HLA-Cw6-positive patients with psoriasis show improved response to methotrexate treatment.

It is well documented that patients with human leucocyte antigen (HLA)-Cw6+ (type 1) psoriasis have increased severity and reduced age of onset of psoriasis. However, not much is known about any differential response of this genetic subgroup to various treatments. We set out to determine if there was any genetic association of the HLA-Cw6 allele with the first-line systemic treatment commonly used in psoriasis, methotrexate. A cohort of patients from Tayside in Scotland was recruited through a novel generic consenting process (GoShare); they were extensively phenotyped and analysed for an association of their HLA-Cw6 genotype status with treatment outcomes. HLA-Cw6+ patients showed notably improved response to methotrexate (P = 0.05), and further analysis demonstrated an even greater response in a subcohort of the HLA-Cw6+ patients, who did not have concomitant psoriatic arthritis (P = 0.01). HLA-Cw6+ patients also exhibited fewer treatment-limiting adverse events. In addition to these findings, the methodology and primary clinical outcome phenotype, which we validate here, will greatly facilitate replication of the present results in independent cohorts.

Improvement in symptoms of obstructive sleep apnoea in children following tonsillectomy versus tonsillotomy: a systematic review and meta-analysis.

BACKGROUND: Tonsillotomy (or intracapsular tonsillectomy) is a modern technique which is seen by some as potentially superior to traditional (extracapsular) tonsillectomy for the removal of tonsillar tissue to treat obstructive sleep apnoea in children. It has been suggested that peri-operative pain and haemorrhage and postoperative haemorrhage are reduced with the tonsillotomy technique. However, no systematic reviews have been carried out to assess its efficacy in treating obstructive sleep apnoea compared to tonsillectomy. OBJECTIVE OF REVIEW: To assess whether subjective improvement in symptoms of obstructive sleep apnoea following tonsillotomy is comparable to that following tonsillectomy, measured using a standardised questionnaire, the Obstructive sleep apnoea-18 (OSA-18) tool. TYPE OF REVIEW: Systematic review of the literature and meta-analysis. SEARCH STRATEGY: PubMed (MEDLINE), followed by Ovid (MEDLINE), Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, and the British Medical Journal were searched for articles published in English between 1995 and 2015 inclusive. EVALUATION METHOD: Literature search, systematic review and meta-analysis. Studies examining improvement in mean OSA-18 score following tonsillotomy, improvement in mean OSA-18 score following tonsillectomy, and examining both were selected, examined and used for meta-analysis. Studies with and without concurrent adenoidectomy were included. RESULTS: Four studies examining tonsillotomy and 16 studies examining tonsillectomy were included in the analysis. Using a random effects model, the pooled improvement in OSA-18 score for tonsillotomy was 2.46 (95% CI 1.92-2.99), and for tonsillectomy, it was 2.10 (95% CI 1.91-2.30). There was no significant difference between the methods. CONCLUSION: That there is no significant difference in subjective outcome between tonsillotomy and tonsillectomy may support wider use of tonsillotomy over tonsillectomy for the treatment of obstructive sleep apnoea in children.

Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study.

BACKGROUND: Progesterone receptor (PR) expression assessment in early invasive breast cancer remains controversial. This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer; particularly in oestrogen receptor (ER)-positive, lymph node (LN)-negative disease. METHODS: A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years (2000-2004) underwent surgery for primary invasive breast cancer with curative intent. Prospective data collection included patient demographics, pathology, ER and PR expression, HER2 status, adjuvant chemotherapy and endocrine therapy. Progesterone receptor expression was compared with (all causes) overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS). RESULTS: Overall survival was 71.0% and BCSS was 83.0% at median follow-up of 8.34 years. Absent PR expression was significantly associated with poorer prognosis for OS, BCSS and DFS (P<0.0001, log-rank), even within the ER-positive, LN-negative group (hazard ratio for BCSS 3.17, 95% CI 1.43-7.01) and was not influenced by endocrine therapy. Cox's regression analysis demonstrated that PR expression was an independent prognostic variable. CONCLUSION: Absence of PR expression is a powerful, independent prognostic variable in operable, primary breast cancer even in ER-positive, LN-negative patients receiving endocrine therapy. Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy.

The open abdomen and temporary abdominal closure systems--historical evolution and systematic review.

AIM: Several techniques for temporary abdominal closure have been developed. We systematically review the literature on temporary abdominal closure to ascertain whether the method can be tailored to the indication. METHOD: Medline, Embase, the Cochrane Central Register of Controlled Trials and relevant meeting abstracts until December 2009 were searched using the following headings: open abdomen, laparostomy, VAC (vacuum assisted closure), TNP (topical negative pressure), fascial closure, temporary abdominal closure, fascial dehiscence and deep wound dehiscence. The data were analysed by closure technique and aetiology. The primary end-points included delayed fascial closure and in-hospital mortality. The secondary end-points were intra-abdominal complications. RESULTS: The search identified 106 papers for inclusion. The techniques described were VAC (38 series), mesh/sheet (30 series), packing (15 series), Wittmann patch (eight series), Bogotá bag (six series), dynamic retention sutures (three series), zipper (15 series), skin only and locking device (one series each). The highest facial closure rates were seen with the Wittmann patch (78%), dynamic retention sutures (71%) and VAC (61%). CONCLUSION: Temporary abdominal closure has evolved from simple packing to VAC based systems. In the absence of sepsis Wittmann patch and VAC offered the best outcome. In its presence VAC had the highest delayed primary closure and the lowest mortality rates. However, due to data heterogeneity only limited conclusions can be drawn from this analysis.

A 12-year follow-up study of all-cause and cardiovascular mortality among 10,532 people newly diagnosed with Type 2 diabetes in Tayside, Scotland.

AIMS: To determine absolute and relative risks of all-cause and cardiovascular mortality among patients newly diagnosed with Type 2 diabetes. METHODS: In an observational cohort study using record-linkage databases, based in Tayside, Scotland, UK, we identified newly diagnosed patients with Type 2 diabetes in 1993-2004. We also identified a set of non-diabetic comparators from lists of patients registered with a general practice, individually matched to the diabetic patients by sex, age and deprivation. We followed up patients for mortality and cardiovascular mortality over a 12-year period and calculated hazard ratios using Cox regression. RESULTS: There were 10,532 patients with Type 2 diabetes and 21,056 non-diabetic comparators. Diabetic patients in every age/sex group had higher absolute mortality rates. Even taking deprivation into account, the hazard ratio for mortality was 1.32 (95% CI 1.25-1.40), decreasing to 1.15 (1.09-1.22) after adjusting for pre-existing cardiovascular disease. The hazard ratios for cardiovascular mortality were higher, decreasing from 1.51 (1.37-1.67) to 1.23 (1.11-1.36) after adjusting for pre-existing cardiovascular disease. The hazard ratios decreased with increasing age at diagnosis, although the difference in absolute rate of mortality increased slightly with age. Increased mortality risks were only evident 2 years after diagnosis and increased thereafter. CONCLUSIONS: Patients with Type 2 diabetes have an increased risk of all-cause and cardiovascular mortality compared with non-diabetic comparators, although this is not observable immediately after diagnosis. Age at diagnosis and duration of the disease independently affect absolute and relative mortality risk.

Index laparoscopic cholecystectomy for acute admissions with cholelithiasis provides excellent training opportunities in emergency general surgery.

BACKGROUND: There is minimal data on the outcome of early laparoscopic cholecystectomy (LC) for acute gallbladder disease when performed by trainees. This study assesses the outcomes of a policy of same admission LC incorporated into a surgical training programme in a major teaching hospital. METHODS: 447 index LCs performed over a 3-year period were reviewed retrospectively. The indications, operating surgeon, operating time, use of IOC, conversion rates, reasons for conversion and post-operative stay were analysed. Multivariate analysis of reasons for conversion was performed. RESULTS: 150 LCs were performed by consultants and 297 by registrars; 67 were performed by year 1-3 specialist registrars (SpR) and 230 by year 4-6 SpRs. The indications were biliary colic (n=7), acute cholecystitis (n=180), chronic cholecystitis (n=260), carcinoma (n=1). No difference was found in demographics, operating time (105 min Vs 115 min), use of IOC (34% Vs 29%; P=0.2) and post-operative stay (2 days Vs 1 day) between consultants and registrars. The conversion rates were higher for consultants compared to registrars (29 (19%) Vs 28 (9%), P=0.004). The overall conversion rate was 11%. There were no bile duct injuries. Predictors for conversion were CRP>50 at admission and acute cholecystitis. CONCLUSION: In a teaching hospital setting most acute admission LCs (66%) were performed by trainees. A step wise training programme with active consultant supervision of all index LCs results in low morbidity, low conversion rates, and a short post-operative stay for acute gallbladder disease. This model of same admission cholecystectomy provides a good training opportunity in emergency general surgery.

A cohort study of the risk of cancer associated with type 2 diabetes.

BACKGROUND: There is evidence to suggest that diabetes may increase the risk of incidence and mortality from cancer. METHODS: In a cohort study using record-linkage health-care datasets for Tayside, Scotland in 1993-2004, we followed up 9577 newly diagnosed patients with type 2 diabetes, and two matched non-diabetic comparators, in the national cancer register. RESULTS AND CONCLUSIONS: The risk ratio for any cancer, adjusted for deprivation, was 0.99 (95%CI 0.90-1.09). Significantly increased risks were observed for pancreatic, liver and colon cancer.

Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis.

OBJECTIVES: Dose-dependant gastrointestinal and cardiovascular side-effects limit the use of NSAIDs in the management of RA. The n-3 essential fatty acids (EFAs) have previously demonstrated some anti-inflammatory and NSAID-sparing properties. The objective of this study was to determine whether cod liver oil supplementation helps reduce daily NSAID requirement of patients with RA. METHODS: Dual-centre, double-blind placebo-controlled randomized study of 9 months' duration. Ninety-seven patients with RA were randomized to take either 10 g of cod liver oil containing 2.2 g of n-3 EFAs or air-filled identical placebo capsules. Documentation of NSAID daily requirement, clinical and laboratory parameters of RA disease activity and safety checks were done at 0, 4, 12, 24 and 36 weeks. At 12 weeks, patients were instructed to gradually reduce, and if possible, stop their NSAID intake. Relative reduction of daily NSAID requirement by >30% after 9 months was the primary outcome measure. RESULTS: Fifty-eight patients (60%) completed the study. Out of 49 patients 19 (39%) in the cod liver oil group and out of 48 patients 5 (10%) in the placebo group were able to reduce their daily NSAID requirement by >30% (P = 0.002, chi-squared test). No differences between the groups were observed in the clinical parameters of RA disease activity or in the side-effects observed. CONCLUSIONS: This study suggests that cod liver oil supplements containing n-3 fatty acids can be used as NSAID-sparing agents in RA patients.

Meta-analysis of sentinel node biopsy in ductal carcinoma in situ of the breast.

BACKGROUND: The need for sentinel lymph node (SLN) biopsy in patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS) is debated. Advocates recommend such biopsy based on a high incidence of SLN involvement in some series. Opponents discourage SLN biopsy based on a perceived low incidence of nodal involvement in this setting. These contradictory arguments are generally based on small studies. The present study is a meta-analysis of the reported data on the incidence of SLN metastasis in patients with DCIS. METHODS: A search of electronic databases identified studies reporting the frequency of SLN metastases in DCIS. The random-effects method was used to combine data. RESULTS: Twenty-two published series were included in the meta-analysis. The estimate for the incidence of SLN metastases in patients with a preoperative diagnosis of DCIS was 7.4 (95 per cent confidence interval (c.i.) 6.2 to 8.9) per cent compared with 3.7 (95 per cent c.i. 2.8 to 4.8) per cent in patients with a definitive (postoperative) diagnosis of DCIS alone. This was a significant difference with an odds ratio of 2.11 (95 per cent c.i. 1.15 to 2.93). CONCLUSION: Patients with a preoperative diagnosis of DCIS should be considered for SLN biopsy.

Population-based demographic study of karyotypes in 1709 patients with adult acute myeloid leukemia.

Few large demographic studies of acute myeloid leukemia (AML) are derived from population-based registries. Demographic and karyotypic data were provided for AML cases from two regional leukemia registry databases in Scotland and the Northern Region of England. A population-based dataset was compiled, comprising 1709 patients aged >16 years (1235 North England/474 Scotland patients). The most common cytogenetic abnormalities involved chromosomes 5 and/or 7 (17%). Patients with the following abnormal chromosome 5/7 combinations: -5, del(5q), -5/-7 and del(5q)/-7 represented a significantly older population (P < 0.01, ANOVA). t(8;21) was the only 'favourable' karyotype found in older age. Karyotypic complexity varied within chromosome 5/7 combination groups; those containing -5, -5/-7, -5/del(7q), del(5q)/-7 or del(5q)/del(7q) combinations were significantly more frequently complex than those containing -7 and del(7q) (P < 0.01, chi2 test). Additional recurring cytogenetic abnormalities within complex karyotypes containing chromosome 5/7 combinations included (in order of frequency), abnormalities of chromosomes 17, 12, 3 and 18. Complex karyotypes not involving chromosomes 5 or 7 represented 30% of all complex karyotypes, occurred in younger patients than those involving chromosomes 5 and 7, and frequently included additional trisomy 8 (26%). In conclusion, we describe subgroups within adverse karyotypes, with different demographics, degree of complexity and additional chromosome abnormalities.

Maxillary incisor palatal erosion: no correlation with dietary variables?

The objectives of the study were to examine a relationship between tooth erosion affecting the palatal aspects of permanent maxillary central incisors with dietary, behavioral and medical variables. The methods included, 251 schoolchildren aged 11 to 13 years were recruited to participate. Each subject had dental impressions of the palatal aspects of both upper central incisors recorded at baseline, 9 and 18 months intervals. From these, electroconductive replicas were fabricated, mapped and compared using a surface matching technique. At the end of the study all participants underwent a structured interview that sought to assay the level of potential erosive dietary, behavioral and medical risk factors. Correlation analyses of the responses given in the final structured interview with the degrees of palatal tooth substance loss (both previous and measured) were under taken. The results showed: (1) The degree of previous erosion did not predict the level of measured ongoing erosion. (2) Brushing the teeth more frequently with fluoridated toothpaste correlated significantly with lower levels of ongoing erosion (P = 0 011). It was concluded that: (1) Evidence of previous palatal erosion did not predict future erosion. (2) The application of topical fluoride as a by-product of tooth brushing may provide an element of protection against palatal erosion. (3) In view of the lack of correlation between exposure to potential risk factors and the level of ongoing palatal tooth surface loss in this study, other factors (such as an individual's susceptibility and salivary buffering power) may well be more important predictors. The clinical relevance included: Preventive advice to patients with dental erosion should not only include the use of topical fluoride, in the form of toothpaste, but recognize individual susceptibility to this condition.

Elevated blood pressure during the first two hours of ambulatory blood pressure monitoring: a study comparing consecutive twenty-four-hour monitoring periods.

OBJECTIVE AND DESIGN: Ambulatory blood pressure monitoring is being used increasingly in clinical practice and hypertension research. We have noted elevated blood pressure during the initial hours of monitoring. The objective of the present study was to examine the consistency, magnitude and duration of this elevation, and to determine whether this effect causes significant differences in the mean ambulatory blood pressure monitoring values comparing the first (day 1) and second (day 2) consecutive 24-h periods of monitoring. METHODS: Fifty patients who were hypertensive based on repeated clinic readings were studied prospectively. Each underwent continuous 48-h ambulatory blood pressure monitoring with a SpaceLabs 90207 monitor. The device recorded blood pressure at 15-min intervals during the daytime (0600-2159 h) and at 30-min intervals at night-time (2200-0559 h). From these readings hourly means were calculated. Repeated-measures analysis of variance was performed to compare the hourly means of days 1 and 2. RESULTS: Repeated-measures analysis of variance indicated that a significant difference existed for both systolic and diastolic blood pressure between day 1 and day 2. Paired Student's t-test revealed that this difference occurred during the first 2 h of monitoring. The daytime blood pressure was higher on day 1 as a result of the initial elevation of blood pressure at the onset of monitoring. The initial elevation of blood pressure was present both in white-coat hypertensives and in essential hypertensives. CONCLUSION: The first 2 h of ambulatory blood pressure monitoring are associated with elevated blood pressure both in white-coat hypertensives and in essential hypertensives. This has a minor effect on mean daytime and 24-h ambulatory blood pressures. We propose that improved ambulatory blood pressure monitoring recordings would be obtained in clinical practice, and more particularly in research applications, if 26-h ambulatory blood pressure monitoring was carried out, excluding the first 2 h from the summary analyses.

Effect of phenylephrine with and without atropine on QT dispersion in healthy normotensive men.

The present study examined if changes in cardiac after-load would affect QT interval dispersion. QT dispersion (QTd) on the 12-lead electrocardiogram is believed to be a noninvasive measure of electrical inhomogeneity in the heart and has recently been identified as a sensitive predictor of sudden cardiac death. In experimental models, an increase in cardiac afterload has been shown to alter action potential durations through mechanoelectrical feedback. This may result in an altered dispersion of action potential repolarization in the ventricle. Until now, there has been little evidence for this occurring in man in vivo. In the present study, the effects of afterload on QTd were examined in 10 healthy male volunteers (mean age [SD] 25 years [4.5]) who received an intravenous infusion of phenylephrine (0.2 to 3.6 microg/kg/min) given in incremental doses, and placebo in a blinded, crossover fashion. Because phenylephrine is known to alter heart rate (HR) significantly (via a reflex vagal response), the study was performed with and without atropine. We found a significant positive correlation between acute changes in blood pressure (BP) and changes in all QTd indexes (deltaQTd/delta systolic BP and deltaQTcd/deltasystolic BP r values 0.67 and 0.60, respectively; p <0.001). This relation was independent of HR changes or reflex vagal activity. Atropine had no significant effect on QTd. These observations have important clinical implications and may partly account for why sudden deaths and arrhythmic complications occur so frequently in conditions associated with increased after-load, such as hypertension and heart failure.

Observer variability in the histopathological reporting of needle biopsy specimens of the prostate.

The Scottish Pathology Consistency Group has in previous studies examined the consistency of histopathological reporting of biopsies from the cervix, bladder, bronchus, and rectum. In the current study, consisting of 100 needle biopsy specimens of the prostate, a single hematoxylin-eosin (H&E) slide from each case was circulated in batches of 10 to the 12 pathologists, who filled in a simple proforma. This had two sections: a diagnostic category (benign; suspicious or malignant) along with a standard Gleason score for those regarded as malignant. The majority diagnosis of the 100 cases was benign, 53; suspicious, 1; and malignant, 46. The Kappa value for benign cases versus others was 0.86 and for malignant cases versus others was 0.91. Analysis of the data on Gleason scores showed a value of 0.54 when cases were divided into two categories (2 to 6 v 7 to 10) and 0.41 when three categories were used (2 to 4; 5 to 6; 7 to 10). Although not initially part of the design of the study, the majority diagnosis was compared with the original reported diagnosis. In a small subset, examination of further levels, basal cell antibody staining, along with further clinical information, was obtained. With this added information, it appears that there were probably 52 benign and 48 malignant cases. Of the 48 malignant cases, the group majority diagnosis was malignant, 46; suspicious, 1; and benign, 1. The original reported diagnosis was 56 benign, 1 suspicious, and 43 malignant. The group therefore appeared to perform better than the original reporting pathologists. When compared with the results of our previous studies, this study has shown that the diagnosis of carcinoma of the prostate on a needle biopsy is robust.

EUROMAC. A European concerted action: maternal alcohol consumption and its relation to the outcome of pregnancy and child development at 18 months. Results--strategy of analysis and analysis of pregnancy outcome.

Analyses were made of the relation between maternal alcohol consumption before and in early pregnancy and five infant outcome variables: birthweight, crown-heel length, occipitofrontal circumference and the Apgar scores at 1 and 5 minutes. The data were analysed for all centres combined and separately. From tabulation of the mean values of the outcome variables by alcohol consumption, it appeared that a poorer outcome was related to consumption of 120 g/week absolute alcohol or more. Multiple regression analysis was used to allow for possible confounding by the child's gestational age at birth and sex, the mother's age, parity and smoking habit, and survey centre. Two threshold models were applied to the combined data, taking the confounders into account. The offset threshold model (assuming no effect of alcohol up to a threshold value, and then a constant multiplicative effect at higher levels) suggested a negative effect on birthweight at about 60 g/week absolute alcohol, but with a wide 85% confidence interval of 5-130 g/week. A step function threshold model, which assumes a constant effect above the threshold value, behaved erratically. Similar analyses for crown-heel length and occipitofrontal circumference provided only a very poor fit to the data. Data on reported congenital anomalies are presented by survey centre and maternal alcohol consumption, but due to the unstandardized method of collection they were not analysed further.

EUROMAC. A European concerted action: maternal alcohol consumption and its relation to the outcome of pregnancy and child development at 18 months. Results--child development at age 18 months.

Children seen in the first part of the study in Berlin, Dundee and Odense were followed up at age 18 months and tested using the Bayley Scales of Infant Development. Five scores were recorded: the Mental Development Index (MDI), the Psychomotor Development Index (PDI) and scores for responsiveness, attention span and activity. The data were analysed for the centres combined and separately, allowing for confounding variables as in the previous chapter. In none of the comparisons was the mean score found to be significantly less in the children of drinkers than in those of abstainers. In many of the comparisons the children of abstainers had the lowest mean scores. In a number of comparisons in Berlin and Dundee, the MDI or PDI was found to be significantly higher in the children of women who had drunk at the upper end of the consumption distribution.

Observer variability in histopathological reporting of malignant bronchial biopsy specimens.

AIMS: To evaluate the ability of histopathologists to classify lung carcinomas on bronchial biopsy material using the current World Health Organisation (WHO) classification. METHODS: Eleven histopathologists each reviewed 100 randomly selected bronchial biopsy specimens which had originally been reported as showing lung carcinoma. A single haematoxylin and eosin stained section from each case was circulated and a standard proforma completed. These were analysed using kappa statistics. RESULTS: The histopathologists were excellent at distinguishing between small cell and non-small-cell carcinoma kappa = 0.86), but not so good at subclassifying the non-small cell carcinoma group kappa = 0.25). CONCLUSIONS: The clinically important distinction between small cell and non-small cell carcinoma of the lung is reliably made by competent histopathologists even on limited material.

Observer variability in histopathological reporting of non-small cell lung carcinoma on bronchial biopsy specimens.

AIMS: To evaluate the ability of histopathologists to sub-classify non-small cell lung carcinomas on bronchial biopsy material using the current World Health Organisation (WHO) classification. METHODS: Twelve histopathologists each reviewed 100 randomly selected bronchial biopsy specimens which had originally been reported as showing non-small cell lung carcinoma. For each case, two sections were circulated, one stained by haematoxylin and eosin and the other by a standard method for mucin (alcian blue/periodic acid Schiff). The participants were allowed to indicate their degree of confidence in their classification of each case. A standard proforma was completed and the results were analysed using kappa statistics. RESULTS: Where the participants were confident in their classification, they were actually quite good at sub-classifying the non-small cell carcinoma sections (kappa = 0.71, standard error = 0.058). Overall, however, the results were only fair (kappa = 0.39, standard error = 0.034). CONCLUSIONS: The majority of non-small cell lung carcinomas can be correctly categorised on adequate bronchial biopsy material. Where a confident diagnosis was made, both squamous carcinoma (kappa = 0.73) and adenocarcinoma (kappa = 0.83) were well recognised.

Airway-stabilizing effect of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids.

BACKGROUND: The protection afforded by long-acting beta(2)-agonists against bronchoconstrictor stimuli can be regarded as a surrogate for their stabilizing effects on airway smooth muscle. AIM: To determine the magnitude of residual bronchoprotection after chronic dosing with long-acting beta(2)-agonists. DESIGN: Retrospective meta-analysis. METHODS: Medline, BIDS and Cochrane Library databases were searched from 1990. A meta-analysis was then performed of 13 eligible randomized placebo-controlled trials (596 patients) in which second-line treatment with a long-acting beta(2)-agonist (salmeterol or formoterol) was used for 1 week or more. The residual protection against bronchoconstrictor stimuli as doubling dose/dilution shift was the main outcome measure. RESULTS: Data were assessed according to Quorum criteria. Combining the results of the meta-analysis, the overall estimated protection amounted to a 0.79 (95%CI 0.63-0.96) doubling dose/dilution shift from placebo. Subgroup analysis showed greater protection at peak vs. trough, but no difference between formoterol vs. salmeterol, or between direct vs. indirect challenge. There was no evidence of significant heterogeneity across all the studies, or within any of the subgroups. DISCUSSION: When used as second-line treatment, the overall additive protective effect of long-acting beta(2)-agonists amounts to a 0.8 doubling dose/dilution shift. This stabilizing effect on airway smooth muscle may explain their beneficial effects on exacerbations.