATCCm, in the absence of colistin or under colistin pressure (versus KpATCC). This led us to identify an insertional inactivation/mutation in the mgrB gene of KpATCCm. In addition, morphology results obtained by AFM showed that colistin removed the capsule from the susceptible strain, but not from the resistant strain. Nanomechanical data on the resistant strain showed that colistin increased the Young modulus of the capsule. Extend force curves recorded on top of the cells allowed us to make the following hypothesis about the nanoarchitecture of the capsule of the two strains: KpATCC has a soft capsule consisting of one layer, whereas the KpATCCm capsule is harder and organized in several layers.Conclusions: We hypothesize that capsular polysaccharides might be implicated in the mechanism of colistin resistance in K. pneumoniae, depending on its genotype

Development of a Good Clinical Practice inspection checklist to assess clinical trial sites in Vietnam

Background Assessing the capacity of a healthcare institution to conduct and manage clinical research studies is challenging, especially in developing countries where resources are limited. The objective of this study was to develop a practical and transparent tool for the Vietnam Ministry of Health (MOH) to assess institutions’ capacity to lead clinical trials in line with local and international regulations. Methods We reviewed the literature, relevant official international and national guidelines, regulations and checklists for clinical sites’ assessment to identify key indicators of clinical research capacity. We developed a Good Clinical Practice (GCP) inspection checklist consisting of a questionnaire with 30 key criteria, including 16 core criteria and 14 recommended criteria, related to four central aspects of clinical research management (ie, governance, operations, infrastructures and human resources). Following a detailed review and assessment by a panel of experts, sponsors and academic investigators, we assessed the checklist’s applicability in a pilot study involving 10 sites with various clinical research experiences. Results Independently of their clinical research experience, all participating institutions fulfilled most of the core criteria. In contrast, a significant variability was observed in the compliance to recommended capacity criteria, especially those related to governance (certifications and reporting) as well as operations (existence of a clinical research coordination unit or electronic trial management system). Conclusions A GCP inspection checklist was successfully developed to support the MOH in the assessment of institutions’ capacity to conduct clinical research. Additional efforts from all stakeholders are now warranted to provide local sites with sustainable capacity development resources that will further build up and harmonise Vietnamese clinical research settings