The comparative effectiveness of initiating fluticasone/salmeterol combination therapy via pMDI versus DPI in reducing exacerbations and treatment escalation in COPD: a UK database study

Rupert Jones,1 Jessica Martin,2 Vicky Thomas,3 Derek Skinner,4 Jonathan Marshall,5 Martina Stagno d’Alcontres,2 David Price2,6 1Clinical Trials and Health Research, Institute of Translational and Stratified Medicine, Plymouth University Peninsula School of Medicine and Dentistry, Plymouth, UK; 2Observational and Pragmatic Research Institute, Singapore; 3Cambridge Research Support, Cambridge, UK; 4Optimum Patient Care, Cambridge, UK; 5Mundipharma International Limited, Cambridge, UK; 6Centre for Academic Primary Care, University of Aberdeen, Aberdeen, UK Abstract: Chronic obstructive pulmonary disease (COPD), a complex progressive disease, is currently the third leading cause of death worldwide. One recommended treatment option is fixed-dose combination therapy of an inhaled corticosteroid (ICS)/long-acting β-agonist. Clinical trials suggest pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) show similar efficacy and safety profiles in COPD. Real-world observational studies have shown that combination therapy has significantly greater odds of achieving asthma control when delivered via pMDIs. Our aim was to compare effectiveness, in terms of moderate/severe COPD exacerbations and long-acting muscarinic antagonist (LAMA) prescriptions, for COPD patients initiating fluticasone propionate (FP)/salmeterol xinafoate (SAL) via pMDI versus DPI at two doses of FP (500 and 1,000 µg/d) using a real-life, historical matched cohort study. COPD patients with ≥2 years continuous practice data, ≥2 prescriptions for FP/SAL via pMDI/DPI, and no prescription for ICS were selected from the Optimum Patient Care Research Database. Patients were matched 1:1. Rate of moderate/severe COPD exacerbations and odds of LAMA prescription were analyzed using conditional Poisson and logistic regression, respectively. Of 472 patients on 500 µg/d, we observed fewer moderate/severe exacerbations in patients using pMDI (99 [42%]) versus DPI (115 [49%]) (adjusted rate ratio: 0.71; 95% confidence interval: 0.54, 0.93), an important result since the pMDI is not licensed for COPD in the UK, USA, or China. At 1,000 µg/d, we observed lower LAMA prescription for pMDI (adjusted odds ratio: 0.71; 95% confidence interval: 0.55, 0.91), but no difference in exacerbation rates, potentially due to higher dose of ICS overcoming low lung delivery from the DPI. Keywords: COPD, inhaler type, exacerbations, pneumonia, diabetes, dose-response, inhaled steroid/LABA combination&nbsp

Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA

Alternative lengthening of telomere (ALT) tumors maintain telomeres by a telomerase-independent mechanism and are characterized by a nuclear structure called the ALT-associated PML body (APB). TRF2 is a component of a telomeric DNA/protein complex called shelterin. However, TRF2 function in ALT cells remains elusive. In telomerase-positive tumor cells, TRF2 inactivation results in telomere de-protection, activation of ATM, and consequent induction of p53-dependent apoptosis. We show that in ALT cells this sequence of events is different. First, TRF2 inactivation/silencing does not induce cell death in p53-proficient ALT cells, but rather triggers cellular senescence. Second, ATM is constitutively activated in ALT cells and colocalizes with TRF2 into APBs. However, it is only following TRF2 silencing that the ATM target p53 is activated. In this context, PML is indispensable for p53-dependent p21 induction. Finally, we find a substantial loss of telomeric DNA upon stable TRF2 knockdown in ALT cells. Overall, we provide insight into the functional consequences of shelterin alterations in ALT cells

Actinic keratosis associated with squamous and basal cell carcinomas: an evaluation of neoplastic progression by a standardized AgNOR analysis.

In an attempt to investigate the neoplastic progression in different stages of actinic keratosis (AK), a standardized AgNOR analysis was performed in 94 cases of AK, 35 of which were associated with squamous cell carcinoma (SCC) or basal cell carcinoma (BCC), and in 31 cases of SCC and 22 cases of BCC. The cases were subdivided into low- and high- AgNOR-expressing (AgNOR status) AK by using the mean area of AgNORs per cell (NORA) value (3.996 ?m2) as the cut-off. In AK samples, a progressive increase of the mean NORA value from Stage I to Stage IV was encountered. In addition, a significantly higher mean NORA value was found in the AK cases associated with SCC, in comparison to those without SCC; by contrast, no significant differences in the mean NORA value were noted between AK cases with or without BCC. A highly significant association between a high AgNOR quantity and the coexistence of SCC was encountered in AK; no association was appreciable between the AgNOR quantity and the co-occurrence of BCC. Moreover, when the co-existence of SCC in AK was considered as the reference point, the AK cases associated with SCC mostly (95.5%) presented a high AgNOR quantity (high sensitivity), but only 57.6% of cases without SCC displayed a low AgNOR quantity (low specificity). Additionally, our data document that the standardised AgNOR analysis represents a strong negative predictor for the association between SCC and AK. Indeed, a low AgNOR quantity mostly is associated with AK cases without SCC

Kinetic solvent effects on 1,3-dipolar cycloadditions of benzonitrile oxide

The kinetics of 1,3-dipolar cycloadditions of benzonitrile oxide with a series of N-substituted maleimides and with cyclopentene are reported for water, a wide range of organic solvents and binary solvent mixtures. The results indicate the importance of both solvent polarity and specific hydrogen-bond interactions in governing the rates of the reactions. The aforementioned reactions are examples for which these factors often counteract, leading to a complex dependence of rate constants on the nature of the solvent. For the reactions of N-ethylmaleimide and N-n-butylmaleimide with benzonitrile oxide, isobaric activation parameters have been determined in several organic solvents, water, and water–1-propanol mixtures. Interestingly, the activation parameters reveal significant differences in solvation in different solvents that are not clearly reflected in the rate constants. In highly aqueous mixtures, enforced hydrophobic interactions lead to an increase in rate constant, relative to organic solvents. However, the overall rate enhancement in water is modest, if present at all, because the solvent polarity diminishes the rate constant. This pattern contrasts with common Diels–Alder reactions, where polarity, hydrogen-bond donor capacity and enforced hydrophobic interactions work together, which can result in impressive rate accelerations in water.

Inhalation therapy in the next decade : Determinants of adherence to treatment in asthma and COPD

Peer reviewedPublisher PD

The Role of FeNO in Cough Management : A Randomised Controlled Trial

This abstract is funded by: Observational & Pragmatic Research Institute Pte Ltd, and Circassia Presented at thematic poster session: A34 ASTHMA CLINICAL STUDIES I Sunday 20th MayPeer reviewedPostprin

Development of the International Severe Asthma Registry (ISAR) : A Modified Delphi Study

This study is cofunded by Optimum Patient Care Global and AstraZeneca.Peer reviewedPostprin