Do 'alternative' help-seeking strategies affect primary care service use? A survey of help-seeking for mental distress

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A review of the most common patient-reported outcomes in COPD – revisiting current knowledge and estimating future challenges

Mario Cazzola,1 Nicola Alexander Hanania,2 William MacNee,3 Katja Rüdell,4 Claire Hackford,4 Nihad Tamimi4 1University of Rome ‘Tor Vergata’, Department of Medicine of Systems, Unit of Respiratory Clinical Pharmacology, Rome, Italy; 2Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA; 3University of Edinburgh/MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh, United Kingdom; 4Patient Reported Outcome Center of Excellence, Global Market Access, Primary Care Business Unit, Pfizer, Tadworth, United Kingdom Abstract: Patient-reported outcome (PRO) measures that quantify disease impact have become important measures of outcome in COPD research and treatment. The objective of this literature review was to comprehensively evaluate psychometric properties of available PRO instruments and the ability of each of them to characterize pharmaceutical treatment effects from published clinical trial evidence. Identified in this study were several PRO measures, both those that have been used extensively in COPD clinical trials (St George’s Respiratory Questionnaire and Chronic Respiratory Questionnaire) and new instruments whose full value is still to be determined. This suggests a great need for more information about the patient experience of treatment benefit, but this also may pose challenges to researchers, clinicians, and other important stakeholders (eg, regulatory agencies, pharmaceutical companies) who develop new treatment entities and payers (including but not limited to health technology assessment agencies such as the National Institute for Health and Care Excellence and the Canadian Agency for Drugs and Technologies in Health). The purpose of this review is to enable researchers and clinicians to gain a broad overview of PRO measures in COPD by summarizing the value and purpose of these measures and by providing sufficient detail for interested audiences to determine which instrument may be the most suitable for evaluating a particular research purpose. Keywords: COPD, patient reported outcome, health related quality of life, quality of life, psychometric properties&nbsp

Transcriptional regulation of UDP-glucuronosyltransferase UGT2B1 expression in primary rat hepatocyte cultures

Rat UDP-glucuronosyltransferase UGT2B1 is involved in metabolism of endogenous and xenobiotic substrates, including opioids, testosterone and bisphenol A. UGT2B1 belongs to the spectrum of hepatic enzymes subject to induction by phenobarbital (PB). In primary rat hepatocyte cultures, UGT2B1 mRNA expression was maximally induced within 3 days by 1.5 mM phenobarbital (PB) or 100 µM permethrin, a pyrethroid acting as a PB-type inducer. Induction was repressed by the hepatotrophic growth factor EGF (16 nM) and by the prostaglandin E receptor agonist misoprostol (1-10 µg/ml), while induction was markedly enhanced in the presence of the antioxidant N-acetylcysteine (10 mM). Noteworthy, PB-dependent induction of cytochrome P450 CYP2B1 was also modulated by EGF, misoprostol or N-acetylcysteine, demonstrating coordinate regulation of UGT2B1 and CYP2B1 expression. To investigate molecular mechanisms of UGT2B1 gene regulation, primary rat hepatocytes were transfected with UGT2B1-luciferase reporter gene constructs and luciferase expression observed following treatment with modulators of UGT2B1 expression. It was shown that a 1311 bp UGT2B1-promoter fragment was responsive to PB-type inducers, as well as to modulators of induction, indicating that transcriptional regulation greatly contributed to control of UGT2B1 mRNA expression. Systematic UGT2B1 promoter deletion analysis revealed that a proximal fragment containing 239 bp of the 5´-UGT2B1 gene flank was sufficient in conferring responsiveness to PB-like inducers and modulators of induction. Comparison to the human CYP3A4 proximal promoter (that contains designated sites involved in xenobiotic responsiveness), suggests that a sequence within the proximal UGT2B1 promoter fragment, comprising a putative nuclear receptor binding site in close proximity to a C/EBP-alpha binding site, may be a target of PB-dependent activation. Striking parallels in regulation of UGT2B1 and CYP2B1 mRNA expression by PB-type inducers, cytokines, cellular redox status and prostaglandin E receptor stimulation, suggest that integrative molecular mechanisms for regulation of different xenobiotic metabolizing enzyme genes exist

The PROactive innovative conceptual framework on physical activity

Although physical activity is considered an important therapeutic target in chronic obstructive pulmonary disease (COPD), what "physical activity" means to COPD patients and how their perspective is best measured is poorly understood. We designed a conceptual framework, guiding the development and content validation of two patient reported outcome (PRO) instruments on physical activity (PROactive PRO instruments). 116 patients from four European countries with diverse demographics and COPD phenotypes participated in three consecutive qualitative studies (63% male, age mean±sd 66±9 years, 35% Global Initiative for Chronic Obstructive Lung Disease stage III-IV). 23 interviews and eight focus groups (n = 54) identified the main themes and candidate items of the framework. 39 cognitive debriefings allowed the clarity of the items and instructions to be optimised. Three themes emerged, i.e. impact of COPD on amount of physical activity, symptoms experienced during physical activity, and adaptations made to facilitate physical activity. The themes were similar irrespective of country, demographic or disease characteristics. Iterative rounds of appraisal and refinement of candidate items resulted in 30 items with a daily recall period and 34 items with a 7-day recall period. For the first time, our approach provides comprehensive insight on physical activity from the COPD patients' perspective. The PROactive PRO instruments' content validity represents the pivotal basis for empirically based item reduction and validation