| 1. |
- Garcia-Prats, Anthony J., et al.
(författare)
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Pharmacokinetics and safety of high-dose rifampicin in children with TB : the Opti-Rif trial
- 2021
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 76:12, s. 3237-3246
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. Objectives: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. Patients and methods: The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L.h, the geometric mean area under the concentration-time curve from 0 to 24h (AUC(0-24)) among adults receiving a 35mg/kg dose]. Results: Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range=0.4-11.7). Evaluated doses were similar to 35 mg/kg (days 1-14) and similar to 50 mg/kg (day 15) for cohort 2 and similar to 60 mg/kg (days 1-14) and similar to 75mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure. Conclusions: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
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| 2. |
- Kaplan, Alexander, et al.
(författare)
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Imaging in cooperation with modeling of selected defect mechanisms during fiber laser welding of stainless steel
- 2008
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Ingår i: Congress proceedings. - Orlando, Fla : Laser institute of America. - 9780912035123 ; , s. 789-798
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Konferensbidrag (refereegranskat)abstract
- Fiber laser welding of stainless steel was studied for different joint configurations and gaps. The higher focusing capability of fiber lasers compared to traditional Nd:YAG and CO2 lasers creates different, usually smaller, keyhole and melt pool geometries. These geometrical aspects, accompanied by a different laser energy redistribution, are essential for the weld pool dynamics and the resulting joint, with or without defects. Typical defects identified during fiber laser welding were spatter, humping, or lack of material at the top or root. High-speed imaging enables observation of the geometry and motions of the melt pool surface and keyhole during welding. This is illuminated by an additional diode laser permitting spectral filtering and also the metal vapor dynamics can be visualized. Mathematical modeling provides the possibility to estimate and study additional phenomena that are difficult to measure, such as effects inside the melt volume or the impact of surface tension forces on dynamic melt motion. For recorded melt surface motion images, in particular, the corresponding surface tension forces and other mechanisms can be estimated by cooperative complementary modeling, enabling to draw conclusions. This advanced method was carried out for the different joint and defect cases studied, resulting in an illustrated theoretical description of the observed physical phenomena.
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| 3. |
- Karia, Ajay Mahendrarai, et al.
(författare)
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Community pharmacist workflow : Space for Pharmacy-based Interventions and Consultation TimE study protocol
- 2020
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Ingår i: International Journal of Pharmacy Practice. - : John Wiley & Sons. - 0961-7671 .- 2042-7174. ; 28:5, s. 441-448
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Tidskriftsartikel (refereegranskat)abstract
- Background Pharmacists' roles are expanding to delivering a wider set of professional services including medication management optimisation, vaccinations and screening services. Robust research determining whether pharmacists have the capacity to offer such services in the Australian community pharmacy setting is lacking. This protocol details a mixed methods study that investigates the variation in pharmacists' daily tasks and the workspace they work in as a measure of their workload capacity for expanding pharmacy services. Methods An observational time and motion study will be conducted in up to twenty community pharmacies in metropolitan and rural regions of Australia. A trained observer will follow a pharmacist and record the type, location and duration of tasks undertaken over the course of their working day. Data will be collected and analysed using the electronic Work Observation Method By Activity Timing (WOMBAT) tool. Pharmacists' work patterns will be described as time for each task, and by proportionating multitasking and interruptions. This information will be combined with workspace data collected using floor plans, photographs and a qualitative assessment of the working environment completed by the observer. Analysis will include heat-mapped floor plans visually highlighting pharmacist movements. Discussion Pharmacists may provide solutions to the strained health workforce and system. There is limited quantitative evidence on whether pharmacists have the time or work setting to support such needs. The use of time and motion methodology is novel to Australian community pharmacy research, and the findings will provide a better understanding of pharmacists' capacity and work environment.
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| 4. |
- Karia, Ajay, et al.
(författare)
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Pharmacist's time spent : Space for Pharmacy-based Interventions and Consultation TimE (SPICE)-an observational time and motion study
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective To describe the pharmacists' workflow, including tasks and time spent, to better understand their work capacity.Design Cross-sectional, observational, time and motion study.Setting Community pharmacies in Western Australia and New South Wales, Australia.Participants Currently registered and practising pharmacists were approached using snowball sampling and selected using purposive techniques to obtain balance representation of metropolitan and rural pharmacies, as well as high and low script volumes where possible.Results Twenty-four pharmacists across 15 pharmacies participated during the 135 sessions totalling over 274 hours of observation. Dispensing (30%), indirect patient services (17%), counselling (15%) and professional management activities (15%) were the top four duties pharmacists performed, while only 2% of time was spent on professional services such as pain clinics and influenza vaccinations. Tasks were frequently interrupted and often performed simultaneously. Breaks and consumer-contact times were limited. More time was spent on professional service activities in non-metropolitan pharmacies, in pharmacies with greater daily prescription volumes and those with one or more support pharmacists.Conclusions This is the first study to quantify the pharmacists' tasks in Australian community pharmacies. Much time is being spent on dispensing, supply and management activities with little time for providing additional professional services. An extra supporting pharmacist is likely necessary to increase professional services. These findings could support future research around barriers and enablers of conducive workflows and of extended professional services.
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| 5. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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| 6. |
- Ngwalero, Precious, et al.
(författare)
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Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis
- 2021
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:11
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Tidskriftsartikel (refereegranskat)abstract
- Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.
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| 7. |
- Sjöquist, Emma S., et al.
(författare)
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Physical Activity Coaching of Patients with Rheumatoid Arthritis in Everyday Practice : A Long-term Follow-up
- 2011
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Ingår i: Musculoskeletal Care. - Chichester : John Wiley & Sons. - 1478-2189 .- 1557-0681. ; 9:2, s. 75-85
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the long-term effects on perceived general health, disease activity, pain, activity limitation and cognitive behavioural factors of a one-year coaching programme performed in ordinary physical therapy practice to promote the adoption of health-enhancing physical activity in patients with early rheumatoid arthritis (RA).METHODS: A total of 228 patients with early RA, from 10 rheumatology clinics in Sweden, were randomly assigned to an intervention group (IG; n = 94) or a control group (CG; n = 134). The IG was coached by physical therapists during the first year to adopt health-enhancing levels of physical activity (30 minutes/day, moderately intensive, ≥ 4 days/week). No coaching was given during the subsequent year between post-intervention and follow-up. Follow-up assessment consisted of a postal questionnaire on physical activity and of visual analogue scales for ratings of general health perception and pain. The Health Assessment Questionnaire Disability Index (HAQ) and the Disease Activity Score in 28 joints (DAS 28) were collected at regular medical check-ups.RESULTS: Sixty-five (69%) participants in the IG and 92 (69%) in the CG completed the entire study period by filling in the follow-up questionnaire on physical activity two years after baseline. The intervention seemed to lack any significant influence on long-term outcome. However, different patterns of change in physical activity behaviour were observed in the two groups.CONCLUSIONS: No long-term improvement in perceived general health or other outcomes were found in the follow-up. This may partly be because the intervention lacked several important behavioural elements for physical activity maintenance. Copyright © 2011 John Wiley & Sons, Ltd.
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| 8. |
- Svensson, Elin, 1985-, et al.
(författare)
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Relative bioavailability of bedaquiline tablets suspended in water : Implications for dosing in children
- 2018
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 84:10, s. 2384-2392
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets.Methods: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48h was conducted at two occasions 14days apart in each participant after administration of 400mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability.Results: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.Conclusions: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.
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