Respiratory effect of beta-blockers in people with asthma and cardiovascular disease: population-based nested case control study.

BACKGROUND: Cardiovascular disease (CVD) is a common comorbidity in people with asthma. However, safety concerns have caused heterogeneity in clinical guideline recommendations over the use of cardioselective beta-blockers in people with asthma and CVD, partly because risk in the general population has been poorly quantified. The aim of this study was to measure the risk of asthma exacerbations with beta-blockers prescribed to a general population with asthma and CVD. METHODS: Linked data from the UK Clinical Practice Research Datalink was used to perform nested case-control studies among people with asthma and CVD matched on age, sex and calendar time. Adjusted incidence rate ratios (IRR) were calculated for the association between oral beta-blocker use and moderate asthma exacerbations (rescue oral steroids) or severe asthma exacerbations (hospitalisation or death) using conditional logistic regression. RESULTS: The cohort consisted of 35,502 people identified with active asthma and CVD, of which 14.1% and 1.2% were prescribed cardioselective and non-selective beta-blockers, respectively, during follow-up. Cardioselective beta-blocker use was not associated with a significantly increased risk of moderate or severe asthma exacerbations. Consistent results were obtained following sensitivity analyses and a self-controlled case series approach. In contrast, non-selective beta-blockers were associated with a significantly increased risk of moderate asthma exacerbations when initiated at low to moderate doses (IRR 5.16, 95% CI 1.83-14.54, P = 0.002), and both moderate and severe exacerbations when prescribed chronically at high dose (IRR 2.68, 95% CI 1.08-6.64, P = 0.033 and IRR 12.11, 95% CI 1.02-144.11, P = 0.048, respectively). CONCLUSIONS: Cardioselective beta-blockers prescribed to people with asthma and CVD were not associated with a significantly increased risk of moderate or severe asthma exacerbations and potentially could be used more widely when strongly indicated.

Detection in blood of autoantibodies to tumour antigens as a case-finding method in lung cancer using the EarlyCDT®-Lung Test (ECLS): study protocol for a randomized controlled trial.

BACKGROUND: Lung cancer is the most common cause of cancer related death worldwide. The majority of cases are detected at a late stage when prognosis is poor. The EarlyCDT®-Lung Test detects autoantibodies to abnormal cell surface proteins in the earliest stages of the disease which may allow tumour detection at an earlier stage thus altering prognosis. The primary research question is: Does using the EarlyCDT®-Lung Test to identify those at high risk of lung cancer, followed by X-ray and computed tomography (CT) scanning, reduce the incidence of patients with late-stage lung cancer (III & IV) or unclassified presentation (U) at diagnosis, compared to standard practice? METHODS: A randomised controlled trial of 12 000 participants in areas of Scotland targeting general practices serving patients in the most deprived quintile of the Scottish Index of Multiple Deprivation. Adults aged 50-75 who are at high risk of lung cancer and healthy enough to undergo potentially curative therapy (Performance Status 0-2) are eligible to participate. The intervention is the EarlyCDT®-Lung Test, followed by X-ray and CT in those with a positive result. The comparator is standard clinical practice in the UK. The primary outcome is the difference, after 24 months, between the rates of patients with stage III, IV or unclassified lung cancer at diagnosis. The secondary outcomes include: all-cause mortality; disease specific mortality; a range of morbidity outcomes; cost-effectiveness and measures examining the psychological and behavioural consequences of screening. Participants with a positive test result but for whom the CT scan does not lead to a lung cancer diagnosis will be offered 6 monthly thoracic CTs for 24 months. An initial chest X-ray will be used to determine the speed and the need for contrast in the first screening CT. Participants who are found to have lung cancer will be followed-up to assess both time to diagnosis and stage of disease at diagnosis. DISCUSSION: The study will determine the clinical and cost effectiveness of EarlyCDT®-Lung Test for early lung cancer detection and assess its suitability for a large-scale, accredited screening service. The study will also assess the potential psychological and behavioural harms arising from false positive or false negative results, as well as the potential benefits to patients of true negative EarlyCDT lung test results. A cost-effectiveness model of lung cancer screening based on the results of the EarlyCDT Lung Test study will be developed. TRIAL REGISTRATION: NCT01925625 . August 19, 2013.

Respiratory effect of beta-blocker eye drops in asthma: population-based study and meta-analysis of clinical trials.

AIMS: To measure the prevalence of beta-blocker eye drop prescribing and respiratory effect of ocular beta-blocker administration in people with asthma. METHODS: We measured the prevalence of ocular beta-blocker prescribing in people with asthma and ocular hypertension, and performed a nested case-control study (NCCS) measuring risk of moderate exacerbations (rescue steroids in primary care) and severe exacerbations (asthma hospitalization) using linked data from the UK Clinical Practice Research Datalink. We then performed a systematic review and meta-analysis of clinical trials evaluating changes in lung function following ocular beta-blocker administration in people with asthma. RESULTS: From 2000 to 2012, the prevalence of non-selective and selective beta-blocker eye drop prescribing in people with asthma and ocular hypertension fell from 23.0% to 13.4% and from 10.5% to 0.9% respectively. In the NCCS, the relative incidence (IRR) of moderate exacerbations increased significantly with acute non-selective beta-blocker eye drop exposure (IRR 4.83, 95% CI 1.56-14.94) but not with chronic exposure. In the meta-analysis, acute non-selective beta-blocker eye drop exposure caused significant mean falls in FEV1 of -10.9% (95% CI -14.9 to -6.9), and falls in FEV1 of ≥20% affecting one in three. Corresponding values for selective beta-blockers in people sensitive to ocular non-selective beta-blockers was -6.3% (95% CI -11.7 to -0.8), and a non-significant increase in falls in FEV1 of ≥20%. CONCLUSION: Non-selective beta-blocker eye drops significantly affect lung function and increase asthma morbidity but are still frequently prescribed to people with asthma and ocular hypertension despite safer agents being available.

Fair access to medicine? Retrospective analysis of UK medical schools application data 2009-2012 using three measures of socioeconomic status.

BACKGROUND: Medical students have historically largely come from more affluent parts of society, leading many countries to seek to broaden access to medical careers on the grounds of social justice and the perceived benefits of greater workforce diversity. The aim of this study was to examine variation in socioeconomic status (SES) of applicants to study medicine and applicants with an accepted offer from a medical school, comparing the four UK countries and individual medical schools. METHODS: Retrospective analysis of application data for 22 UK medical schools 2009/10-2011/12. Data were analysed for all 32,964 UK-domiciled applicants aged <20 years to 22 non-graduate medical schools requiring applicants to sit the United Kingdom Clinical Aptitude Test (UKCAT). Rates of applicants and accepted offers were compared using three measures of SES: (1) Postcode-assigned Index of Multiple Deprivation score (IMD); (2) School type; (3) Parental occupation measured by the National Statistics Socio Economic Classification (NS-SEC). RESULTS: There is a marked social gradient of applicants and applicants with accepted offers with, depending on UK country of residence, 19.7-34.5% of applicants living in the most affluent tenth of postcodes vs 1.8-5.7% in the least affluent tenth. However, the majority of applicants in all postcodes had parents in the highest SES occupational group (NS-SEC1). Applicants resident in the most deprived postcodes, with parents from lower SES occupational groups (NS-SEC4/5) and attending non-selective state schools were less likely to obtain an accepted offer of a place at medical school further steepening the observed social gradient. Medical schools varied significantly in the percentage of individuals from NS-SEC 4/5 applying (2.3%-8.4%) and gaining an accepted offer (1.2%-7.7%). CONCLUSION: Regardless of the measure, those from less affluent backgrounds are less likely to apply and less likely to gain an accepted offer to study medicine. Postcode-based measures such as IMD may be misleading, but individual measures like NS-SEC can be gamed by applicants. The previously unreported variation between UK countries and between medical schools warrants further investigation as it implies solutions are available but inconsistently applied.

Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2 inhibitors: Meta-analysis of controlled clinical trials.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause bronchospasm in susceptible patients with asthma, often termed aspirin-exacerbated respiratory disease (AERD), with the risk being greatest after acute exposure. Selective NSAIDs that preferentially inhibit COX-2 might be safer. OBJECTIVE: We sought to systematically evaluate changes in symptoms and pulmonary function after acute selective NSAID or COX-2 inhibitor exposure in patients with the AERD phenotype. METHODS: A systematic review of databases was performed to identify all blinded, placebo-controlled clinical trials evaluating acute selective NSAID or COX-2 inhibitor exposure in patients with AERD. Effect estimates for changes in respiratory function and symptoms were pooled by using fixed-effects meta-analysis, with heterogeneity investigated. RESULTS: No significant difference in respiratory symptoms (risk difference, -0.01; 95% CI, -0.03 to 0.01; P = .57), decrease in FEV1 of 20% or greater (RD, 0.00; 95% CI, -0.02 to 0.02; P = .77), or nasal symptoms (RD, -0.01; 95% CI, -0.04 to 0.02; P = .42) occurred with COX-2 inhibitors (eg, celecoxib). Selective NSAID exposure caused respiratory symptoms in approximately 1 in 13 patients with AERD (RD, 0.08; 95% CI, 0.02 to 0.14; P = .01). No significant differences were found according to leukotriene antagonist exposure or whether NSAIDs were randomly allocated. CONCLUSION: According to clinical trial evidence in patients with stable mild-to-moderate asthma with AERD, acute exposure to COX-2 inhibitors is safe, and selective NSAIDs exhibit a small risk. Thus COX-2 inhibitors could be used in patients with AERD or in patients with general asthma unwilling to risk nonselective NSAID exposure when oral challenge tests are unavailable.

Long-acting ß-agonist prescribing in people with asthma in primary care.

Long-acting ß2-agonist (LABA) monotherapy is contraindicated in asthma following reports of serious adverse events. Anonymised Scottish health data were used to determine the prevalence of LABA prescribing and LABA monotherapy (sustained and episodic) in asthma during 2006. Of 73 486 asthma patients identified, 5592 (7.6%; 95% CI 7.4% to 7.8%) were prescribed LABAs as a separate inhaler of which 991 patients had LABA monotherapy (17.7% (95% CI 16.7% to 18.7%) of patients at risk). Asthma reviews were associated with reductions in sustained (OR 0.44; 95% CI 0.32 to 0.61) but not episodic monotherapy (OR 1.16; 95% CI 0.85 to 1.57). These findings support recent changes in UK asthma guidelines recommending LABAs in fixed-dose combination inhalers.

Pedigree and genotyping quality analyses of over 10,000 DNA samples from the Generation Scotland: Scottish Family Health Study.

BACKGROUND: Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based biobank of 24,000 participants with rich phenotype and DNA available for genetic research. This paper describes the laboratory results from genotyping 32 single nucleotide polymorphisms (SNPs) on DNA from over 10,000 participants who attended GS:SFHS research clinics. The analysis described here was undertaken to test the quality of genetic information available to researchers. The success rate of each marker genotyped (call rate), minor allele frequency and adherence to Mendelian inheritance are presented. The few deviations in marker transmission in the 925 parent-child trios analysed were assessed as to whether they were likely to be miscalled genotypes, data or sample handling errors, or pedigree inaccuracies including non-paternity. METHODS: The first 10,450 GS:SFHS clinic participants who had spirometry and smoking data available and DNA extracted were selected. 32 SNPs were assayed, chosen as part of a replication experiment from a Genome-Wide Association Study meta-analysis of lung function. RESULTS: In total 325,336 genotypes were returned. The overall project pass rate (32 SNPs on 10,450 samples) was 97.29%. A total of 925 parent-child trios were assessed for transmission of the SNP markers, with 16 trios indicating evidence of inconsistency in the recorded pedigrees. CONCLUSIONS: The Generation Scotland: Scottish Family Health Study used well-validated study methods and can produce good quality genetic data, with a low error rate. The GS:SFHS DNA samples are of high quality and the family groups were recorded and processed with accuracy during collection of the cohort.

Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function.

RATIONALE: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. METHODS: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. MEASUREMENTS AND MAIN RESULTS: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (ß = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (ß = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)). CONCLUSIONS: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

How can student experience enhance the development of a model of interprofessional clinical skills education in the practice placement setting?

The practice placement setting offers opportunities and challenges for engaging students in high-quality interprofessional learning. The Fife Interprofessional Clinical Skills Model for Education was established to develop structured interprofessional learning opportunities for students during their clinical attachments in NHS Fife. This short report describes the delivery and evaluation of the model, which was piloted with students from the nursing, medicine and allied health professions. Scheduled workshops were delivered within primary and secondary care locations. The learning activities involved exploring and comparing their professional identities, discussing roles and responsibilities within the healthcare team and practicing nontechnical clinical skills. Students who participated in the workshops reported that they developed a better understanding of each other's roles and responsibilities and also identified that this would be transferable knowledge to their future practice. Exploring the student experience has assisted in developing relevant and accessible interprofessional learning opportunities within the practice placement setting.

Prescribing of ß-adrenoceptor antagonists in asthma: an observational study.

BACKGROUND: ß-Antagonists have recently been proposed for the treatment of chronic asthma; however, concerns regarding risk of acute bronchoconstriction in clinical trials remain. OBJECTIVE: To determine the frequency of oral ß-blocker prescribing in patients with asthma and associations with severe asthma exacerbations requiring oral steroids in patients with active asthma defined by prior asthma-related medication use. METHODS: Patients with asthma registered on 31 March 2007 and all asthma-related medications from the preceding 2 years were identified from anonymised clinical data from one-third of Scottish general practices. The main outcome measure was the relative incidence of active asthma patients receiving oral steroids following a new oral ß-antagonist prescription. RESULTS: Of the 53,994 adult patients identified with asthma 1527 (2.8%; 95% CI 2.69% to 2.97%) patients were prescribed an oral ß-antagonist of which 441 (28.9%, 95% CI 26.7% to 31.2%) had active asthma and received a new ß-blocker prescription. The average number of patients prescribed rescue steroids at baseline in 367 patients with sufficient follow-up was 3.4 (0.9%) patients every 2 weeks. Rescue steroids were prescribed to 3 (0.8%) patients in the first 2 weeks and to 3 (0.8%) patients in the second 2 weeks following the new oral ß-antagonist (incidence rate ratio (IRR) 0.87, 95% CI 0.25 to 2.99 and IRR 0.89, 95% CI 0.26 to 2.97, respectively). No significant difference was found following stratification for ß-antagonist selectivity. CONCLUSION: These results suggest that prescribing new oral ß-blockers for the purpose of investigating potentially beneficial effects of chronic treatment would not lead to large increases in patients treated with oral steroids acutely in general practice.

Assessing asthma control in UK primary care: use of routinely collected prospective observational consultation data to determine appropriateness of a variety of control assessment models.

BACKGROUND: Assessing asthma control using standardised questionnaires is recommended as good clinical practice but there is little evidence validating their use within primary care. There is however, strong empirical evidence to indicate that age, weight, gender, smoking, symptom pattern, medication use, health service resource use, geographical location, deprivation, and organisational issues, are factors strongly associated with asthma control. A good control measure is therefore one whose variation is most explained by these factors. METHOD: Eight binary (Yes = poor control, No = good control) models of asthma control were constructed from a large UK primary care dataset: the Royal College of Physicians 3-Questions (RCP-3Qs); the Jones Morbidity Index; three composite measures; three single component models. Accounting for practice clustering of patients, we investigated the effects of each model for assessing control. The binary models were assessed for goodness-of-fit statistics using Pseudo R-squared and Akaikes Information Criteria (AIC), and for performance using Area Under the Receiver Operator Characteristic (AUROC). In addition, an expanded RCP-3Q control scale (0-9) was derived and assessed with linear modelling. The analysis identified which model was best explained by the independent variables and thus could be considered a good model of control assessment. RESULTS: 1,205 practices provided information on 64,929 patients aged 13+ years. The RCP-3Q model provided the best fit statistically, with a Pseudo R-squared of 18%, and an AUROC of 0.79. By contrast, the composite model based on the GINA definition of controlled asthma had a higher AIC, an AUROC of 0.72, and only 10% variability explained. In addition, although the Peak Expiratory Flow Rate (PEFR) model had the lowest AIC, it had an AUROC of 71% and only 6% of variability explained. However, compared with the RCP-3Qs binary model, the linear RCP-3Q Total Score Model (Scale 0-9), was found to be a more robust 'tool' for assessing asthma control with a lower AIC (28,6163) and an R-squared of 33%. CONCLUSION: In the absence of a gold standard for assessing asthma control in primary care, the results indicate that the RCP-3Qs is an effective control assessment tool but, for maximum effect, the expanded scoring model should be used.

Generation Scotland: the Scottish Family Health Study; a new resource for researching genes and heritability.

BACKGROUND: Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland. METHODS/DESIGN: Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process. DISCUSSION: As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population.

Adverse respiratory effect of acute ß-blocker exposure in asthma: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: ß-Blockers are avoided in asthma over concerns regarding acute bronchoconstriction. Risk is greatest following acute exposure, including the potential for antagonism of ß2-agonist rescue therapy. METHODS: A systematic review of databases was performed to identify all randomized, blinded, placebo-controlled clinical trials evaluating acute ß-blocker exposure in asthma. Effect estimates for changes in respiratory function, symptoms, and ß2-agonist response were pooled using random effects meta-analysis with heterogeneity investigated. RESULTS: Acute selective ß-blockers in the doses given caused a mean change in FEV1 of −6.9% (95% CI, −8.5 to −5.2), a fall in FEV1 of ≥20% in one in eight patients (P=.03), symptoms affecting one in 33 patients (P=.18), and attenuation of concomitant ß2-agonist response of −10.2% (95% CI, −14.0 to −6.4). Corresponding values for acute nonselective ß-blockers in the doses given were −10.2% (95% CI, −14.7 to −5.6), one in nine patients (P=.02), one in 13 patients (P=.14), and −20.0% (95% CI, −29.4 to −10.7). Following investigation of heterogeneity, clear differences were found for celiprolol and labetalol. A dose-response relationship was demonstrated for selective ß-blockers. CONCLUSIONS: Selective ß-blockers are better tolerated but not completely risk-free. Risk from acute exposure may be mitigated using the smallest dose possible and ß-blockers with greater ß1-selectivity. ß-Blocker-induced bronchospasm responded partially to ß2-agonists in the doses given with response blunted more by nonselective ß-blockers than selective ß-blockers. Use of ß-blockers in asthma could possibly be based upon a risk assessment on an individual patient basis.

Cohort Profile: Generation Scotland: Scottish Family Health Study (GS:SFHS). The study, its participants and their potential for genetic research on health and illness.

GS:SFHS is a family-based genetic epidemiology study with DNA and socio-demographic and clinical data from about 24 000 volunteers across Scotland aged 18-98 years, from February 2006 to March 2011. Biological samples and anonymized data form a resource for research on the genetics of health, disease and quantitative traits of current and projected public health importance. Specific and important features of GS:SFHS include the family-based recruitment, with the intent of obtaining family groups; the breadth and depth of phenotype information, including detailed data on cognitive function, personality traits and mental health; consent and mechanisms for linkage of all data to comprehensive routine health-care records; and 'broad' consent from participants to use their data and samples for a wide range of medical research, including commercial research, and for re-contact for the potential collection of other data or samples, or for participation in related studies and the design and review of the protocol in parallel with in-depth sociological research on (potential) participants and users of the research outcomes. These features were designed to maximize the power of the resource to identify, replicate or control for genetic factors associated with a wide spectrum of illnesses and risk factors, both now and in the future.

Patient, practice and organisational influences on asthma control: observational data from a national study on primary care in the United Kingdom.

BACKGROUND: Achieving asthma control is central to optimising patient quality of life and clinical outcome. Contemporary models of chronic disease management across a variety of countries point to the importance of micro, meso and macro level influences on patient care and outcome. However, asthma outcomes research has almost invariably concentrated on identifying and addressing patient predictors. Little is known about higher level organisational influences. OBJECTIVE: This paper explores the contribution of organisational factors on poor asthma control, allowing for patient factors, at three organisational levels: the individual patient, local service deliverers, and strategic regional providers. DESIGN, SETTING AND PARTICIPANTS: Prospective cross-sectional observational cohort study of 64,929 people with asthma from 1205 primary care practices spread throughout the United Kingdom (UK). Patient clinical data were recorded during a routine asthma review. METHOD: Data were analysed using simple descriptive, multiple regression and complex multi-level modelling techniques, accounting for practice clustering of patients. RESULTS: Poor asthma control was associated with areas of higher deprivation [regression coefficient 0.026 (95% confidence intervals 0.006; 0.046)] and urban practice [-0.155 (-0.275; -0.035)] but not all local and regional variation was explained by the data. In contrast, patient level predictors of poor control were: short acting bronchodilator overuse [2.129 (2.091; 2.164)], days-off due to asthma [1.203 (1.148; 1.258)], PEFR<80 [0.76 (0.666; 0.854)], non-use of a self-management plan (SMP) [0.554 (0.515; 0.593)], poor inhaler technique [0.53 (0.475; 0.585)], poor medication compliance [0.385 (-0.007; 0.777)], and gender [0.314 (0.281; 0.347)]. Pattern of medication use, smoking history, age, body mass index (BMI), and health service resource use were also significant factors for predicting control. CONCLUSIONS: Targeting of health service resource requires knowledge of the factors associated with poor control of asthma symptoms. In the UK the contribution of local and regional structures appears minimal in explaining variation in asthma outcomes. However, unexplained variation in the data suggests other unrecorded factors may play a part. While patient personal characteristics (including self-management plan use, inhaler technique, medication compliance) appear to be the predominant influence the complex nature of the disease means that some, perhaps more subtle, influences are affecting the variability at all levels and this variance needs to be explored. Further research in other international contexts is required to identify the likely applicability of these findings to other health care systems.

A randomized primary care trial of steroid titration against mannitol in persistent asthma: STAMINA trial.

BACKGROUND: We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in primary care. METHODS: One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV(1) (PD(10)) (AHR strategy) or a control group (reference strategy) over a 1-year period. RESULTS: One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD(10) and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD(10) between AHR vs control groups. The final mean daily ciclesonide dose was higher (P < .0001) in AHR vs control groups (514 µg vs 208 µg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV(1) (P < .05), salivary eosinophilic cationic protein (P < .05), exhaled nitric oxide (P < .05), symptoms (P < .005), and reliever use (P < .001). CONCLUSIONS: Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01216579; URL: www.clinicaltrials.gov.

Symptoms, spirometry, exhaled nitric oxide, and asthma exacerbations in clinical practice.

BACKGROUND: Patient symptoms, spirometry measurements, exacerbation rates, and exhaled nitric oxide (FE(NO)) levels have all been used to quantify asthma severity. OBJECTIVE: To determine the relationships among these disease surrogates in clinical practice. METHODS: Data were collected from 5 primary care asthma clinics on patient symptoms, reliever use, spirometry measurements, maintenance pharmacotherapy, disease severity (British Thoracic Society treatment step), and FE(NO) level. Exacerbation data (asthma-related unscheduled health care contact or rescue oral corticosteroid therapy) for the 12 months before and 3 months after the clinic visit were then obtained. RESULTS: A total of 267 adult asthmatic patients (mean [SEM] age, 51.6 [1.1] years; forced expiratory volume in 1 second, 86.3% [1.2%] of predicted) participated, and 157 exacerbations were captured. For the 12 months before the clinic visit, exacerbation rate was positively correlated with dose of inhaled corticosteroid (P < .001), treatment step (P < .001), reliever use (P = .002), and symptom score (P < .001) but was negatively correlated with FE(NO) level (P = .04); only symptom scores correlated with exacerbation rate in the 3 months after the visit. Levels of FE(NO) were significantly lower in frequently exacerbating patients receiving higher doses of maintenance inhaled corticosteroids compared with patients with mild disease who were corticosteroid naive (19.7 vs 40.4 ppb, P < .001). Measurement of FE(NO) was an insensitive method (sensitivity, 66.7%; specificity, 51.9% at a cutoff value of 20 ppb) for identifying patients who subsequently exacerbated. CONCLUSION: Levels of FE(NO) are paradoxically decreased in patients with more severe asthma and frequent exacerbations and may, therefore, be of limited utility in primary care.

Twelve tips for developing and maintaining a simulated patient bank.

Simulated patients have become almost indispensable in the education and training of health care professionals. Their contribution to the creation of a safe, yet realistic, learner centred environment is invaluable. Their support in enabling learners at all stages of their professional careers to develop both competence and confidence through repeated practice helps to ensure that learning from real patients can be maximized. A simulated patient bank can enable tracking and training of simulated patients to be coordinated in an effective and efficient way both for patients and learners. This paper shares experiences of developing a simulated patient bank against the background of changes in health care delivery and education and training. Twelve tips to developing and maintaining a simulated patient bank have been identified. The tips focus on the needs of the simulated patient bank and ensure that training is at an appropriate level for the learners, patient care is not compromised and simulated patients feel they are valued members of the educational team.