Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro

Two solution-based pressurised metered dose inhaler (pMDI) formulations were prepared such that they delivered aerosols with identical mass median aerodynamic diameters, but contained either beclomethasone dipropionate (BDP) alone (glycerol-free formulation) or BDP and glycerol in a 1:1 mass ratio (glycerol-containing formulation). The two formulations were deposited onto Calu-3 respiratory epithelial cell layers cultured at an air interface. Equivalent drug mass (∼1000 ng or ∼2000 ng of the formulation) or equivalent particle number (1000 ng of BDP in the glycerol-containing versus 2000 ng of BDP in the glycerol-free formulation) were deposited as aerosolised particles on the air interfaced surface of the cell layers. The transfer rate of BDP across the cell layer after deposition of the glycerol-free particles was proportional to the mass deposited. In comparison, the transfer of BDP from the glycerol-containing formulation was independent of the mass deposited, suggesting that the release of BDP is modified in the presence of glycerol. The rate of BDP transfer (and the extent of metabolism) over 2 h was faster when delivered in glycerol-free particles, 465.01 ng ± 95.12 ng of the total drug (20.99 ± 4.29%; BDP plus active metabolite) transported across the cell layer, compared to 116.17 ng ± 3.07 ng (6.07 ± 0.16%) when the equivalent mass of BDP was deposited in glycerol-containing particles. These observations suggest that the presence of glycerol in the maturated aerosol particles may influence the disposition of BDP in the lungs.© 2013 Elsevier B.V. All rights reserved

Ramsification and the Ramifications of Prior's Puzzle

Ramsification is a well-known method of defining theoretical terms that figures centrally in a wide range of debates in metaphysics. Prior's puzzle is the puzzle of why, given the assumption that that-clauses denote propositions, substitution of "the proposition that P" for "that P" within the complements of many propositional attitude verbs sometimes fails to preserve truth, and other times fails to preserve grammaticality. On the surface, Ramsification and Prior's puzzle appear to have little to do with each other. But Prior's puzzle is much more general than is ordinarily appreciated, and Ramsification requires a solution to the generalized form of Prior's puzzle. Without such a solution, a wide range of theories will either fail to imply their Ramsey sentences, or have Ramsey sentences that are ill-formed. As a consequence, definitions of theoretical terms given using the Ramsey sentence will be either incorrect or nonsensical. I present a partial solution to the puzzle that requires making use of a neo-Davidsonian language for scientific theorizing, but the would-be Ramsifier still faces serious challenges

The ABCD of usability testing

We introduce a methodology for tracking and auditing feedback, errors and suggestions for software packages. This short paper describes how we innovate on the evaluation mechanism, introducing an (Antecedent, Barrier, Consequence and Development) ABCD form, embedded within an eParticipation platform to enable end users to easily report on any usability issues. This methodology will be utilised to improve the STEP cloud eParticipation platform (part of the current STEP Horizon2020 project http://step4youth.eu. The platform is currently being piloted in real life contexts, with the participation of public authorities that are integrating the eParticipation platform into their regular decision-making practices. The project is involving young people, through engagement and motivation strategies and giving them a voice in Environmental decision making at the local level. The pilot evaluation aims to demonstrate how open engagement needs to be embedded within public sector processes and the usability methodology reported here will help to identify the key barriers for wide scale deployment of the platform

COUNTERFACTUALS AND THE ANALYSIS OF NECESSITY *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73782/1/j.1520-8583.2006.00108.x.pd

Use of Coronary Computed Tomographic Angiography to guide management of patients with coronary disease

Background In a prospective, multicenter, randomized controlled trial, 4,146 patients were randomized to receive standard care or standard care plus coronary computed tomography angiography (CCTA). Objectives The purpose of this study was to explore the consequences of CCTA-assisted diagnosis on invasive coronary angiography, preventive treatments, and clinical outcomes. Methods In post hoc analyses, we assessed changes in invasive coronary angiography, preventive treatments, and clinical outcomes using national electronic health records. Results Despite similar overall rates (409 vs. 401; p = 0.451), invasive angiography was less likely to demonstrate normal coronary arteries (20 vs. 56; hazard ratios [HRs]: 0.39 [95% confidence interval (CI): 0.23 to 0.68]; p < 0.001) but more likely to show obstructive coronary artery disease (283 vs. 230; HR: 1.29 [95% CI: 1.08 to 1.55]; p = 0.005) in those allocated to CCTA. More preventive therapies (283 vs. 74; HR: 4.03 [95% CI: 3.12 to 5.20]; p < 0.001) were initiated after CCTA, with each drug commencing at a median of 48 to 52 days after clinic attendance. From the median time for preventive therapy initiation (50 days), fatal and nonfatal myocardial infarction was halved in patients allocated to CCTA compared with those assigned to standard care (17 vs. 34; HR: 0.50 [95% CI: 0.28 to 0.88]; p = 0.020). Cumulative 6-month costs were slightly higher with CCTA: difference $462 (95$303 to $621). Conclusions In patients with suspected angina due to coronary heart disease, CCTA leads to more appropriate use of invasive angiography and alterations in preventive therapies that were associated with a halving of fatal and non-fatal myocardial infarction. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590

The Growing-Block: Just one thing after another?

In this article, we consider two independently appealing theories—the Growing-Block view and Humean Supervenience—and argue that at least one is false. The Growing-Block view is a theory about the nature of time. It says that (a) past and present things exist, while future things do not, and (b) the passage of time consists in new things coming into existence. Humean Supervenience is a theory about the nature of entities like laws, nomological possibility, counterfactuals, dispositions, causation, and chance. It says that none of these entities are fundamental, since if there were, this would entail the existence of irreducible necessary connections between matters of fact. Instead, these entities supervene on a fundamental, nonnomological “Humean mosaic” of property instances at spacetime points. We will further explain and motivate the Growing-Block view and Humean Supervenience in sections 2 and 3, but first, we turn to our master argument

Pictures, perspective and possibility

10.1007/s11098-009-9337-2Philosophical Studies1492135-15

Coronary CT Angiography and 5-Year Risk of Myocardial Infarction.

BACKGROUND: Although coronary computed tomographic angiography (CTA) improves diagnostic certainty in the assessment of patients with stable chest pain, its effect on 5-year clinical outcomes is unknown. METHODS: In an open-label, multicenter, parallel-group trial, we randomly assigned 4146 patients with stable chest pain who had been referred to a cardiology clinic for evaluation to standard care plus CTA (2073 patients) or to standard care alone (2073 patients). Investigations, treatments, and clinical outcomes were assessed over 3 to 7 years of follow-up. The primary end point was death from coronary heart disease or nonfatal myocardial infarction at 5 years. RESULTS: The median duration of follow-up was 4.8 years, which yielded 20,254 patient-years of follow-up. The 5-year rate of the primary end point was lower in the CTA group than in the standard-care group (2.3% [48 patients] vs. 3.9% [81 patients]; hazard ratio, 0.59; 95% confidence interval [CI], 0.41 to 0.84; P=0.004). Although the rates of invasive coronary angiography and coronary revascularization were higher in the CTA group than in the standard-care group in the first few months of follow-up, overall rates were similar at 5 years: invasive coronary angiography was performed in 491 patients in the CTA group and in 502 patients in the standard-care group (hazard ratio, 1.00; 95% CI, 0.88 to 1.13), and coronary revascularization was performed in 279 patients in the CTA group and in 267 in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91 to 1.27). However, more preventive therapies were initiated in patients in the CTA group (odds ratio, 1.40; 95% CI, 1.19 to 1.65), as were more antianginal therapies (odds ratio, 1.27; 95% CI, 1.05 to 1.54). There were no significant between-group differences in the rates of cardiovascular or noncardiovascular deaths or deaths from any cause. CONCLUSIONS: In this trial, the use of CTA in addition to standard care in patients with stable chest pain resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years than standard care alone, without resulting in a significantly higher rate of coronary angiography or coronary revascularization. (Funded by the Scottish Government Chief Scientist Office and others; SCOT-HEART ClinicalTrials.gov number, NCT01149590 .)

The 3d/4d controversy and non-present objects

The &quot;endurance versus perdurance&quot;, or &quot;3D versus 4D&quot;, controversy has been much-discussed in recent philosophy. But on the standard way of formulating the 3D and 4D views, both views have unwanted consequences. The aim of this paper is to show that this is so, and to present an improved formulation of the views at issue in the 3D/4D controversy. I take it that the clearest and best expression of the standard way of understanding the 3D/4D controversy is to be found in the writings of David Lewis. In his book, On the Plurality of Worlds, Lewis says this: Let us say that something persists iff, somehow or other, it exists at various times; this is the neutral word. Something perdures iff it persists by having different temporal parts, or stages, at different times, though no one part of it is wholly present at more than one time; whereas it endures iff it persists by being wholly present at more than one time. Perdurance corresponds to the way a road persists through space; part of it is here, and part of it is there, and no part is wholly present at two different places. Endurance corresponds to the way a universal, if there are such things, would be wholly presen

Rifaximin Treatment in Hepatic Encephalopathy

Background Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. Methods In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. Results Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P Conclusions Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.