Deborah Morrison

AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade

Mitogen-activated protein kinase (MAPK) cascades propagate a variety of cellular activities. Processive relay of signals through RAF–MEK–ERK modulates cell growth and proliferation. Signalling through this ERK cascade is frequently amplified in cancers, and drugs such as sorafenib (which is prescribed to treat renal and hepatic carcinomas) and PLX4720 (which targets melanomas) inhibit RAF kinases. Natural factors that influence ERK1/2 signalling include the second messenger cyclic AMP. However, the mechanisms underlying this cascade have been difficult to elucidate. We demonstrate that the A-kinase-anchoring protein AKAP-Lbc and the scaffolding protein kinase suppressor of Ras (KSR-1) form the core of a signalling network that efficiently relay signals from RAF, through MEK, and on to ERK1/2. AKAP-Lbc functions as an enhancer of ERK signalling by securing RAF in the vicinity of MEK1 and synchronizing protein kinase A (PKA)-mediated phosphorylation of Ser 838 on KSR-1. This offers mechanistic insight into cAMP-responsive control of ERK signalling events.

Digital Asthma Self-Management Interventions: A Systematic Review

Background Many people with asthma tolerate symptoms and lifestyle limitations unnecessarily by not utilizing proven therapies. Better support for self-management is known to improve asthma control, and increasingly the Internet and other digital media are being used to deliver that support. Objective Our goal was to summarize current knowledge, evidenced through existing systematic reviews, of the effectiveness and implementation of digital self-management support for adults and children with asthma and to examine what features help or hinder the use of these programs. Methods A comprehensive search strategy combined 3 facets of search terms: (1) online technology, (2) asthma, and (3) self-management/behavior change/patient experience. We undertook searches of 14 databases, and reference and citation searching. We included qualitative and quantitative systematic reviews about online or computerized interventions facilitating self-management. Title, abstract, full paper screening, and quality appraisal were performed by two researchers independently. Data extraction was undertaken using standardized forms. Results A total of 3810 unique papers were identified. Twenty-nine systematic reviews met inclusion criteria: the majority were from the United States (n=12), the rest from United Kingdom (n=6), Canada (n=3), Portugal (n=2), and Australia, France, Spain, Norway, Taiwan, and Greece (1 each). Only 10 systematic reviews fulfilled pre-determined quality standards, describing 19 clinical trials. Interventions were heterogeneous: duration of interventions ranging from single use, to 24-hour access for 12 months, and incorporating varying degrees of health professional involvement. Dropout rates ranged from 5-23%. Four RCTs were aimed at adults (overall range 3-65 years). Participants were inadequately described: socioeconomic status 0/19, ethnicity 6/19, and gender 15/19. No qualitative systematic reviews were included. Meta-analysis was not attempted due to heterogeneity and inadequate information provision within reviews. There was no evidence of harm from digital interventions. All RCTs that examined knowledge (n=2) and activity limitation (n=2) showed improvement in the intervention group. Digital interventions improved markers of self care (5/6), quality of life (4/7), and medication use (2/3). Effects on symptoms (6/12) and school absences (2/4) were equivocal, with no evidence of overall benefits on lung function (2/6), or health service use (2/15). No specific data on economic analyses were provided. Intervention descriptions were generally brief making it impossible to identify which specific “ingredients” of interventions contribute most to improving outcomes. Conclusions Digital self-management interventions show promise, with evidence of beneficial effects on some outcomes. There is no evidence about utility in those over 65 years and no information about socioeconomic status of participants, making understanding the “reach” of such interventions difficult. Digital interventions are poorly described within reviews, with insufficient information about barriers and facilitators to their uptake and utilization. To address these gaps, a detailed quantitative systematic review of digital asthma interventions and an examination of the primary qualitative literature are warranted, as well as greater emphasis on economic analysis within trials.

Qualitative systematic reviews of treatment burden in stroke, heart failure and diabetes - Methodological challenges and solutions

BackgroundTreatment burden can be defined as the self-care practices that patients with chronic illness must perform to respond to the requirements of their healthcare providers, as well as the impact that these practices have on patient functioning and well being. Increasing levels of treatment burden may lead to suboptimal adherence and negative outcomes. Systematic review of the qualitative literature is a useful method for exploring the patient experience of care, in this case the experience of treatment burden. There is no consensus on methods for qualitative systematic review. This paper describes the methodology used for qualitative systematic reviews of the treatment burdens identified in three different common chronic conditions, using stroke as our exemplar.MethodsQualitative studies in peer reviewed journals seeking to understand the patient experience of stroke management were sought. Limitations of English language and year of publication 2000 onwards were set. An exhaustive search strategy was employed, consisting of a scoping search, database searches (Scopus, CINAHL, Embase, Medline & PsycINFO) and reference, footnote and citation searching. Papers were screened, data extracted, quality appraised and analysed by two individuals, with a third party for disagreements. Data analysis was carried out using a coding framework underpinned by Normalization Process Theory (NPT).ResultsA total of 4364 papers were identified, 54 were included in the review. Of these, 51 (94%) were retrieved from our database search. Methodological issues included: creating an appropriate search strategy; investigating a topic not previously conceptualised; sorting through irrelevant data within papers; the quality appraisal of qualitative research; and the use of NPT as a novel method of data analysis, shown to be a useful method for the purposes of this review.ConclusionThe creation of our search strategy may be of particular interest to other researchers carrying out synthesis of qualitative studies. Importantly, the successful use of NPT to inform a coding frame for data analysis involving qualitative data that describes processes relating to self management highlights the potential of a new method for analyses of qualitative data within systematic reviews.

Randomised controlled trial of azithromycin in smokers with asthma

To the Editor: Smokers with asthma have poor symptom control, accelerated decline in lung function and an attenuated response to corticosteroids compared to nonsmokers with asthma [1]. There is an unmet need for alternative or additional drugs for smokers with asthma who are unable to stop smoking [2]. Macrolide antibiotics have anti-inflammatory activity [3] and in clinical studies there is good evidence for efficacy in the treatment of diffuse pan-bronchiolitis and cystic fibrosis, as well as in preventing chronic rejection after lung transplantation [4, 5]. In asthma, chronic treatment is associated with a reduction in bronchial hyperreactivity in mild-to-moderate asthma [6] and in exacerbation rates in non-eosinophilic severe asthma [7]. To date, no studies have examined the efficacy of macrolide antibiotics exclusively in current smokers with asthma. A randomised double-blind parallel-group trial compared azithromycin, 250 mg per day, with placebo for 12 weeks. All subjects were aged 18–70 years, were current smokers (≥5 pack-years history) with chronic asthma (>1 year duration; defined by international criteria [8]) and had to be free of exacerbation and respiratory tract infection for a minimum 6-week period prior to randomisation. A baseline visit was performed following a 4-week run-in period on inhaled corticosteroid (ICS) therapy equivalent to 400 μg beclometasone ± a long-acting β2-agonist (LABA). Ethical approval was obtained and all subjects provided written informed consent. Study visits were performed at 4, 8 and 12 weeks. Clinic visit peak expiratory flow (PEF) after 12 weeks treatment was the primary outcome measure. A sample size of 68 …

The Heart failure and Optimal Outcomes from Pharmacy Study (HOOPS): rationale, design, and baseline characteristics.

The effect on mortality and morbidity of pharmacist‐led intervention to optimize pharmacological therapy in patients with systolic heart failure (HF) has not been tested in a large‐scale, long‐term, clinical trial.

Details of development of the resource for adults with asthma in the RAISIN (randomized trial of an asthma internet self-management intervention) study

BackgroundAround 300 million people worldwide have asthma and prevalence is increasing. Self-management can be effective in improving a range of outcomes and is cost effective, but is underutilised as a treatment strategy. Supporting optimum self-management using digital technology shows promise, but how best to do this is not clear. We aimed to develop an evidence based, theory informed, online resource to support self-management in adults with asthma, called ‘Living well with Asthma’, as part of the RAISIN (Randomized Trial of an Asthma Internet Self-Management Intervention) study.MethodsWe developed Living well with Asthma in two phases.Phase 1: A low fidelity prototype (paper-based) version of the website was developed iteratively through input from a multidisciplinary expert panel, empirical evidence from the literature, and potential end users via focus groups (adults with asthma and practice nurses). Implementation and behaviour change theories informed this process.Phase 2: The paper-based designs were converted to a website through an iterative user centred process. Adults with asthma (n = 10) took part in think aloud studies, discussing the paper based version, then the web-based version. Participants considered contents, layout, and navigation. Development was agile using feedback from the think aloud sessions immediately to inform design and subsequent think aloud sessions. Think aloud transcripts were also thematically analysed, further informing resource development.ResultsThe website asked users to aim to be symptom free. Key behaviours targeted to achieve this include: optimising medication use (including inhaler technique); attending primary care asthma reviews; using asthma action plans; increasing physical activity levels; and stopping smoking. The website had 11 sections, plus email reminders, which promoted these behaviours. Feedback on the contents of the resource was mainly positive with most changes focussing on clarification of language, order of pages and usability issues mainly relating to navigation difficulties.ConclusionsOur multifaceted approach to online intervention development underpinned by theory, using evidence from the literature, co-designed with end users and a multidisciplinary panel has resulted in a resource which end users find relevant to their needs and easy to use. Living well with Asthma is undergoing evaluation within a randomized controlled trial.

Managing multimorbidity in primary care in patients with chronic respiratory conditions

The term multimorbidity is usually defined as the coexistence of two or more chronic conditions within an individual, whereas the term comorbidity traditionally describes patients with an index condition and one or more additional conditions. Multimorbidity of chronic conditions markedly worsens outcomes in patients, increases treatment burden and increases health service costs. Although patients with chronic respiratory disease often have physical comorbidities, they also commonly experience psychological problems such as depression and anxiety. Multimorbidity is associated with increased health-care utilisation and specifically with an increased number of prescription drugs in individuals with multiple chronic conditions such as chronic obstructive pulmonary disease. This npj Primary Care Respiratory Medicine Education Section case study involves a patient in a primary care consultation presenting several common diseases prevalent in people of this age. The patient takes nine different drugs at this moment, one or more pills for each condition, which amounts to polypharmacy. The problems related with polypharmacy recommend that a routine medication review by primary care physicians be performed to reduce the risk of adverse effects of polypharmacy among those with multiple chronic conditions. The primary care physician has the challenging role of integrating all of the clinical problems affecting the patient and reviewing all medicaments (including over-the-counter medications) taken by the patient at any point in time, and has the has the key to prevent the unwanted consequences of polypharmacy. Multimorbid chronic disease management can be achieved with the use of care planning, unified disease templates, use of information technology with appointment reminders and with the help of the wider primary care and community teams.

Sexual dysfunction in cardiovascular disease

A 53 year old man attends for a routine check-up. He underwent coronary artery bypass grafting after a myocardial infarction earlier in the year, and seems to be making good progress. He says he needs to discuss an embarrassing problem. He explains that he has been having erectile dysfunction, which is making him miserable and preventing normal marital relations.

Findings from a pilot Randomised trial of an Asthma Internet Self-management Intervention (RAISIN).

Objective To evaluate the feasibility of a phase 3 randomised controlled trial (RCT) of a website (Living Well with Asthma) to support self-management. Design and setting Phase 2, parallel group, RCT, participants recruited from 20 general practices across Glasgow, UK. Randomisation through automated voice response, after baseline data collection, to website access for minimum 12 weeks or usual care. Participants Adults (age≥16 years) with physician diagnosed, symptomatic asthma (Asthma Control Questionnaire (ACQ) score ≥1). People with unstable asthma or other lung disease were excluded. Intervention ‘Living Well with Asthma’ is a desktop/laptop compatible interactive website designed with input from asthma/ behaviour change specialists, and adults with asthma. It aims to support optimal medication management, promote use of action plans, encourage attendance at asthma reviews and increase physical activity. Outcome measures Primary outcomes were recruitment/retention, website use, ACQ and mini-Asthma Quality of Life Questionnaire (AQLQ). Secondary outcomes included patient activation, prescribing, adherence, spirometry, lung inflammation and health service contacts after 12 weeks. Blinding postrandomisation was not possible. Results Recruitment target met. 51 participants randomised (25 intervention group). Age range 16–78 years; 75% female; 28% from most deprived quintile. 45/51 (88%; 20 intervention group) followed up. 19 (76% of the intervention group) used the website, for a mean of 18 min (range 0–49). 17 went beyond the 2 ‘core’ modules. Median number of logins was 1 (IQR 1–2, range 0–7). No significant difference in the prespecified primary efficacy measures of ACQ scores (−0.36; 95% CI −0.96 to 0.23; p=0.225), and mini-AQLQ scores (0.38; −0.13 to 0.89; p=0.136). No adverse events. Conclusions Recruitment and retention confirmed feasibility; trends to improved outcomes suggest use of Living Well with Asthma may improve self-management in adults with asthma and merits further development followed by investigation in a phase 3 trial. Trial registration number ISRCTN78556552; Results.

Chronic obstructive pulmonary disease and comorbidities: a large cross-sectional study in primary care

BACKGROUND Chronic obstructive pulmonary disease (COPD) is common, and a major cause of morbidity and mortality worldwide. Recent studies suggest that comorbidities of COPD increase the risk of hospitalisation, polypharmacy, and mortality, but their estimated prevalence varies widely in the literature. AIM To evaluate the prevalence of 38 physical and mental health comorbidities in people with COPD, and compare findings with those for people without COPD in a large nationally representative dataset. DESIGN AND SETTING A cross-sectional data analysis on 1 272 685 adults in Scotland from 314 primary care practices. METHOD Data on COPD, along with 31 physical and seven mental health comorbidities, were extracted. The prevalence of comorbidities was compared between people who did, and did not, have COPD, standardised by age, sex, and socioeconomic deprivation. RESULTS From the total sample, 51 928 patients had COPD (4.1%). Of these, 86.0% had at least one comorbidity, compared with 48.9% of people without COPD. Of those with COPD, 22.3% had ≥5 comorbid conditions compared with 4.9% of those who did not have COPD (adjusted odds ratio 2.63, 95% confidence interval = 2.56 to 2.70). In total, 29 of the 31 physical conditions and six of the seven mental health conditions were statistically significantly more prevalent in people who had COPD than those who did not. CONCLUSION Patients with COPD have extensive associated comorbidities. There is a real need for guidelines and health care to reflect this complexity, including how to detect those common comorbidities that relate to both physical and mental health, and how best to manage them. Primary care, which is unique in terms of offering expert generalist care, is best placed to provide this integrated approach.