Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014

Irreducible uncertainty in near-term climate projections

Model simulations of the next few decades are widely used in assessments of climate change impacts and as guidance for adaptation. Their non-linear nature reveals a level of irreducible uncertainty which it is important to understand and quantify, especially for projections of near-term regional climate. Here we use large idealised initial condition ensembles of the FAMOUS global climate model with a 1 %/year compound increase in CO2 levels to quantify the range of future temperatures in model-based projections. These simulations explore the role of both atmospheric and oceanic initial conditions and are the largest such ensembles to date. Short-term simulated trends in global temperature are diverse, and cooling periods are more likely to be followed by larger warming rates. The spatial pattern of near-term temperature change varies considerably, but the proportion of the surface showing a warming is more consistent. In addition, ensemble spread in inter-annual temperature declines as the climate warms, especially in the North Atlantic. Over Europe, atmospheric initial condition uncertainty can, for certain ocean initial conditions, lead to 20 year trends in winter and summer in which every location can exhibit either strong cooling or rapid warming. However, the details of the distribution are highly sensitive to the ocean initial condition chosen and particularly the state of the Atlantic meridional overturning circulation. On longer timescales, the warming signal becomes more clear and consistent amongst different initial condition ensembles. An ensemble using a range of different oceanic initial conditions produces a larger spread in temperature trends than ensembles using a single ocean initial condition for all lead times. This highlights the potential benefits from initialising climate predictions from ocean states informed by observations. These results suggest that climate projections need to be performed with many more ensemble members than at present, using a range of ocean initial conditions, if the uncertainty in near-term regional climate is to be adequately quantified

Core or Cusps: The Central Dark Matter Profile of a Strong Lensing Cluster with a Bright Central Image at Redshift 1

We report on SPT-CLJ2011-5228, a giant system of arcs created by a cluster at z = 1.06. The arc system is notable for the presence of a bright central image. The source is a Lyman break galaxy at z s = 2.39 and the mass enclosed within the Einstein ring of radius 14 arcsec is $\sim {10}^{14.2}\ {M}_{\odot }$. We perform a full reconstruction of the light profile of the lensed images to precisely infer the parameters of the mass distribution. The brightness of the central image demands that the central total density profile of the lens be shallow. By fitting the dark matter as a generalized Navarro–Frenk–White profile—with a free parameter for the inner density slope—we find that the break radius is ${270}_{-76}^{+48}$ kpc, and that the inner density falls with radius to the power −0.38 ± 0.04 at 68% confidence. Such a shallow profile is in strong tension with our understanding of relaxed cold dark matter halos; dark matter-only simulations predict that the inner density should fall as ${r}^{-1}$. The tension can be alleviated if this cluster is in fact a merger; a two-halo model can also reconstruct the data, with both clumps (density varying as ${r}^{-0.8}$ and ${r}^{-1.0}$) much more consistent with predictions from dark matter-only simulations. At the resolution of our Dark Energy Survey imaging, we are unable to choose between these two models, but we make predictions for forthcoming Hubble Space Telescope imaging that will decisively distinguish between them

Core or Cusps: The Central Dark Matter Profile of a Strong Lensing Cluster with a Bright Central Image at Redshift 1

We report on SPT-CLJ2011-5228, a giant system of arcs created by a cluster at z = 1.06. The arc system is notable for the presence of a bright central image. The source is a Lyman break galaxy at z s = 2.39 and the mass enclosed within the Einstein ring of radius 14 arcsec is $\sim {10}^{14.2}\ {M}_{\odot }$. We perform a full reconstruction of the light profile of the lensed images to precisely infer the parameters of the mass distribution. The brightness of the central image demands that the central total density profile of the lens be shallow. By fitting the dark matter as a generalized Navarro–Frenk–White profile—with a free parameter for the inner density slope—we find that the break radius is ${270}_{-76}^{+48}$ kpc, and that the inner density falls with radius to the power −0.38 ± 0.04 at 68% confidence. Such a shallow profile is in strong tension with our understanding of relaxed cold dark matter halos; dark matter-only simulations predict that the inner density should fall as ${r}^{-1}$. The tension can be alleviated if this cluster is in fact a merger; a two-halo model can also reconstruct the data, with both clumps (density varying as ${r}^{-0.8}$ and ${r}^{-1.0}$) much more consistent with predictions from dark matter-only simulations. At the resolution of our Dark Energy Survey imaging, we are unable to choose between these two models, but we make predictions for forthcoming Hubble Space Telescope imaging that will decisively distinguish between them

Follow-up of internal mammary artery stent with 64-slice CT

We present a case of 81-year-old woman complaining chest pain after minimal efforts who underwent multiple coronary artery bypass grafts (CABGs) during the last 15 years. A significant in-stent re-stenosis was found at ostium of left internal mammary artery (LIMA). A non-invasive CT coronary angiography (CT-CA) was performed after 6-month follow-up. CT-CA is a reliable non-invasive technique for the follow-up of stents in coronary artery bypass grafts

Adapting a Markov Monte Carlo simulation model for forecasting the number of Coronary Artery Revascularisation Procedures in an era of rapidly changing technology and policy

<p>Abstract</p> <p>Background</p> <p>Treatments for coronary heart disease (CHD) have evolved rapidly over the last 15 years with considerable change in the number and effectiveness of both medical and surgical treatments. This period has seen the rapid development and uptake of statin drugs and coronary artery revascularization procedures (CARPs) that include Coronary Artery Bypass Graft procedures (CABGs) and Percutaneous Coronary Interventions (PCIs). It is difficult in an era of such rapid change to accurately forecast requirements for treatment services such as CARPs. In a previous paper we have described and outlined the use of a Markov Monte Carlo simulation model for analyzing and predicting the requirements for CARPs for the population of Western Australia (Mannan et al, 2007). In this paper, we expand on the use of this model for forecasting CARPs in Western Australia with a focus on the lack of adequate performance of the (standard) model for forecasting CARPs in a period during the mid 1990s when there were considerable changes to CARP technology and implementation policy and an exploration and demonstration of how the standard model may be adapted to achieve better performance.</p> <p>Methods</p> <p>Selected key CARP event model probabilities are modified based on information relating to changes in the effectiveness of CARPs from clinical trial evidence and an awareness of trends in policy and practice of CARPs. These modified model probabilities and the ones obtained by standard methods are used as inputs in our Markov simulation model.</p> <p>Results</p> <p>The projected numbers of CARPs in the population of Western Australia over 1995–99 only improve marginally when modifications to model probabilities are made to incorporate an increase in effectiveness of PCI procedures. However, the projected numbers improve substantially when, in addition, further modifications are incorporated that relate to the increased probability of a PCI procedure and the reduced probability of a CABG procedure stemming from changed CARP preference following the introduction of PCI operations involving stents.</p> <p>Conclusion</p> <p>There is often knowledge and sometimes quantitative evidence of the expected impacts of changes in surgical practice and procedure effectiveness and these may be used to improve forecasts of future requirements for CARPs in a population.</p

Stent implantation into the tracheo-bronchial system in rabbits: histopathologic sequelae in bare metal vs. drug-eluting stents

BACKGROUND: Stent implantation into the tracheo-bronchial system may be life-saving in selected pediatric patients with otherwise intractable stenosis of the upper airways. Following implantation, significant tissue proliferation may occur, requiring re-interventions. We sought to evaluate the effect of immunosuppressive coating of the stents on the extent of tissue proliferation in an animal model. METHODS: Bare metal and sirolimus-coated stents (Bx Sonic and Cypher Select, Johnson & Johnson, Cordis) were implanted into non-stenotic lower airways of New Zealand white rabbits (weight 3.1 to 4.8 kg). Three stents with sirolimus coating and six bare metal stents could be analyzed by means of histology and immunohistochemistry 12 months after implantation. RESULTS: On a macroscopic evaluation, all stents were partially covered with a considerable amount of whitish tissue. Histologically, these proliferations contained fiber-rich connective tissue and some fibromuscular cells without significant differences between both stent types. The superficial tissue layer was formed by typical respiratory epithelium and polygonal cells. Abundant lymphocyte infiltrations and moderate granulocyte infiltrations were found in both groups correspondingly, whereas foreign-body reaction was more pronounced around sirolimus-eluting stents. CONCLUSIONS: After stent implantation in the tracheo-bronchial system of rabbits, we found tissue reactions comparable to those seen after stent implantation into the vascular system. There was no difference between coated and uncoated stents with regard to quality and quantity of tissue proliferation. We found, however, a significantly different inflammatory reaction with a more pronounced foreign-body reaction in sirolimus-coated stents. In our small series, drug-eluting stents did not exhibit any benefit over bare metal stents in an experimental setting