Influence of macrolide maintenance therapy and bacterial colonisation on exacerbation frequency and progression of COPD (COLUMBUS):Study protocol for a randomised controlled trial

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by progressive development of airflow limitation that is poorly reversible. Because of a poor understanding of COPD pathogenesis, treatment is mostly symptomatic and new therapeutic strategies are limited. There is a direct relationship between the severity of the disease and the intensity of the inflammatory response. Besides smoking, one of the hypotheses for the persistent airway inflammation is the presence of recurrent infections. Macrolide antibiotics have bacteriostatic as well as anti-inflammatory properties in patients with cystic fibrosis and other inflammatory pulmonary diseases. There is consistent evidence that macrolide therapy reduces infectious exacerbations, decreases the requirement for additional antibiotics and improves nutritional measures. Because of these positive effects we hypothesised that maintenance macrolide therapy may also have beneficial effects in patients with COPD who have recurrent exacerbations. The effects on development of bacterial resistance to macrolides due to this long-term treatment are unknown. Until now, studies investigating macrolide therapy in COPD are limited. The objective of this study is to assess whether maintenance treatment with macrolide antibiotics in COPD patients with three or more exacerbations in the previous year decreases the exacerbation rate in the year of treatment and to establish microbial resistance due to the long-term treatment. METHODS/DESIGN: The study is set up as a prospective randomised double-blind placebo-controlled single-centre trial. A total of 92 patients with COPD who have had at least three exacerbations of COPD in the previous year will be included. Subjects will be randomised to receive either azithromycin 500 mg three times a week or placebo. Our primary endpoint is the reduction in the number of exacerbations of COPD in the year of treatment. DISCUSSION: We investigate whether long-term therapy with macrolide antibiotics can prevent exacerbations in patients with COPD. Additionally, our study aims to assess the effect of long-term use of macrolide on the development of antimicrobial resistance and on inflammatory parameters related to COPD. We believe this study will provide more data on the effects of macrolide treatment in patients in COPD and will add more knowledge on its working mechanisms. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT0098524

Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial

Background Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care. Methods We did a randomised, double-blind, placebo-controlled, single-centre trial in the Netherlands between May 19, 2010, and June 18, 2013. Patients (>= 18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone (<= 10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00985244. Findings We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1.94 (95% CI 1.50-2.52) for the azithromycin group and 3.22 (2.62-3.97) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0.58, 95% CI 0.42-0.79; p=0.001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0.015). Interpretation Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care

Is heart rate variability related to gait impairment in patients with Parkinson's disease? A pilot study.

Contains fulltext : 80070.pdf (publisher's version ) (Closed access)BACKGROUND AND PURPOSE: Impairments in gait and autonomic function are common in patients with Parkinson's disease (PD). These are likely independent symptoms, based on different etiologic mechanisms. However, a few recent reports have observed an association between motor function, in particular gait impairment, and autonomic function in PD. In those studies, the Unified Parkinson's Disease Rating Scale (UPDRS) was used to evaluate gait and motor function. The present study was performed to further examine this putative relationship using quantitative measures of autonomic function and gait in order to shed light on the underlying pathophysiology of these symptoms. METHODS: Nine healthy young, 15 healthy elderly and 18 PD patients were studied. Heart rate variability (HRV) measures were collected during rest. Gait speed, swing time and swing time variability were measured during a 1-min walk at comfortable speed. The motor portion of the UPDRS was also evaluated in all subjects. RESULTS: HRV values were highest in the young adults, intermediate in the healthy elderly controls, and lowest in the PD patients. Gait measures tended to deteriorate with age and were significantly worse in the PD patients, compared to the elderly controls. HRV was not correlated with any measure of gait performance (p>0.129) nor with the UPDRS-motor score (p>0.147). DISCUSSION AND CONCLUSIONS: The present findings support the idea that gait and autonomic function impairments co-exist in PD, but their etiology is based on distinct pathophysiological pathways, with minimal overlap

On composite marginal likelihoods

Clustered data, Computational efficiency, Composite likelihood, Genetics, Longitudinal data, Missing data, Pairwise likelihood, Pseudolikelihood, Spatial data, Statistical efficiency, Survival analysis, Time series,

The Genome Sequence of Taurine Cattle:A Window to Ruminant Biology and Evolution

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.Fil: Bovine Genome Sequencing and Analysis Consortium. Bovine Genome Sequencing And Analysis Consortium; Estados UnidosFil: Amadio, Ariel Fernando. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Santa Fe. Estación Experimental Agropecuaria Rafaela; ArgentinaFil: Poli, Mario Andres. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Genética; Argentin