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

Cough and its importance in COPD

Patients with COPD most frequently complain of breathlessness and cough and these are both increased during exacerbations. Studies have generally focused on quality of life during end-stage disease, where breathlessness becomes dominant and cough less important. There are very little data on the frequency and severity of cough in COPD or its impact on quality of life at different stages of disease. Little is known about the factors that influence objective cough counts in COPD. Cough may be a marker for progressive disease in milder COPD patients who continue to smoke, and it may be useful in case-finding for milder disease in the community. The cough reflex sensitivity is heightened in COPD compared with healthy volunteers and similar to that in subjects with asthma. The degree of airflow obstruction does not predict cough reflex sensitivity or objective cough counts, implying an independent process. Effective treatments for cough in COPD have not yet been identified. Improved outcome measures of cough, a better understanding of cough in the natural history of COPD, and its importance to patients are needed

Asthma and COPD in primary health care, quality according to national guidelines: a cross-sectional and a retrospective study

<p>Abstract</p> <p>Background</p> <p>In recent decades international and national guidelines have been formulated to ensure that patients suffering from specific diseases receive evidence-based care. In 2004 the National Swedish Board of Health and Welfare (SoS) published guidelines concerning the management of patients with asthma and COPD. The guidelines identify quality indicators that should be fulfilled. The aim of this study was to survey structure and process indicators, according to the asthma and COPD guidelines, in primary health care, and to identify correlations between structure and process quality results.</p> <p>Methods</p> <p>A cross-sectional study of existing structure by using a questionnaire, and a retrospective study of process quality based on a review of measures documented in asthma and COPD medical records. All 42 primary health care centres in the county council of Östergötland, Sweden, were included.</p> <p>Results</p> <p>All centres showed high quality regarding structure, although there was a large difference in time reserved for Asthma and COPD Nurse Practice (ACNP). The difference in reserved time was reflected in process quality results. The time needed to reach the highest levels of spirometry and current smoking habit documentation was between 1 and 1 1/2 hours per week per 1000 patients registered at the centre. Less time resulted in fewer patients examined with spirometry, and fewer medical records with smoking habits documented. More time did not result in higher levels, but in more frequent contact with each patient. In the COPD group more time resulted in higher levels of pulse oximetry and weight registration.</p> <p>Conclusion</p> <p>To provide asthma and COPD patients with high process quality in primary care according to national Swedish guidelines, at least one hour per week per 1000 patients registered at the primary health care centre should be reserved for ACNP.</p

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

Expansion of the Multi-Link Frontier™ Coronary Bifurcation Stent: Micro-Computed Tomographic Assessment in Human Autopsy and Porcine Heart Samples

BACKGROUND: Treatment of coronary bifurcation lesions remains challenging, beyond the introduction of drug eluting stents. Dedicated stent systems are available to improve the technical approach to the treatment of these lesions. However dedicated stent systems have so far not reduced the incidence of stent restenosis. The aim of this study was to assess the expansion of the Multi-Link (ML) Frontier™ stent in human and porcine coronary arteries to provide the cardiologist with useful in-vitro information for stent implantation and selection. METHODOLOGY/PRINCIPAL FINDINGS: Nine ML Frontier™ stents were implanted in seven human autopsy heart samples with known coronary artery disease and five ML Frontier™ stents were implanted in five porcine hearts. Proximal, distal and side branch diameters (PD, DD, SBD, respectively), corresponding opening areas (PA, DA, SBA) and the mean stent length (L) were assessed by micro-computed tomography (micro-CT). PD and PA were significantly smaller in human autopsy heart samples than in porcine heart samples (3.54±0.47 mm vs. 4.04±0.22 mm, p = 0.048; 10.00±2.42 mm(2) vs. 12.84±1.38 mm(2), p = 0.034, respectively) and than those given by the manufacturer (3.54±0.47 mm vs. 4.03 mm, p = 0.014). L was smaller in human autopsy heart samples than in porcine heart samples, although data did not reach significance (16.66±1.30 mm vs. 17.30±0.51 mm, p = 0.32), and significantly smaller than that given by the manufacturer (16.66±1.30 mm vs. 18 mm, p = 0.015). CONCLUSIONS/SIGNIFICANCE: Micro-CT is a feasible tool for exact surveying of dedicated stent systems and could make a contribution to the development of these devices. The proximal diameter and proximal area of the stent system were considerably smaller in human autopsy heart samples than in porcine heart samples and than those given by the manufacturer. Special consideration should be given to the stent deployment procedure (and to the follow-up) of dedicated stent systems, considering final intravascular ultrasound or optical coherence tomography to visualize (and if necessary optimize) stent expansion

Detecting unilateral phrenic paralysis by acoustic respiratory analysis

The consequences of phrenic nerve paralysis vary from a considerable reduction in respiratory function to an apparently normal state. Acoustic analysis of lung sound intensity (LSI) could be an indirect non-invasive measurement of respiratory muscle function, comparing activity on the two sides of the thoracic cage. Lung sounds and airflow were recorded in ten males with unilateral phrenic paralysis and ten healthy subjects (5 men/5 women), during progressive increasing airflow maneuvers. Subjects were in sitting position and two acoustic sensors were placed on their back, on the left and right sides. LSI was determined from 1.2 to 2.4 L/s between 70 and 2000 Hz. LSI was significantly greater on the normal (19.3±4.0 dB) than the affected (5.7±3.5 dB) side in all patients (p = 0.0002), differences ranging from 9.9 to 21.3 dB (13.5±3.5 dB). In the healthy subjects, the LSI was similar on both left (15.1±6.3 dB) and right (17.4±5.7 dB) sides (p = 0.2730), differences ranging from 0.4 to 4.6 dB (2.3±1.6 dB). There was a positive linear relationship between the LSI and the airflow, with clear differences between the slope of patients (about 5 dB/L/s) and healthy subjects (about 10 dB/L/s). Furthermore, the LSI from the affected side of patients was close to the background noise level, at low airflows. As the airflow increases, the LSI from the affected side did also increase, but never reached the levels seen in healthy subjects. Moreover, the difference in LSI between healthy and paralyzed sides was higher in patients with lower FEV1 (%). The acoustic analysis of LSI is a relevant non-invasive technique to assess respiratory function. This method could reinforce the reliability of the diagnosis of unilateral phrenic paralysis, as well as the monitoring of these patients.Peer ReviewedPostprint (published version

Multidetector computed tomography angiography for assessment of in-stent restenosis: meta-analysis of diagnostic performance

<p>Abstract</p> <p>Background</p> <p>Multi-detector computed tomography angiography (MDCTA)of the coronary arteries after stenting has been evaluated in multiple studies.</p> <p>The purpose of this study was to perform a structured review and meta-analysis of the diagnostic performance of MDCTA for the detection of in-stent restenosis in the coronary arteries.</p> <p>Methods</p> <p>A Pubmed and manual search of the literature on in-stent restenosis (ISR) detected on MDCTA compared with conventional coronary angiography (CA) was performed. Bivariate summary receiver operating curve (SROC) analysis, with calculation of summary estimates was done on a stent and patient basis. In addition, the influence of study characteristics on diagnostic performance and number of non-assessable segments (NAP) was investigated with logistic meta-regression.</p> <p>Results</p> <p>Fourteen studies were included. On a stent basis, Pooled sensitivity and specificity were 0.82(0.72–0.89) and 0.91 (0.83–0.96). Pooled negative likelihood ratio and positive likelihood ratio were 0.20 (0.13–0.32) and 9.34 (4.68–18.62) respectively. The exclusion of non-assessable stents and the strut thickness of the stents had an influence on the diagnostic performance. The proportion of non-assessable stents was influenced by the number of detectors, stent diameter, strut thickness and the use of an edge-enhancing kernel.</p> <p>Conclusion</p> <p>The sensitivity of MDTCA for the detection of in-stent stenosis is insufficient to use this test to select patients for further invasive testing as with this strategy around 20% of the patients with in-stent stenosis would be missed. Further improvement of scanner technology is needed before it can be recommended as a triage instrument in practice. In addition, the number of non-assessable stents is also high.</p