Metabolic Effects Associated with ICS in Patients with COPD and Comorbid Type 2 Diabetes: A Historical Matched Cohort Study

Background Management guidelines for chronic obstructive pulmonary disease (COPD) recommend that inhaled corticosteroids (ICS) are prescribed to patients with the most severe symptoms. However, these guidelines have not been widely implemented by physicians, leading to widespread use of ICS in patients with mild-to-moderate COPD. Of particular concern is the potential risk of worsening diabetic control associated with ICS use. Here we investigate whether ICS therapy in patients with COPD and comorbid type 2 diabetes mellitus (T2DM) has a negative impact on diabetic control, and whether these negative effects are dose-dependent. Methods and Findings This was a historical matched cohort study utilising primary care medical record data from two large UK databases. We selected patients aged >= 40 years with COPD and T2DM, prescribed ICS (n = 1360) or non-ICS therapy (n = 2642) between 2008 and 2012. The primary endpoint was change in HbA(1c) between the baseline and outcome periods. After 1:1 matching, each cohort consisted of 682 patients. Over the 12-18-month outcome period, patients prescribed ICS had significantly greater increases in HbA1c values compared with those prescribed non-ICS therapies; adjusted difference 0.16% (95% confidence interval [Cl]: 0.05-0.27%) in all COPD patients, and 0.25% (95% Cl: 0.10-0.40%) in mild-to-moderate COPD patients. Patients in the ICS cohort also had significantly more diabetes-related general practice visits per year and received more frequent glucose strip prescriptions, compared with those prescribed non-ICS therapies. Patients prescribed higher cumulative doses of ICS (> 250 mg) had greater odds of increased HbA(1c) and/or receiving additional antidiabetic medication, and increased odds of being above the Quality and Outcomes Framework (QOF) target for HbA1c levels, compared with those prescribed lower cumulative doses ( Conclusion For patients with COPD and comorbid T2DM, ICS therapy may have a negative impact on diabetes control. Patients prescribed higher cumulative doses of ICS may be at greater risk of diabetes progression

Early Onset Prion Disease from Octarepeat Expansion Correlates with Copper Binding Properties

Insertional mutations leading to expansion of the octarepeat domain of the prion protein (PrP) are directly linked to prion disease. While normal PrP has four PHGGGWGQ octapeptide segments in its flexible N-terminal domain, expanded forms may have up to nine additional octapeptide inserts. The type of prion disease segregates with the degree of expansion. With up to four extra octarepeats, the average onset age is above 60 years, whereas five to nine extra octarepeats results in an average onset age between 30 and 40 years, a difference of almost three decades. In wild-type PrP, the octarepeat domain takes up copper (Cu2+) and is considered essential for in vivo function. Work from our lab demonstrates that the copper coordination mode depends on the precise ratio of Cu2+ to protein. At low Cu2+ levels, coordination involves histidine side chains from adjacent octarepeats, whereas at high levels each repeat takes up a single copper ion through interactions with the histidine side chain and neighboring backbone amides. Here we use both octarepeat constructs and recombinant PrP to examine how copper coordination modes are influenced by octarepeat expansion. We find that there is little change in affinity or coordination mode populations for octarepeat domains with up to seven segments (three inserts). However, domains with eight or nine total repeats (four or five inserts) become energetically arrested in the multi-histidine coordination mode, as dictated by higher copper uptake capacity and also by increased binding affinity. We next pooled all published cases of human prion disease resulting from octarepeat expansion and find remarkable agreement between the sudden length-dependent change in copper coordination and onset age. Together, these findings suggest that either loss of PrP copper-dependent function or loss of copper-mediated protection against PrP polymerization makes a significant contribution to early onset prion disease

The genome-wide dynamics of purging during selfing in maize

Self-fertilization (also known as selfing) is an important reproductive strategy in plants and a widely applied tool for plant genetics and plant breeding. Selfing can lead to inbreeding depression by uncovering recessive deleterious variants, unless these variants are purged by selection. Here we investigated the dynamics of purging in a set of eleven maize lines that were selfed for six generations. We show that heterozygous, putatively deleterious single nucleotide polymorphisms are preferentially lost from the genome during selfing. Deleterious single nucleotide polymorphisms were lost more rapidly in regions of high recombination, presumably because recombination increases the efficacy of selection by uncoupling linked variants. Overall, heterozygosity decreased more slowly than expected, by an estimated 35% to 40% per generation instead of the expected 50%, perhaps reflecting pervasive associative overdominance. Finally, three lines exhibited marked decreases in genome size due to the purging of transposable elements. Genome loss was more likely to occur for lineages that began with larger genomes with more transposable elements and chromosomal knobs. These three lines purged an average of 398 Mb from their genomes, an amount equivalent to three Arabidopsis thaliana genomes per lineage, in only a few generations

Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis

BACKGROUND: Most patients with chronic obstructive pulmonary disease (COPD) receive inhaled long-acting bronchodilators and inhaled corticosteroids. Conventional meta-analyses established that these drugs reduce COPD exacerbations when separately compared with placebo. However, there are relatively few head-to-head comparisons and conventional meta-analyses focus on single comparisons rather than on a simultaneous analysis of competing drug regimens that would allow rank ordering of their effectiveness. Therefore we assessed, using a networkmeta analytic technique, the relative effectiveness of the common inhaled drug regimes used to reduce exacerbations in patients with COPD. METHODS: We conducted a systematic review and searched existing systematic reviews and electronic databases for randomized trials of >=4 weeks' duration that assessed the effectiveness of inhaled drug regimes on exacerbations in patients with stable COPD. We extracted participants and intervention characteristics from included trials and assessed their methodological quality. For each treatment group we registered the proportion of patients with >=1 exacerbation during follow-up. We used treatment-arm based logistic regression analysis to estimate the absolute and relative effects of inhaled drug treatments while preserving randomization within trials. RESULTS: We identified 35 trials enrolling 26,786 patients with COPD of whom 27% had >=1 exacerbation. All regimes reduced exacerbations statistically significantly compared with placebo (odds ratios ranging from 0.71 (95%confidence interval [CI] 0.64 to 0.80) for long-acting anticholinergics to 0.78 (95% CI 0.70 to 0.86) for inhaled corticosteroids). Compared with long-acting bronchodilators alone, combined treatment was not more effective (comparison with long-acting beta-agonists: odds ratio 0.93 [95% CI 0.84 to 1.04] and comparison with long-acting anticholinergics: odds ratio 1.02 [95% CI 0.90 to 1.16], respectively). If FEV1 was 40% predicted. This effect modification was significant for inhaled corticosteroids (P=0.02 for interaction) and combination treatment (P=0.01) but not for long-acting anticholinergics (P=0.46). A limitation of this analysis is its exclusive focus on exacerbations and lack of FEV1 data for individual patients. CONCLUSIONS: We found no evidence that one single inhaled drug regimen is more effective than another in reducing exacerbations. Inhaled corticosteroids when added to long-acting beta-agonists reduce exacerbations only in patients with COPD with FEV1<=40%

Population genomics of speciation and admixture

The application of population genomics to the understanding of speciation has led to the emerging field of speciation genomics. This has brought new insight into how divergence builds up within the genome during speciation and is also revealing the extent to which species can continue to exchange genetic material despite reproductive barriers. It is also providing powerful new approaches for linking genotype to phenotype in admixed populations. In this chapter, we give an overview of some of the methods that have been used and some of the novel insights gained. We also outline some of the pitfalls of the most commonly used methods and possible problems with interpretation of the results

Influence of nonuniform kinetics on particle aggregation

Many pathways for the synthesis of novel materials involve aggregation processes that occur in the presence of diffusion barriers and spatially nonuniform kinetics (i.e., the ratio of the timescales of diffusion and reaction depends on the cluster size). In this study, we simulate clusters that grow by diffusion and spatially nonhomogeneous kinetics on two-dimensional square lattices. The influence of nonuniform kinetics on the fractal dimension, particle density distribution, and average diffusion path length is investigated. It is found that if the simulations are performed for a sufficiently long time, the fractal dimension and packing density are not significantly influenced. Specifically, the decrease in the fractal dimension and the increase in the packing density as compared to their values inthe case of diffusion-limited aggregation are relatively small. However, the effective diffusion path length prior to attachment is significantly enhanced, especially for smaller cluster sizes. The implications of these observations for particle aggregation processes are discussed.link_to_subscribed_fulltex

Morphology of conducting polymeric coatings: Quantitative comparison between theory and experiment

The density profile of electrosynthesized polymeric layers on carbon fibers is obtained from gravimetric and scanning electron microscopy (SEM) data. The coating density ρ is found to decrease with increasing radial distance, r, subject to the power law ρ(r)∝1/√r. Based on a modified diffusion-limited aggregation (DLA) model, it is shown that lattice Monte Carlo simulation of the coating process predicts the experimentally observed power law exponent. © 2003 Elsevier Science Ltd. All rights reserved.link_to_subscribed_fulltex