Innovative cross-over study designs were explored in non-human primate (NHP) studies to determine the value of this approach for the evaluation of drug efficacy against tuberculosis (TB). Firstly, ...the pharmacokinetics (PK) of each of the drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E), that are standardly used for the treatment of tuberculosis, was established in the blood of macaques after oral dosing as a monotherapy or in combination. Two studies were conducted to evaluate the pharmacokinetics and pharmacodynamics of different drug combinations using cross-over designs. The first employed a balanced, three-period Pigeon design with an extra period; this ensured that treatment by period interactions and carry-over could be detected comparing the treatments HR, HZ and HRZ using H37Rv as the challenge strain of
(M. tb). Although the design accounted for considerable variability between animals, the three regimens evaluated could not be distinguished using any of the alternative endpoints assessed. However, the degree of pathology achieved using H37Rv in the model during this study was less than expected. Based on these findings, a second experiment using a classical AB/BA design comparing HE with HRZ was conducted using the M. tb Erdman strain. More extensive pathology was observed, and differences in computerized tomography (CT) scores and bacteriology counts in the lungs were detected, although due to the small group sizes, clearer differences were not distinguished. Type 1 T helper (Th1) cell response profiles were characterized using the IFN-γ ELISPOT assay and revealed differences between drug treatments that corresponded to decreases in disease burden. Therefore, the studies performed support the utility of the NHP model for the determination of PK/PD of TB drugs, although further work is required to optimize the use of cross-over study designs.
Innovative cross-over study designs were explored in non-human primate (NHP) studies to determine the value of this approach for the evaluation of drug efficacy against tuberculosis (TB). Firstly, ...the pharmacokinetics (PK) of each of the drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E), that are standardly used for the treatment of tuberculosis, was established in the blood of macaques after oral dosing as a monotherapy or in combination. Two studies were conducted to evaluate the pharmacokinetics and pharmacodynamics of different drug combinations using cross-over designs. The first employed a balanced, three-period Pigeon design with an extra period; this ensured that treatment by period interactions and carry-over could be detected comparing the treatments HR, HZ and HRZ using H37Rv as the challenge strain of Mycobacterium tuberculosis (M. tb). Although the design accounted for considerable variability between animals, the three regimens evaluated could not be distinguished using any of the alternative endpoints assessed. However, the degree of pathology achieved using H37Rv in the model during this study was less than expected. Based on these findings, a second experiment using a classical AB/BA design comparing HE with HRZ was conducted using the M. tb Erdman strain. More extensive pathology was observed, and differences in computerized tomography (CT) scores and bacteriology counts in the lungs were detected, although due to the small group sizes, clearer differences were not distinguished. Type 1 T helper (Th1) cell response profiles were characterized using the IFN-γ ELISPOT assay and revealed differences between drug treatments that corresponded to decreases in disease burden. Therefore, the studies performed support the utility of the NHP model for the determination of PK/PD of TB drugs, although further work is required to optimize the use of cross-over study designs.
Scoping reviews are used to identify knowledge gaps, set research agendas, and identify implications for decision-making. The conduct and reporting of scoping reviews is inconsistent in the ...literature. We conducted a scoping review to identify: papers that utilized and/or described scoping review methods; guidelines for reporting scoping reviews; and studies that assessed the quality of reporting of scoping reviews.
We searched nine electronic databases for published and unpublished literature scoping review papers, scoping review methodology, and reporting guidance for scoping reviews. Two independent reviewers screened citations for inclusion. Data abstraction was performed by one reviewer and verified by a second reviewer. Quantitative (e.g. frequencies of methods) and qualitative (i.e. content analysis of the methods) syntheses were conducted.
After searching 1525 citations and 874 full-text papers, 516 articles were included, of which 494 were scoping reviews. The 494 scoping reviews were disseminated between 1999 and 2014, with 45% published after 2012. Most of the scoping reviews were conducted in North America (53%) or Europe (38%), and reported a public source of funding (64%). The number of studies included in the scoping reviews ranged from 1 to 2600 (mean of 118). Using the Joanna Briggs Institute methodology guidance for scoping reviews, only 13% of the scoping reviews reported the use of a protocol, 36% used two reviewers for selecting citations for inclusion, 29% used two reviewers for full-text screening, 30% used two reviewers for data charting, and 43% used a pre-defined charting form. In most cases, the results of the scoping review were used to identify evidence gaps (85%), provide recommendations for future research (84%), or identify strengths and limitations (69%). We did not identify any guidelines for reporting scoping reviews or studies that assessed the quality of scoping review reporting.
The number of scoping reviews conducted per year has steadily increased since 2012. Scoping reviews are used to inform research agendas and identify implications for policy or practice. As such, improvements in reporting and conduct are imperative. Further research on scoping review methodology is warranted, and in particular, there is need for a guideline to standardize reporting.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Laboratory test-tank experiments and an oceanographic field programme carried out in the Chukchi sea near point Franklin, Alas., confirmed the phenomenon of surface brine extrusion during sea ice ...formation, followed by sinking and eventual gravity-induced flow along the bottom. Small quantities of dissolved aromatic hydrocarbons resulting from spills of crude oil or refined products during periods of ice growth could be transported to the benthos with sinking brine. These aromatic components would no longer be subject to loss by evaporation and could only be diluted by eventual mixing with uncontaminated water. This would proceed only slowly during the ice-covered period. There are 46 references.
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