A repeat-dose thorough QT study of inhaled fluticasone furoate/vilanterol combination in healthy subjects

AIMS

This study was designed as a thorough QT (TQT) study to evaluate the effects of fluticasone furoate(FF)/vilanterol (VI) in healthy subjects. Supportive data from a TQT study conducted with FF are also presented.

METHODS

This was a randomized, placebo-and positive-controlled, double-dummy, double-blind, four-way crossover study, in which healthy subjects (n = 85) were randomized to 7 days of once-daily treatment of FF/VI (200/25 or 800/100 μg) or placebo or single-dose oral moxifloxacin (single-blind, 400 mg). In the supportive TQT study, subjects (n = 40) were randomized to single-dose inhaled FF(4000 μg), oral moxifloxacin (400 mg) or placebo.

RESULTS

There was a lack of effect of FF/VI (200/25 μg) on QTcF (Fridericia''s correction); all time-matched mean differences from baseline relative to placebo (0–24 h) were <5 ms, with upper 90% confidence intervals (CI) of <10 ms. At 800/100 μg, FF/VI had no significant clinicaleffect on QTcF except at 30 min postdose when the 90% CI was >10 ms [mean (90% CI), 9.6 ms (7.2, 12.0)]. No effect on QTci (individually corrected) was observed at either strength of FF/VI, with mean time-matched treatment differences <5 ms at all time points [upper 90% CIs <10 ms (0–24 h)]. Assay sensitivity was confirmed; moxifloxacin prolonged QTcF and QTci, with time-matched mean differences from baseline relative toplacebo of >10 ms (1–8 h postdose).

CONCLUSIONS

Repeat once-daily dosing of FF/VI (200/25 μg), which is the highest therapeutic strength used in phase III studies, is not associated with QTc prolongation in healthy subjects. Supratherapeutic strength FF/VI (800/100 μg) demonstrated a small transient effect on QTcF but not on QTci.     

Persistence of SARS-CoV-2 N-Antibody Response in Healthcare Workers,London, UK

Prospective serosurveillance of severe acute respiratory syndrome coronavirus 2 in 1,069 healthcare workers in London, UK, demonstrated that nucleocapsid antibody titers were stable and sustained for <12 weeks in 312 seropositive participants. This finding was consistent across demographic and clinical variables and contrasts with reports of short-term antibody waning.     

Chronic treatment with tempol does not significantly ameliorate renal tissue hypoxia or disease progression in a rodent model of polycystic kidney disease

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Nicotine dependence and likelihood of quitting smoking

This study examined the hypothesis that high nicotine dependent smokers would have more difficulty with initial cessation of smoking than low dependent smokers as measured by the Fagerstrom Tolerance Questionnaire (FTQ). Two replications of a nicotine-fading smoking program were conducted at different worksites. Significantly less heavily dependent smokers quit smoking during treatment. The correlation between the FTQ and smoking rate at posttreatment remained even when the pretreatment rate of smoking was partialled out. It was concluded that the concept of nicotine dependence should be re-examined especially in the context of improving the quit rates of behavioral programs at the worksite.     

The impact of different nanoparticle surface chemistry and size on uptake and toxicity in a murine macrophage cell line

This study investigated the uptake, kinetics and cellular distribution of different surface coated quantum dots (QDs) before relating this to their toxicity. J774.A1 cells were treated with organic, COOH and NH₂ (PEG) surface coated QDs (40 nM). Model 20 nm and 200 nm COOH-modified coated polystyrene beads (PBs) were also examined (50 μg ml^− 1). The potential for uptake of QDs was examined by both fixed and live cell confocal microscopy as well as by flow cytometry over 2 h. Both the COOH 20 nm and 200 nm PBs were clearly and rapidly taken up by the J774.A1 cells, with uptake of 20 nm PBs being relatively quicker and more extensive. Similarly, COOH QDs were clearly taken up by the macrophages. Uptake of NH₂ (PEG) QDs was not detectable by live cell imaging however, was observed following 3D reconstruction of fixed cells, as well as by flow cytometry. Cells treated with organic QDs, monitored by live cell imaging, showed only a small amount of uptake in a relatively small number of cells. This uptake was insufficient to be detected by flow cytometry. Imaging of fixed cells was not possible due to a loss in cell integrity related to cytotoxicity. A significant reduction (p < 0.05) in the fluorescent intensity in a cell-free environment was found with organic QDs, NH₂ (PEG) QDs, 20 nm and 200 nm PBs at pH 4.0 (indicative of an endosome) after 2 h, suggesting reduced stability. No evidence of exocytosis was found over 2 h. These findings confirm that surface coating has a significant influence on the mode of NP interaction with cells, as well as the subsequent consequences of that interaction.     

The oral health care experiences of NSW Aboriginal Community Controlled Health Services

Objectives: Aboriginal people continue to experience a disproportionately heavy burden of oral disease. A range of oral health services may be available to Aboriginal communities, including those provided by Aboriginal Community Controlled Health Services (ACCHSs). This study explored the oral health care experiences and activities of ACCHSs to inform policy and program decision making. Methods: Mixed methods, including an online survey and semi‐structured interviews with senior ACCHS staff, were used. Areas of inquiry included perceived community need for oral health care, oral health care models, accessibility of other oral health services and barriers to providing oral health care. Twenty‐nine NSW ACCHSs participated in the study. Results: The activities of NSW ACCHSs in oral health care are diverse and reflect the localised approaches they take to delivering primary health care. ACCHSs commonly face barriers in delivering oral health care, as do Aboriginal communities in accessing other oral health services. Conclusion: NSW ACCHSs are important but under‐acknowledged providers of a range of oral health services to Aboriginal communities and are well placed to provide this care as part of their comprehensive primary health care model. Implications: ACCHS roles in improving Aboriginal oral health would be strengthened by greater acknowledgement of their contributions and expertise and the development of transparent, long‐term funding policies that respond to community need.     

Occupational therapy students' attitudes towards inclusion education in Australia,United Kingdom,United States and Taiwan

This international, cross‐cultural study investigated the attitudes of occupational therapy students from Australia, United Kingdom, United States and Taiwan towards inclusive education for students with disabilities. The possible impact of professional education on students' attitudes was also explored. A total of 485 students from 11 entry‐level occupational therapy education programmes from Australia, the United Kingdom, the United Sates and Taiwan participated in the study. Among them, 264 were freshmen (first‐year students) and 221 were seniors (final‐year students). Data collected from a custom‐designed questionnaire were analysed both quantitatively and qualitatively. In general, the occupational therapy students reported having positive attitudes towards inclusion. Considerable differences, however, existed among the student groups from the four countries. Professional education appeared to have a significant impact on students' attitudes towards inclusion from first year to senior year. Although students were in favour of inclusion, they also cautioned that their support for inclusive practices depended on various factors such as adequate preparation, support and assistance to students with disabilities. Limitations of the study included the small, convenience sample and different degree structures of the participating programmes. Future research studies need to compare occupational therapy students' attitudes with students from other health care professions. A longitudinal study on the impact of the professional education programme on students' attitudes towards inclusive education is warranted. Copyright © 2009 John Wiley & Sons, Ltd.     

Direct Impairment of Vascular Function by Diesel Exhaust Particulate through Reduced Bioavailability of Endothelium-Derived Nitric Oxide Induced by Superoxide Free Radicals

Background

Diesel exhaust particulate (DEP) is a key arbiter of the adverse cardiovascular effects of air pollution.

Objectives

We assessed the in vitro effects of DEP on vascular function, nitric oxide (NO) availability, and the generation of oxygen-centered free radicals.

Methods

We assessed the direct vascular effects of DEP (10–100 μg/mL) in isolated rat aortic rings using myography. We investigated NO scavenging and oxygen-centered free radical generation using an NO electrode and electron paramagnetic resonance (EPR) with the Tempone-H (1-hydroxyl-2,2,6,6-tetramethyl-4-oxo-piperidine) spin trap, respectively.

Results

Acetylcholine-induced relaxation was attenuated by DEP (maximum relaxation reduced from 91 ± 4% to 49 ± 6% with 100 μg/mL DEP; p < 0.001) but was restored by superoxide dismutase (SOD; maximum relaxation, 73 ± 6%; p < 0.001). DEP caused a modest inhibition of relaxation to NO donor drugs, an effect that could be reversed by SOD (p < 0.01). At 10 μg/mL, DEP did not affect verapamil-induced relaxation (p = 0.73), but at 100 μg/mL DEP inhibited relaxation (p < 0.001) by a mechanism independent of SOD. NO concentrations generated by 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO; 10 μM) were reduced by DEP (100 μg/mL; from 5.2 ± 0.4 to 3.3 ± 0.4 μM; p = 0.002). Free radical generation was increased by DEP (10 μg/mL; 9-fold increase in EPR spectra; p = 0.004) in a manner that could be attenuated by SOD (p = 0.015).

Conclusions

DEP caused oxidative stress through the generation of oxygen-centered free radicals that reduced the bioavailability of endothelium-derived NO without prior interaction with the lung or vascular tissue. These findings provide a mechanism for the adverse cardiovascular effects of particulate air pollution.     

Test of Visual Perceptual Skills--Revised: An Overview and Critique

Paediatric occupational therapists frequently assess and treat children and youth presenting with visual perceptual problems. Difficulties in this skill area can have a negative impact on a number of occupational performance and functional skill areas for children and youth including their ability to successfully complete activities of daily living, participate in play/recreational activities, complete school-related work and accomplish age-related developmental tasks. Therefore, it is important for occupational therapists to utilize visual perceptual assessments that possess sound measurement properties (such as validity, reliability, responsiveness and clinical utility). The Test of Visual Perceptual Skills--Revised is an instrument frequently used by paediatric occupational therapists to evaluate children and youth presenting with visual perceptual dysfunction. Occupational therapists need to be cognizant of the measurement properties of the assessments they use in order to provide the best quality care for the paediatric clients they serve. Therefore, a review and critique of the Test of Visual Perceptual Skills--Revised is presented.     

Quantitative analysis of selegiline and three metabolites (N-desmethylselegiline,methamphetamine, and amphetamine) in human plasma by high-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry

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