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Background The aims of this study were to compare neoplasia detection rates for nontargeted biopsies (Seattle protocol) versus acetic acid-targeted biopsies (Portsmouth protocol) during Barrett’s surveillance and to explore feasibility, patient/clinician experience, acceptance, and barriers/enablers to study participation and implementation of the acetic acid technique. Methods This was a mixed-methods feasibility study including a pilot multicenter, randomized, crossover trial with qualitative interviews. Patients under Barrett’s surveillance with no history of neoplasia were included. Patients underwent two endoscopies, one with each protocol, 8 weeks apart. Outcomes included recruitment and retention rates, neoplasia yield, and number of biopsies. Results 200 patients were recruited from 6 centers, and 174 (87.0 %) underwent both procedures. Neoplasia prevalence was 4.7 % (9/192). High grade dysplasia and cancer were detected with both protocols. Five low grade dysplasias were detected (two with acetic acid, four with nontargeted biopsies; one lesion was detected with both techniques). A total of 2139 biopsies were taken in the nontargeted arm and 226 in the acetic acid arm. Both patients and clinicians found the acetic acid technique acceptable. Based on these data, a noninferiority, tandem, crossover trial would require an estimated 2828 patients. Conclusions We demonstrated the feasibility of performing a crossover endoscopy trial in Barrett’s surveillance. Low neoplasia yield makes this design necessary and qualitative results demonstrated patient and clinician acceptance. The reduced numbers of biopsies suggest that the acetic acid technique could result in cost savings, providing the lack of missed pathology can be proven in a fully powered definitive trial.

BackgroundAsthma exacerbations affect the quality of life of patients with asthma and have a major effect on the overall costs of asthma care. An asthma self-management plan that advises the temporary quadrupling of inhaled corticosteroid dose may prevent asthma exacerbations, but this needs to be confirmed before being adopted widely.ObjectivesTo compare the clinical effectiveness and cost-effectiveness of an asthma self-management plan that advises patients to temporarily quadruple the dose of inhaled corticosteroid when asthma control starts to deteriorate with a standard self-management plan.DesignA multicentre, parallel-group, pragmatic randomised trial, with follow-up for 12 months.SettingPrimary and secondary care across 207 sites in the UK.ParticipantsAsthma patients aged ≥ 16 years treated with an inhaled corticosteroid who had experienced at least one exacerbation in the previous 12 months.InterventionsParticipants were randomised (1 : 1) to a usual-care self-management plan or to a modified self-management plan that advised a temporary quadrupling of the inhaled corticosteroid at the point of asthma deterioration, both of which were actively implemented and supported by local research staff.Primary outcomeThe primary outcome of ‘time to first asthma exacerbation’ was defined as the need for systemic corticosteroids (for at least 3 consecutive days) and/or unscheduled health-care consultations for asthma (i.e. reaching zone 3 or 4 of the Asthma UK self-management plan).ResultsA total of 1922 participants were randomised: the primary analysis included 938 participants (97%) in the usual-care group and 933 participants (97%) in the modified self-management group. The number of participants having at least one exacerbation of asthma in the year after randomisation was 484 (51.6%) in the usual-care group and 420 (45.0%) in the modified self-management group [adjusted hazard ratio 0.81, 95% confidence interval (CI) 0.71 to 0.92;p = 0.002]. There were fewer serious adverse events reported in the modified self-management group than in the usual-care group (11 vs. 32, respectively). Eight and six events of pneumonia, lower respiratory tract infections or influenza were reported in the usual-care group and the modified self-management group, respectively. Health-care-related costs were lower in the modified self-management group. The modified self-management group was £24 (bootstrapped 95% CI –£122 to £71) less costly than usual care, with a greater quality-adjusted life-year gain of 0.02 (bootstrapped 95% CI –0.005 to 0.04). Therefore, the modified self-management group was ‘dominant’, with a 94–95% probability of being cost-effective at the £20,000–30,000 threshold.LimitationsAs the Fourfold Asthma STudy (FAST) was an open-label pragmatic trial, the possibility of treatment bias that may have affected the participants in the modified self-management group cannot be ruled out. Poorer than expected completion of participant diary cards, particularly within the usual-care self-management group, could have led to a null bias, underestimating the true effect of the intervention.ConclusionsAn asthma self-management plan that advises patients to temporarily quadruple their dose of inhaled corticosteroid at the point of asthma symptoms worsening does reduce clinically important asthma exacerbations. In addition, the plan is cost-effective compared with the usual-care self-management plan.Future workTo effectively implement asthma self-management plans that advise a temporary quadrupling of inhaled steroid at asthma deterioration into routine practice.Trial registrationCurrent Controlled Trials ISRCTN15441965.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 70. See the NIHR Journals Library website for further project information.

BACKGROUND: \ud Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma.\ud \ud METHODS: \ud We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma.\ud \ud RESULTS: \ud A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group.\ud \ud CONCLUSIONS: \ud In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN15441965 .).

Objective To assess the relative efficacy and safety of basal insulin regimens in adults with type 1 diabetes mellitus (T1DM). Methods A systematic review and Bayesian network meta-analysis (NMA) of randomized controlled trials comparing two or more basal insulin regimens were conducted. The following basal insulin regimens were included: Neutral Protamine Hagedorn (iNPH) (once [od], twice [bid], and four times daily [qid]), insulin detemir (iDet) (od and bid), insulin glargine 100 IU (iGlarg) (od), and insulin degludec (iDegl) (od). We searched the following databases: MEDLINE via OVID, Embase via OVID, and the Cochrane Library (Wiley). Study quality was appraised using Cochrane risk-of-bias checklist for randomized controlled trials. Two outcomes (change in hemoglobin A 1c [HbA 1c ] and rate of severe/major hypoglycemia [SH]) were analyzed. Network inconsistency was assessed using Bucher and chi-square tests. Results Thirty studies met the eligibility criteria. Twenty-five were included in the HbA 1c network and 16 in the SH network. All studies were of moderate quality. No network inconsistency was evident in the HbA 1c network. Of the seven regimens of interest, iDet (bid) had the highest probability of being best (mean change in HbA 1c −0.48; 95% credible interval −0.69 to −0.29). In contrast, the SH network demonstrated both considerable uncertainty and significant network inconsistency (χ 2 test, P = 0.003). Conclusions Of the specified frequency regimens, iDet (bid) had the highest probability of being the best basal insulin regimen in terms of reduction in HbA 1c . Ranking of the regimens in terms of the SH rate was highly uncertain and no clear conclusion could be made.

Objectives To assess the cost-effectiveness of basal insulin regimens for adults with type 1 diabetes mellitus in England. Methods A cost-utility analysis was conducted in accordance with the National Institute for Health and Care Excellence reference case. The UK National Health Service and personal and social services perspective was used and a 3.5% discount rate was applied for both costs and outcomes. Relative effectiveness estimates were based on a systematic review of published trials and a Bayesian network meta-analysis. The IMS CORE Diabetes Model was used, in which net monetary benefit (NMB) was calculated using a threshold of £20,000 per quality-adjusted life-year (QALY) gained. A wide range of sensitivity analyses were conducted. Results Insulin detemir (twice daily) [iDet (bid)] had the highest mean QALY gain (11.09 QALYs) and NMB (£181,456) per patient over the model time horizon. Compared with the lowest cost strategy (insulin neutral protamine Hagedorn once daily), it had an incremental cost-effectiveness ratio of £7844/QALY gained. Insulin glargine (od) [iGlarg (od)] and iDet (od) were ranked as second and third, with NMBs of £180,893 and £180,423, respectively. iDet (bid) remained the most cost-effective treatment in all the sensitivity analyses performed except when high doses were assumed (>30% increment compared with other regimens), where iGlarg (od) ranked first. Conclusions iDet (bid) is the most cost-effective regimen, providing the highest QALY gain and NMB. iGlarg (od) and iDet (od) are possible options for those for whom the iDet (bid) regimen is not acceptable or does not achieve required glycemic control.

Introduction Barrett’s surveillance traditionally requires mapping biopsies to identify neoplasia. Acetic acid (AA) allows only targeted biopsies, potentially reducing the number of biopsies required. This study aims to compare neoplasia detection with AA targeted biopsies and protocol guided non-targeted biopsies during Barrett’s surveillance. Methods Multicentre randomised crossover feasibility study in UK secondary care. Patients under surveillance for Barrett’s metaplasia (>2 cm) with no history of dysplasia or cancer were recruited. All patients underwent two gastroscopies 8 weeks apart, one with AA guided biopsy of abnormal areas only (Portsmouth Protocol) and one with non-targeted mapping biopsies (Seattle Protocol). Neoplasia yield (low grade dysplasia LGD, high grade dysplasia (HGD) and cancer) from each strategy was evaluated and the number of biopsies recorded. Results 200 patients recruited from 6 centres. Mean age 66 years. 145 were male. Mean length C4M6. 175 patients completing both procedures. The prevalence of LGD, HGD and cancer was 11/192 (5.8%). All HGD and cancer was found with both protocols and confirmed with definitive treatment. One LGD was found with Portsmouth protocol not found with Seattle. 5 LGD were found with Seattle protocol not found with Portsmouth. This difference was not significant (p=0.2188), and on follow up gastroscopy no neoplastic changes were found in any of the LGD cases. 2139 biopsies were taken using Seattle protocol at a cost of £1 25 987 (306 biopsies per neoplasia, £18,023). 226 biopsies with Portsmouth Protocol at a cost of £13 311 (75 biopsies per neoplasia, £6,656) a 4 fold difference. In terms of HGD/cancer, 1070 biopsies/neoplasia found using Seattle protocol and 113 biopsies/neoplasia using Portsmouth Protocol, a 9.5 fold difference. Conclusions This is the first RCT comparing these techniques. No HGD or cancer was missed with either technique. There was a 4 fold reduction in biopsies per neoplasia detected with Portsmouth compared to Seattle protocol and a 9.5 fold difference when restricted to high risk neoplasia. If implemented nationally then this could lead to a massive reduction in histopathology work load and costs. LGD remains controversial and we believe inflammation could have resulted in false positive LGD as subsequent OGD and biopsies did not reveal any LGD. This feasibility data would support a definitive trial of AA targeted biopsies in a surveillance population.

Aims: To compare neoplasia detection with AA targeted biopsies and protocol guided non-targeted biopsies during Barrett's surveillance. Methods: Multicentre randomized crossover feasibility study. Patients under surveillance for Barrett's metaplasia with no history of dysplasia/cancer were recruited. All patients underwent two gastroscopies 8 weeks apart, one with AA guided biopsy of abnormal areas only (Portsmouth Protocol) and one with non-targeted mapping biopsies (Seattle Protocol). Neoplasia yield and no. biopsies from each strategy was evaluated. Results: 200 patients recruited from 6 centres. Mean age 66yrs. Mean length C4M6. 175 patients completed both procedures. The prevalence of LGD, HGD and cancer was 11/192 (5.8%). All HGD and cancer was found with both protocols and confirmed with definitive treatment. One LGD was found with Portsmouth protocol and 5 LGD with Seattle protocol. This difference was not significant, and on follow up gastroscopy no neoplastic changes were found in any of the LGD cases. 2139 biopsies were taken using Seattle protocol at a cost of £125,987 (306 biopsies/neoplasia). 226 biopsies with Portsmouth Protocol at a cost of £13,311 (75 biopsies/neoplasia) a 4 fold difference. In terms of HGD/cancer, 1070 biopsies/neoplasia found using Seattle protocol and 113 biopsies/neoplasia using Portsmouth Protocol, a 9.5 fold difference. Conclusions: This is the first RCT comparing these techniques. No HGD or cancer was missed with either technique. There was a 4 fold reduction in biopsies per neoplasia detected with Portsmouth compared to Seattle protocol and a 9.5 fold difference when restricted to high risk neoplasia. If implemented nationally then this could lead to a massive reduction in histopathology work load and costs. LGD remains controversial and we believe inflammation could have resulted in false positive LGD as subsequent OGD and biopsies did not reveal any LGD. This feasibility data would support a definitive trial of AA targeted biopsies in a surveillance population.

Patients with advanced cancer often suffer from cachexia, a debilitating and complex extreme weight loss syndrome which is also associated with shorter survival times. A pragmatic randomised controlled trial was conducted to determine whether an oral nutritional supplement containing the omega-3 fatty acid eicosapentaenoic acid (EPA) was able to improve quality of life and survival times of patients with advanced solid tumour cancer in a mixed tumour cancer type population.

Background and study aims Up to 25 % colorectal adenomas are missed during colonoscopy. The aim of this study was to investigate whether the endocuff could improve polyp detection in an organized bowel cancer screening program (BCSP). Patients and methods This parallel group, single-blinded, randomized controlled trial included patients with positive fecal occult blood test (FOBT) who were attending for BCSP colonoscopy. The primary outcome was the number of polyps per patient. Secondary outcomes included the number of adenomas per patient, adenoma and polyp detection rates, and withdrawal times. Results A total of 534 BCSP patients were randomized to endocuff-assisted or standard colonoscopy. The mean age was 67 years and the male to female ratio was 1.8:1. We detected no significant difference in the number of polyps per patient (standard 1.8, endocuff 1.6; P = 0.44), adenomas per patient (standard 1.4, endocuff 1.3; P = 0.54), polyp detection rate (standard 69.8 %, endocuff 70.3 %; P = 0.93), adenoma detection rate (standard 63.0 %, endocuff 60.9 %; P = 0.85), advanced adenoma detection rate (standard 18.5 %, endocuff 16.9 %; P = 0.81), and cancer detection rate (standard 5.7 %, endocuff 5.3 %; P = 0.85). The mean withdrawal time was significantly shorter among patients in the endocuff group compared with the standard colonoscopy group (16.9 vs. 19.5 minutes; P Conclusions This study did not find improved polyp or adenoma detection with endocuff-assisted colonoscopy in the FOBT-positive BCSP population. A shorter withdrawal time with endocuff may reflect improved views and stability provided by the endocuff.Trial registered at ClinicalTrials.gov (NCT02529007).

© Journal of Thoracic Disease. Background: To investigate the effect of BC1036 on health-related quality of life (QOL) in subjects with persistent cough. The secondary objective was to investigate the effect of BC1036 on subjective cough severity. Methods: This was a randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 289 subjects with persistent cough. Subjects received BC1036 or placebo twice daily for 14 days. The primary endpoint comprised cough-related QOL assessed using the validated Leicester Cough Questionnaire (LCQ) at Day 14. Secondary endpoints comprised the LCQ scores at Day 7 and Day 28, cough severity VAS scores at each visit and pulmonary function tests. Results: At baseline, mean total LCQ score in the BC1036 group was lower (i.e., worse QOL) than placebo (P < 0.001), indicating significant between-group heterogeneity. Mean baseline-adjusted change in LCQ score at Day 14 was greater for BC1036 [mean (SD) 2.4±3.5] compared to placebo [mean (SD) score 2.2±3.0] , but did not reach statistical significance (P=0.60). Mean cough severity VAS score decreased to a greater extent in the BC1036 group compared to placebo, but again the results were not statistically significant (-12.2±23.28 in BC1036 group and -11.0±21.34 in placebo group at Day 14, P=0.688). There was no significant change in pulmonary function measurements. The adverse event (AE) profile was similar in both groups. Conclusions: This study showed that BC1036 was well tolerated and, although the primary endpoint did not achieve statistical significance, the magnitude of improvement was greater with BC1036 compared to placebo with respect to improving QOL and reducing cough severity. Clinical trial registration: ClinicalTrials.gov: NCT01656668.

Background Asthma is one of the commonest chronic diseases in the UK. Acute exacerbations of asthma are unpredictable, disruptive and frightening. They cause considerable morbidity and account for a large component of the health service costs of asthma. The widespread use of an asthma self-management plan, designed to encourage disease monitoring and timely intervention, can reduce exacerbations and is, therefore, recommended for all patients with asthma. Unfortunately, the majority of patients are not provided with such a plan. There are a variety of reasons for this but uncertainty about what to include in the plan when asthma control is deteriorating, but before the need for orally administered corticosteroids, is a contributing factor. The aim of this trial is to determine whether an asthma self-management plan, which includes a temporary quadrupling of the dose of inhaled corticosteroid when asthma control starts to deteriorate, reduces asthma exacerbations requiring orally administered corticosteroids or unscheduled health care consultation for asthma. Methods A multicentre, pragmatic, randomised trial in adults aged over 16 years with a clinical diagnosis of asthma, treated with a licensed dose of inhaled corticosteroid and at least one exacerbation in the previous 12 months requiring treatment with systemic corticosteroids. Participants will be randomised to either a self-management plan, which includes a temporary (maximum of 14 days) fourfold increase in inhaled corticosteroid or the same plan without an increase in inhaled corticosteroid. Participants will be followed up at 6 and 12 months and will attend the clinic for an additional visit if their asthma control deteriorates. The primary outcome is time to first asthma exacerbation, defined as the need for systemic corticosteroids and/or unscheduled health care consultation for asthma. The estimated sample size is 1800 participants. Discussion The FAST trial is an independent study that has been prioritised and commissioned by the National Institute for Health Research (NIHR) in the United Kingdom. It will provide high-quality evidence to inform clinical decision-making on the role of an asthma self-management plan, which includes a temporary fourfold increase of inhaled corticosteroid, when asthma control starts to deteriorate. The first participant was randomised on 17th May 2013 and recruitment will close on 31 January 2016 with the last patient last visit taking place in January 2017. Trial registration ISRCTN: 15441965, registered on 25 April 2013. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1608-6) contains supplementary material, which is available to authorized users.

Traditional white-light endoscopy cannot reliably distinguish between small (10 mm) adenomatous and hyperplastic colon polyps. High-definition white-light (HDWL) endoscopy and i-Scan may improve in vivo characterization of small colon polyps.To compare HDWL endoscopy and HDWL plus i-Scan for the assessment of small colon polyps and to measure performance against the American Society for Gastrointestinal Endoscopy (ASGE) thresholds for assessment of diminutive colon polyps.Prospective cohort study.Single academic hospital.Patients undergoing bowel cancer screening colonoscopy.In vivo assessment of all polyps10 mm by using HDWL and i-Scan image enhancement.The primary outcome measure was overall diagnostic accuracy of in vivo assessment of colon polyps10 mm. Secondary outcome measures were sensitivity and specificity for adenomatous histology, negative predictive value for adenomatous histology of diminutive rectosigmoid polyps, and accuracy of prediction of polyp surveillance intervals.A total of 209 polyps in 84 patients were included. There were no significant differences between HDWL endoscopy and i-Scan in characterization of polyps10 mm (accuracy 93.3% vs 94.7%; P = 1.00; sensitivity 95.5% vs 97.0%; P = .50; specificity 89.3% vs 90.7%; P = 1.00). The negative predictive value for adenomatous histology of diminutive rectosigmoid polyps was 100% with both HDWL endoscopy and i-Scan. U.K. and U.S. polyp surveillance intervals were predicted with 95.2% accuracy with HDWL endoscopy and 97.2% accuracy with i-Scan.Single-center study.HDWL endoscopy may be as accurate as HDWL with i-Scan image enhancement for the in vivo characterization of small colon polyps. Both modalities fulfil the ASGE performance thresholds for the assessment of diminutive colon polyps. (NCT01761279.).

Background: falls disproportionately affect older people, who are at increased risk of falls and injury. This pilot study investigates shock-absorbing flooring for fall-related injuries in wards for frail older people.Methods: we conducted a non-blinded cluster randomised trial in eight hospitals in England between April 2010 and August 2011. Each site allocated one bay as the ‘study area’, which was randomised via computer to intervention (8.3-mm thick Tarkett Omnisports EXCEL) or control (2-mm standard in situ flooring). Sites had an intervention period of 1 year. Anybody admitted to the study area was eligible. The primary outcome was the fall-related injury rate. Secondary outcomes were injury severity, fall rate and adverse events.Results: during the intervention period, 226 participants were recruited to each group (219 and 223 were analysed in the intervention and control group, respectively). Of 35 falls (31 fallers) in the intervention group, 22.9% were injurious, compared with 42.4% of 33 falls (22 fallers) in the control group [injury incident rate ratio (IRR) = 0.58, 95% CI = 0.18–1.91]. There were no moderate or major injuries in the intervention group and six in the control group. The fall IRR was 1.07 (95% CI = 0.64–1.81). Staff at intervention sites raised concerns about pushing equipment, documenting one pulled back.Conclusions: future research should assess shock-absorbing flooring with better ‘push/pull’ properties and explore increased faller risk. We estimate a future trial will need 33,480–52,840 person bed-days per arm.Trial registration: ClinicalTrials.gov (ID: NCT00817869); UKCRN (ID: 5735).

BackgroundBacterial infections are implicated in the pathogenesis of asthma exacerbation but guidelines recommend that antibiotics should not be administered. Telithromycin shows clinical benefit compared with placebo but toxicity limits its use.ObjectiveTo evaluate the efficacy of azithromycin compared with placebo in reducing the severity of asthma exacerbations.DesignMulticentre, randomised, double-blind, placebo-controlled study.SettingAccident and emergency and acute medical units, and one primary care centre.ParticipantsAdults with a history of asthma presenting within 48 hours (of initial presentation requesting medical care) with an acute deterioration in asthma control [increased wheeze, dyspnoea and/or cough with reduced peak expiratory flow (PEF)] requiring treatment with corticosteroids.InterventionsAzithromycin (500 mg once daily) or two placebo capsules once a day for 3 days.Main outcome measureDiary card summary symptom score assessed at 10 days after randomisation.ResultsIn total, 4582 patients were screened at 31 centres, of whom 199 were randomised to the study (azithromycin,n = 97; placebo,n = 102) (of the intended 380). The major reasons for non-recruitment were already receiving antibiotics (n = 2044; 44.6% of screened subjects), unable to contact (n = 315; 6.9%), declined participation (n = 191; 4.2%) and other (e.g. underlying health condition, on steroids;n = 1833; 40.0%). The mean age of participants was 39.9 years and 69.8% were female; 61.1% had never smoked, 22.7% were former smokers and 16.2% were current smokers (mean pack-years 3.45). The median time from presentation to drug administration was 22 hours. Lung function at baseline (exacerbation) was PEF 69.4% predicted, forced expiratory volume in 1 second (FEV1) 64.8% predicted and FEV1/forced vital capacity ratio 69.2%. Baseline characteristics were well balanced across treatment arms and centres. The mean (standard deviation) scores on the primary outcome asthma symptom score were 4.14 (1.38) at baseline and 2.09 (1.71) at the end of treatment for the azithromycin group, and 4.18 (1.48) at baseline and 2.20 (1.51) at the end of treatment for the placebo group. Using multilevel modelling there was no statistically significant difference in symptom scores between groups at day 10 (unbiased estimated mean difference –0.166, 95% confidence interval –0.670 to 0.337); similarly, no significant between-group differences were seen in symptom scores on any other day between baseline and day 10. No significant between-group differences were seen in the Acute Asthma Quality of Life Questionnaire (AQLQ) score, Mini AQLQ score or any measure of lung function on any day, and there were no differences in time to a 50% reduction in symptom score. Sputum bacterial culture was positive in 6% of subjects, atypical pathogen polymerase chain reaction (PCR) and/or serology was positive in 4.5% of subjects and virus PCR analysis was positive in 18.1% of subjects. There was no difference in the primary outcome between the active group and the placebo group among those with a positive sputum bacterial test, although numbers for these analyses were small.ConclusionsIn the population of patients randomised to treatment, the addition of azithromycin to standard medical care demonstrated no statistically significant or clinically important benefit, although this could not be ruled out based on the confidence intervals. A limitation of this study was that, for each subject randomised, > 10 failed screening because they had already been prescribed antibiotic therapy. Further clinical trials are needed in settings of less antibiotic usage.Trial registrationClinicalTrials.gov NCT01444469; EudraCT 2011–001093–26.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

Importance: Guidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use.Objective: To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit.Design, Setting, and Participants: The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom-based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids.Interventions: Azithromycin 500 mg daily or matched placebo for 3 days.Main Outcomes and Measures: The primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of -0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score.Results: Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference, -0.166; 95% CI, -0.670 to 0.337), nor on any day between exacerbation and day 10. No significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score.Conclusions and Relevance: In this randomized population, azithromycin treatment resulted in no statistically or clinically significant benefit. For each patient randomized, more than 10 were excluded because they had already received antibiotics.Trial Registration: clinicaltrials.gov Identifier: NCT01444469.

Chapter 5 covers respiratory diseases and respiratory failure, including clinical presentations of respiratory disease, assessment of diffuse lung disease, hypoxaemia, respiratory failure, and oxygen therapy, pneumonia, mycobacterial infection, asthma, chronic obstructive pulmonary disease (COPD), lung cancer, mediastinal lesions, pneumothorax, pleural disease, asbestos-related lung disease, diffuse parenchymal (interstitial) lung disease, sarcoidosis, pulmonary hypertension, acute respiratory distress syndrome, bronchiectasis and cystic fibrosis, bronchiolitis, eosinophilic lung disease, airways obstruction, aspiration syndromes, and near-drowning, pulmonary vasculitis, the immunocompromised host, sleep apnoea, and rare pulmonary diseases.

Background and study aims: The resolution of endoscopes has increased in recent years. Modern Fujinon colonoscopes have a charge-coupled device (CCD) pixel density of 650000 pixels compared with the 410000 pixel CCD in standard-definition scopes. Acquiring high-definition scopes represents a significant capital investment and their clinical value remains uncertain. The aim of the current study was to investigate the impact of high-definition endoscopes on the in vivo histology prediction of colonic polyps. Patients and methods: Colonoscopy procedures were performed using Fujinon colonoscopes and EPX-4400 processor. Procedures were randomized to be performed using either a standard-definition EC-530 colonoscope or high-definition EC-530 and EC-590 colonoscopes. Polyps of Results: A total of 293 polyps of Conclusions: There was no difference between high- and standard-definition colonoscopes when white light was used, but FICE significantly improved the in vivo diagnosis of small polyps when high-definition scopes were used compared with standard definition.

Summary Background There is wide variation in the techniques deployed to diagnose tuberculosis in the UK, with little agreement on which tools or strategies are cost effective. This analysis therefore comprehensively evaluated the cost effectiveness of currently available diagnostic strategies for routine diagnosis of TB in the NHS. Methods The analysis compared strategies consisting of Nucleic Acid Amplification Techniques, culture and microscopy. A decision tree was used to estimate costs and Quality-Adjusted Life Years (QALYs) from a UK health service perspective. The sensitivity and specificity of each test determined the true and false positive and negative results in patients suspected of having active tuberculosis. These results led to either early, correct diagnosis or delayed diagnosis and the associated costs and QALYs. The presence of active tuberculosis combined with the side effects of treatment was associated with reduction in quality of life. Costs included were test costs, drug costs and the management of tuberculosis. Drug costs were based on generic UK list prices. Uncertainty in the model was explored through probabilistic and deterministic sensitivity analyses. Results/conclusions The cost effective strategy at threshold of £20,000 per QALY was a strategy using only sputum microscopy and culture routinely, meaning Nucleic Acid Amplification Techniques are not cost effective at baseline. When the prevalence of tuberculosis was increased, however, nucleic acid amplification became cost effective at the same threshold. Aside from the prevalence, the results were shown to be robust. At low tuberculosis prevalence, Nucleic Acid Amplification Techniques may not be cost effective but their potential in higher prevalence situations is considerable.

Objectives: At present, all colonic polyps are removed and sent for histopathological evaluation, resulting in laboratory and reporting costs. Recent American Society for Gastrointestinal Endoscopy (ASGE) guidelines have set standards for in-vivo diagnosis in place of conventional histopathology, and all future technologies will have to be tested against these standards. Data on flexible spectral imaging color enhancement (FICE) were very limited. This study aims to evaluate the accuracy of FICE and indigo carmine (IC) for in-vivo histology prediction for polyps of less than 10 mm in size and to assess the economic impact of this strategy. Methods: In a screening population, polyps of less than 10 mm were assessed using white light (WLI) by FICE, by IC, and the predicted diagnosis was recorded. Polyps were then removed and sent for histological analysis. Accuracy of the predicted rescope interval was calculated using British Society of Gastroenterology and ASGE guidelines. Two models for using in-vivo diagnosis were proposed and savings in terms of histopathology costs calculated. Results: A total of 232 polyps of less than 10 mm were examined. FICE improved the accuracy of in-vivo diagnosis of adenoma to 88% compared with 75% with WLI (P

Chronic obstructive pulmonary disease (COPD) has a rising global incidence and acute exacerbation of COPD (AECOPD) carries a high health-care economic burden. Classification and regression tree (CART) analysis is able to create decision trees to classify risk groups. We analysed routinely collected laboratory data to identify prognostic factors for inpatient mortality with AECOPD from our large district hospital. Data from 5,985 patients with 9,915 admissions for AECOPD over a 7-year period were examined. Randomly allocated training (n = 4,986) or validation (n = 4,929) data sets were developed and CART analysis was used to model the risk of all-cause death during admission. Inpatient mortality was 15.5%, mean age was 71.5 (±11.5) years, 56.2% were male, and mean length of stay was 9.2 (±12.2) days. Of 29 variables used, CART analysis identified three (serum albumin, urea, and arterial pCO2) to predict in-hospital mortality in five risk groups, with mortality ranging from 3.0 to 23.4%. C statistic indices were 0.734 and 0.701 on the training and validation sets, respectively, indicating good model performance. The highest-risk group (23.4% mortality) had serum urea >7.35 mmol/l, arterial pCO2 >6.45 kPa, and normal serum albumin (>36.5 g/l). It is possible to develop clinically useful risk prediction models for mortality using laboratory data from the first 24 h of admission in AECOPD.

Background: This article investigated the prevalence of peanut allergy in three cohorts of children born in the same geographical location, Isle of Wight, UK and seeks to determine whether the prevalence of peanut allergy has changed between 1994 and 2004. Methods: Three cohorts of children (age 3-4 years) born on the Isle of Wight, were assessed for peanut allergy and the outcomes compared: Cohort A: Born in 1989; reviewed at 4 years of age (n = 2181). Cohort B: Born between 1994 and 1996; reviewed between 3 and 4 years of age (n = 1273). Cohort C: Born between 2001 and 2002; reviewed at 3 years of age (n = 891). Results: Peanut sensitization increased significantly from 1.3% in Cohort A to 3.3% (P = 0.003) in Cohort B before falling back to 2.0% in Cohort C (P = 0.145). Similarly, clinical peanut allergy increased significantly from 0.5% in Cohort A to 1.4% (P = 0.023) in Cohort B, with a subsequent fall to 1.2% in Cohort C (P = 0.850). Conclusions: Our data from three cohorts of 3- to 4-year-old children born in the same geographical area shows that peanut allergy prevalence has changed over time. Peanut sensitization and reported allergy in children born in 1994-1996 increased from 1989 but seems to have stabilized or slightly decreased since the late 1990s, although not significant.

Background: There is evidence of activation of the extrinsic coagulation cascade in the asthmatic airway, and both plasma and locally derived factors may be involved. The hypothesis that the normal haemostatic balance of healthy airways sampled by sputum induction favours fibrin formation in asthmatic airways, and that inhaled corticosteroids (ICS) and plasma exudation influence this balance, was tested. Methods: ELISA and activity assays were used to measure α2-macroglobulin (an index of plasma leakage) and coagulation factors in hypertonic saline-induced sputum of 30 stable subjects (10 controls, 10 with moderate asthma and 10 with severe asthma). Additionally, the moderate cohort were weaned off their ICS, followed by further sputum induction 5 days after cessation of steroids. Results: ICS wean induced a significant rise in plasminogen (median (interquartile range (IQR)): 13.92 (6.12–16.17) vs 4.82 (2.14–13.32) ng/ml; 95% CI 0.003 to 8.596, p = 0.0499) and tissue plasminogen activator (tPA; 5.57 (3.57–14.35) vs 3.88 (1.74–4.05) ng/ml; 95% CI 0.828 to 9.972, p = 0.0261) levels in sputum, such that tPA in untreated moderate asthma was significantly (p = 0.0029) higher than normal (2.14 (0.0–2.53) ng/ml). Subjects with severe asthma had significantly more α2-macroglobulin (p = 0.0003), tissue factor (p = 0.023), plasminogen activator inhibitor (p = 0.0091), thrombin-activatable fibrinolysis inhibitor (p = 0.0031) and fibrin degradation products (p = 0.0293) in their sputum than control subjects. Conclusion: Untreated moderate asthma is associated with increased fibrinolysis that is corrected by ICS. Severe asthma and high dose corticosteroid therapy is associated with a profibrinogenic, antifibrinolytic environment in the airways. This study suggests that inhibition of fibrin deposition in severe asthma may be a therapeutic approach.

We describe a unique case of a recurrence of Wegener's granulomatosis (WG) that presented with oral pain involving a left maxillary molar, which thereafter led to an extraction. Oral lesions with a classical appearance of strawberry gingivitis developed following the extraction. The primary disease did not have any oral manifestations. Both the primary disease and recurrence responded to rituximab, a monoclonal B-cell depleting antibody. Rituximab is emerging as a drug with significant potential to improve treatment of primary and, as described in this case, recurrent WG.

Background. The prevalence of synchronous or metastatic tumors in patients with head and neck squamous cell carcinoma (HNSCC) ranges from 6% to 20% and has implications for prognosis and management of the primary disease. There is no consensus about the role of chest CT prior to definitive treatment patients with HNSCC. Methods. A systematic review of all chest CT studies in relation to HNSCC was performed, together with a review of our local database. Results. Twenty-four studies were identified in addition to our local data. Prevalence of positive chest CT was 7.93%. Patients were significantly more likely to have a positive chest CT with N2 or N3 neck disease (p = .0062) and stage III or IV disease (p = .0001), and significantly less likely with tumors of the oral cavity (p = .0007). Conclusion. We advocate chest CT as part of the initial investigations for patients with HNSCC. © 2009 Wiley Periodicals, Inc. Head Neck, 2009

Aim To examine a model of care for breast cancer patients based on the concept of point of need access and investigate the effectiveness of this model compared to routine 6-monthly clinical reviews. Design A parallel randomised controlled trial was used to examine point of need access to specialist care via the nurse specialist, compared to routine hospital based 6-monthly clinical review at year two post breast cancer diagnosis. A total of 237 patients were recruited to the study. Methods Outcome measures at baseline, 9 and 18months included psychological morbidity using the GHQ12 questionnaire, quality of life using the FACT-B plus endocrine subscale, fear and isolation. An analysis of covariance was used to detect changes over time. Recurrences and methods of detection were recorded as secondary outcome measures. Results Two hundred and fourteen patients completed the study. Overall patients were not exposed to risks of increased psychological morbidity ( p =0.767) or decline of quality of life ( p =0.282) when routine review was discontinued and no significant differences were detected during an 18-month period. Patients not receiving regular review did not feel isolated, and at the end of 18months did not wish to return to 6-monthly clinical reviews. The presentation of recurrences and short symptom history demonstrate that the recurrences observed were unlikely to have been detected at a routine visit. Conclusions Point of need access is acceptable to the majority of patients. Although a third of patients may wish to maintain a regular review, patient choice is important. Findings suggest that after 2years following the diagnosis of breast cancer there is no evidence to support the view that regular clinical review improves psychological morbidity or quality of life. Patients do not appear to be compromised in terms of early detection of recurrence. Point of need access can be provided by suitably trained specialist nurses and provides a fast, responsive management system at a time when patients really need it.

Two hundred and five patients with ACL rupture, who had been diagnosed pre-operatively by either MRI scan or knee arthroscopy, had reconstructions between 2003 and 2007. The diagnostic meniscal findings were compared with those at reconstruction, and any further damage along with time from diagnosis to reconstruction was recorded. Those patients with no meniscal damage at the time of diagnosis, and who had no further damage at surgery had a median time of 6 months. This time was significantly different from those with no meniscal damage at diagnosis, but who were found subsequently to have sustained damage to one meniscus, when the median time was 11 months (P = 0.0017) or both menisci, when the median time was 32 months (P = 0.0184). For patients with solitary ACL rupture undergoing a trial of conservative management, an early and thorough assessment of functional stability is essential. If the instability is unacceptable, the patient should be informed of the time dependent risk to the menisci with further delay to surgical reconstruction.

The multicentric nature of Warthin's tumour has been well recognised, though the factors predicting its occurrence and its influence on management remain speculative. In this cross sectional study, the authors analysed the presentation, management and outcome of solitary and multicentric Warthin's tumour, treated in the maxillofacial unit and investigated factors that could influence the occurrence of multicentric and recurrent tumours. Warthin's tumour was found in 24% (150/628) of patients presenting with parotid neoplasms and multicentric tumours were found in 13% (21/ 161) of parotidectomy specimens. Age, sex, side, site and smoking history were not predictors of multicentricity ( P >0.40). Clinical examination (19%), imaging investigations (28%) and intra-operative palpation (33%) were poor at detecting multicentric tumours. Superficial parotidectomy was the most commonly performed operation. The recurrence rate was 0% in the solitary and 10% in the multicentric tumour group. Intra-operative rupture was not uncommon (11%), but was not associated with tumour recurrence ( P =>0.999). Incomplete excision ( P =0.007) and multicentricity ( P =0.026) were predictors of recurrence.

Few published "track and trigger systems" used to identify sick adult patients incorporate patient age as a variable. We investigated the relationship between vital signs, patient age and in-hospital mortality and investigated the impact of patient age on the function as predictors of in-hospital mortality of the two most commonly used track and trigger systems.Using a database of 9987 vital signs datasets, we studied the relationship between admission vital signs and in-hospital mortality for a range of selected vital signs, grouped by patient age. We also used the vital signs data set to study the impact of patient age on the relationship between patient triggers using the "MET criteria" and "MEWS", and in-hospital mortality.At hospital discharge, there were 9152 (91.6%) survivors and 835 (8.4%) non-survivors. As admission vital signs worsened, mortality increased for each age range. Where groups of patients had triggered a certain MET criterion, mortality was higher as patient age increased. Mortality varied significantly with age (p0.05; Fishers exact test) for breathing rate36breathsmin(-1), systolic BP90mmHg and decreased conscious level. For each age group, mortality also increased as total MEWS score increased. As the number of simultaneously occurring MEWS abnormalities, or simultaneously occurring MET criteria, increased, mortality increased for each age range.Age has a significant impact on in-hospital mortality. Our data suggest that the inclusion of age as a component of these systems could be advantageous in improving their function.

Asthma affects 5.4 million people in the UK, around 1 in 12 of the population. Between 5 and 10% of asthma (depending on the definition used) is categorised as difficult asthma, a term which generally refers to patients who continue to experience symptoms and frequent exacerbations despite the prescription of high-dose asthma therapy. Difficult asthma is an indication for specialist review by an appropriate respiratory physician, but close liaison between primary, secondary and tertiary care is critical and it is therefore important that primary care health professionals should be aware of the principles of management. One of the most important questions to ask is whether the individual with difficult asthma is taking their treatment Identifying this, however, is not easy. GPs could assess prescription uptake, looking for low use of preventers and excess use of short-acting bronchodilators. Newer means of assessing adherence have been developed. Inhaler devices that can monitor completion and timing of actuations have been produced. Meters that measure FeNO are available. A recent UK study found that 12 out of 100 patients referred for difficult asthma did not have reversible airflow obstruction or a history suggestive of asthma. Diagnoses included COPD, cystic fibrosis, cardiomyopathy, respiratory muscle dysfunction and severe anxiety with vocal cord dysfunction.

Background: Prevalence and incidence of food hypersensitivity (FHS) and its trends in early childhood are unclear. Methods: A birth cohort born on the Isle of Wight (UK) between 2001 and 2002 was followed-up prospectively. Children were clinically examined and skin prick tested at set times and invited for food challenges when indicated. Results: Nine hundred and sixty-nine children were recruited and 92.9%, 88.5% and 91.9% of them respectively were assessed at 1, 2 and 3 years of age. Prevalence of sensitization to foods was 2.2%, 3.8% and 4.5% respectively at these ages. Cumulatively, 5.3% [95% confidence interval (CI): 3.9-7.1] children were sensitized to a food. Using open food challenge and a good clinical history, the cumulative incidence of FHS was 6.0% (58/969, 95% CI: 4.6-7.7). Based on double-blinded, placebo-controlled, food challenge (DBPCFC) and a good clinical history, the cumulative incidence was 5.0% (48/969, 95% CI: 3.7-6.5). There is no evidence to suggest that the incidence of FHS has increased, comparing these results with previous studies. Overall, 33.7% of parents reported a food-related problem and of these, 16.1% were diagnosed with FHS by open challenge and history and 12.9% by DBPCFC and history. Main foods implicated were milk, egg and peanut. Conclusions: By the age of 3 years, 5-6% of children suffer from FHS based on food challenges and a good clinical history. There were large discrepancies between reported and diagnosed FHS. Comparing our data with a study performed in the USA more than 20 years ago, there were no significant differences in the cumulative incidence of FHS.

Background Correct diagnosis of food hypersensitivity (FHS) is important to ensure appropriate patient care and to accurately establish the population prevalence and incidence. Food challenges play a very important role in the diagnosis of FHS, but it is unclear when open food challenges (OFCs) opposed to double-blind placebo-controlled food challenges (DBPCFCs) should be used. This study investigated the use of OFCs and DBPCFCs when diagnosing FHS. Methods Children with a reported history of FHS or with sensitization to a food without known previous consumption were invited to undergo food challenges. Children of consenting parents underwent an OFC and those with a positive OFC were approached to undergo a DBPCFC. Food challenges were either performed as 1-day or 1-week challenges depending on sensitization status and clinical history. Results Forty-one children underwent both OFCs and DBPCFCs. The positive predictive values for 1-day and 1-week OFCs were 73% (8/11; 95% CI: 39–94%) and 57% (20/35; 95% CI: 39–74%) respectively. There was no evidence to indicate that the younger children were more likely to have a positive OFC confirmed by a DBPCFC compared to older children (Fisher’s exact P = 0.53). In the 1-day challenges parents indicated a preference for OFC rather than DBPCFC. By contrast, in the 1-week challenge parents indicated a preference for DBPCFC (P = 0.0192). Conclusion Open food challenge may be suitable for diagnosing immediate objective symptoms, whereas DBPCFC may be needed for the diagnosis of delayed and mainly subjective symptoms, irrespective of the child’s age.

BACKGROUND: There is a paucity of longitudinal studies of allergen sensitization in childhood. OBJECTIVE: To investigate the pattern of sensitization in early childhood. METHODS: A nested cohort of children (n = 543) were followed up from birth and given a skin prick test (SPT) at 1, 2, and 3 years of age. A detailed clinical history was obtained. RESULTS: The prevalences of sensitization to aeroallergens were 1.3%, 6.4%, and 10.7% at 1, 2, and 3 years of age. The figures for food allergens were 2.8%, 3.9%, and 3.7%. There was a statistically significant increase in the prevalence of sensitization to >or=1 allergen between years 1 and 2 (P < .001) and years 2 and 3 (P = .032). Among those with a positive SPT at 1 year, 29% tested positive to additional allergens at 2 years (P = .0054). Sensitization to milk or egg at 1 year was a predictor for increased sensitization to peanut at 3 years (odds ratio, 34.8; P < .0001). Sensitization to egg at 1 year was associated with increased sensitization to aeroallergens at 3 years (odds ratios, house dust mite, 27.1, P < .001; cat, 8.9, P < .01; grass, 11.8, P = .005). For peanut and cat allergens, wheal size increases with the age of the child (P = .009 and P = .017, respectively). CONCLUSION: Sensitization to allergens as demonstrated by positive SPT tends to increase with age, and this change can be detected in the first 3 years of life. CLINICAL IMPLICATIONS: The high predictive value for early sensitization and a linear increase in SPT reactivity provide an opportunity for early intervention.

Objective This study's objective was to determine whether offering dietary advice was effective in supporting patients in adjusting energy intake. Design We performed a prospective, randomized, controlled trial of dietary intervention involving 59 patients on continuous ambulatory peritoneal dialysis over a 4-month follow-up period. Setting The study involved outpatients on home-based renal replacement therapy. Participants All participants were adult patients on continuous ambulatory peritoneal dialysis. All eligible patients were invited to take part. Subjects were randomized into two groups: control and intervention. Those with diabetes mellitus, malabsorption, malignancy, or eating disorders were excluded. Intervention Baseline measurements to assess current dietary intake and nutritional status were performed in all subjects. Measurements included a 5-day food diary, subjective global assessment (SGA), anthropometry, and serum biochemistry. After analysis of the food diaries, the participants in the control group were given follow-up dietary advice that would enable them to match intake with current dietary recommendations for this group of 1.2 g of protein per kilogram of ideal body weight, 25 cal/kg ideal body weight. Participants in the intervention group were given follow-up dietary advice that would encourage them to match energy intake with an estimate of total energy expenditure based on their calculated basal metabolic rate and physical activity level as designated using information from SGA, with a significantly lower protein intake of 0.8 to 1.0 g/kg ideal body weight and an emphasis on calories from carbohydrate and fat. Both groups completed further 5-day food diaries at 2 and 4 months to assess their ability to make the recommended changes. SGA, anthropometry, and biochemistry were all remeasured at the end of the study period. Main Outcome Measure Differences in energy and protein intakes between and within the two groups from baseline to 4 months were assessed. Results Protein and energy intakes did not change during 4 months in either group, and there was no significant difference in intake between the two groups. In the control group (n = 27), 18 subjects (69%) matched their reported dietary energy intake to the recommended intake. In the intervention group (n = 28), 17 subjects (63%) matched their reported dietary intake to their estimated total energy expenditure. In the control group (n = 27), 8 subjects (28%) achieved the protein intake recommended to them of 1.2 g/kg. In the intervention group (n = 28), 23 subjects (85%) achieved the protein intake recommended to them of greater than 0.8 g/kg. Conclusion Patients not meeting their dietary prescription did not adjust their intake to match the recommended advice they had been given from a dietitian. Food diary analysis showed that subjects ate less than the recommended intakes for energy and protein. This inability to change suggests that subjects may be eating to the limit of their appetite. SGA sections concerning appetite, body weight, body mass index, and estimates of energy expenditure support the view that energy intake matches requirements.

Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFbeta1 and TGFbeta2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT-PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor beta receptor 1 (TGFbetaR1), and are therefore susceptible to TGFbeta1 and TGFbeta2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFbeta2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFbeta1 may have a major effect. This mechanism of tumour-associated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic.

Background: Uveal melanoma arises in an immune-privileged site and can itself add to the immunosuppressive environment. Previous studies on cutaneous melanoma have shown the presence of tolerogenic dendritic cells (DCs), which could play an important role in the progression of the tumour. Aim: To examine the presence and functional status of DCs in a small series of uveal melanomas. Methods: 10 cases of uveal melanoma were examined for the expression of FXIIIa, CD68, human leucocyte antigen (HLA)-DR, CD40, CD83, transforming growth factor βR1 and indolamine 2,3 dioxygenase by immunohistochemical analysis on sections embedded in paraffin wax. Results: CD68-positive macrophages were present in all of the tumours and were evenly distributed throughout. DCs expressing FXIIIa-positive were seen in 7 cases, and were often found concentrated in foci within the tumour mass. These cells were dendritic and expressed high levels of HLA-DR. The DCs did not express the maturation markers CD83 or CD40. In one case, concentration of DCs around the area of tumour necrosis was observed, and some of these cells expressed CD83. Conclusion: Numerous tolerising antigen-presenting cells may play a role in melanoma-related immunosuppression in the eye, although activation of DCs may be associated with tumour necrosis.

Background There are very few population-based studies investigating the incidence of food hypersensitivity during the first year of life. Objective To determine the incidence of parentally reported food hypersensitivity and objectively diagnosed food hypersensitivity during the first year of life. Methods A birth cohort was recruited (n = 969). At 3, 6, 9, and 12 months, information regarding feeding practices and reported symptoms of atopy were obtained. At 1 year, infants underwent a medical examination and skin prick testing to a battery of allergens. Symptomatic infants underwent food challenges. Results Adverse reactions to foods were reported by 132 (14.2%) parents at 3, 83 (9.1%) at 6, 49 (5.5%) at 9, and 65 (7.2%) at 12 months. Of the subjects, 1.0% (8/763) were sensitized to aeroallergens and 2.2% (17/763) to food allergens. Between 6 and 9 months and 9 and 12 months, 1.4% (14/969) and 2.8% (27/969) infants were diagnosed with food hypersensitivity on the basis of open food challenges and 0.9% (9/969) and 2.5% (24/969) on the basis of double-blind, placebo-controlled food challenges. Cumulative incidence of food hypersensitivity by 12 months was 4% (39/969; 95% CI, 2.9% to 5.5%) on the basis of open food challenges and 3.2% (31/969; 95% CI, 2.2% to 4.5%) on the basis of double-blind, placebo-controlled food challenges. Conclusion Between 2.2% and 5.5% of infants have food hypersensitivity in the first year of life. The rate of parental perception of food hypersensitivity is higher than the prevalence of atopic sensitization to main food allergens or objectively assessed food hypersensitivity. Clinical implications In the first year of life, the rate of parentally perceived food hypersensitivity is considerably higher than objectively assessed food hypersensitivity.

Background Maternal food intake during pregnancy may influence the development of food hypersensitivity (FHS) in the child. A food frequency questionnaire estimating the frequency with which some of the mains food allergens are consumed was designed and validated. Materials and methods Pregnant women were recruited at the ante-natal clinic of St. Mary's Hospital, Isle of Wight, UK. A food frequency questionnaire was developed and validated by comparing responses to information recorded in 7 days food diaries. The reliability of the food frequency questionnaire was evaluated by asking women to complete the questionnaire on two separate occasions at 30 and 36 weeks gestation. Results Fifty-seven women completed the validity study and 91 women completed the reliability study. For both validity and reliability, questions with dichotomous response categories showed the highest level of agreement. Frequency of intake of foods commonly ‘hidden’ in foods produced the lowest validity and reliability scores. In the validity study responses to the food frequency questionnaire identically matched information recorded in the food diaries 80% of the time, on average. In the reliability study, responses were identical on both questionnaires 85% of the time on average. Conclusion In this study a food frequency questionnaire estimating the frequency with which some of the main food allergens are consumed during pregnancy was designed and validated. This food frequency questionnaire could be used in future studies to assess the role of maternal food intake in the development of FHS in the infant.

Top of pageAbstract Anderson-Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by |[alpha]|-galactosidase A (AGA) deficiency. There is evidence that LSDs could be corrected by gene transfer, expression and enzyme secretion from a subset of cells or a specific tissue. Such gene therapy has several advantages over an alternative enzyme replacement approach, as it offers long-term therapeutic effect, eliminates risks associated with repeated parenteral administrations and is less expensive. We describe here a non-viral AGA gene delivery and expression/secretion from skeletal muscle in AGA knockout mice (animal model of Fabry disease). We studied combination of plasmid vectors with SP1017 Pluronic block copolymer, a non-ionic carrier capable of increasing the level and duration of expression of genes injected into muscle. Single intra-muscular administration of naked plasmid DNA encoding AGA resulted in enzyme secretion into the bloodstream and enzyme re-uptake by distant organs. However, when plasmids were used in combination with SP1017 to enhance gene expression, a highly specific dependence on the promoter type emerged. SP1017 only increased the CMV-driven (pX61) expression of AGA but had no effect on the muscle-specific promoter (pX61MCK) - controlled AGA expression. There was a drastic and rapid decrease in AGA activity when plasmid that contains AGA under the transcriptional control of the CMV promoter was used (Fig. 1A and 1C). It was caused by humoral (Fig. 2A) and cellular (Fig. 2B) immune responses against AGA recognized as a neoantigen. The decline in AGA activity could be delayed by putting AGA under control of the MCK promoter or prevented by transient immunosuppresion with cyclophosphamide (Cy) (Fig. 1B) but combination with SP1017 did not alter the specific anti-AGA responses. This promoter-specific effect of Pluronics on gene expression has implications for the future design and applications of polymeric adjuvants.

Background Measurement and comparison of surgical performance is accepted as necessary and inevitable. Risk-stratified (case-mix adjusted) models of clinical outcomes form a metric with which to assess performance, but require accurate data. Collecting such data in the clinical environment is time consuming and difficult. This study aimed to construct effective models, for operative and non-operative admissions, from routine clinical data residing in hospital computers, so minimizing data collection and quality problems, and facilitating national implementation. Methods Data for 3181 non-operative emergency, 5039 elective and 3043 emergency operative admissions for the 2 years beginning 1 August 1997 were used to generate logistic regression equations for risk of death, which were applied prospectively to the following 3 years' data. Results The models use urea, haemoglobin, white blood cell count, sodium, potassium, age on admission, sex, British United Provident Association (BUPA) Operative Severity Score (for operative admissions) and, implicitly, mode of admission and mortality at discharge. All three models successfully stratified risk into five or more bands. Conclusion Effective models of mortality, applicable to all general surgical admissions, can be constructed from existing routine clinical data, largely obtained from a single venesection. The data set is a candidate national clinical minimum data set.

Studies in adult patients have suggested that 30% of those diagnosed with asthma do not have the condition and it is likely that the diagnosis is missed in many others. Initial clinical assessment should explore symptoms of wheeze, breathlessness, chest tightness and cough. The probability of asthma is increased if more than one of these symptoms is present and particularly if symptoms are worse at night and in the early morning or are exacerbated by triggers such as exercise, allergen exposure, cold air or drugs. The BTS/SIGN guideline advocates spirometry after taking the history. If airflow obstruction is present, a trial of treatment can commence, but a firm diagnosis also requires a symptomatic response and an improvement in the measured airflow obstruction. The FeNO level correlates well with airway inflammation, and is therefore a good indicator of asthma and in particular of the likely response to inhaled corticosteroids. The test is especially useful for patients with suggestive symptoms but normal spirometry. The cornerstone of asthma monitoring is a structured clinical review conducted in primary care on at least an annual basis. Health outcomes are improved by education in self-management, incorporating written personalised asthma action plans. Checking concordance with existing therapies and inhaler technique before escalating treatment is an important part of improving the pharmacological management of asthma. Any patient prescribed more than one short-acting bronchodilator device a month should be identified and have their asthma assessed urgently and measures taken to improve overall control.

This study set out to evaluate the feasibility and acceptability of routine early ultrasound (12-14 weeks) within a district general hospital (DGH) for identifying high-risk and abnormal pregnancies. This was a pilot study for screening by ultrasound examination all women who presented to their community midwife before 12 weeks' gestation. The study involved 991 women who presented clinically pregnant before 12 weeks' gestation between May 1998 and May 1999. Women were offered routinely two ultrasound examinations during their pregnancy, the first at 12-14 weeks' gestation and the second at 20-21 weeks' gestation. The main outcome measures were: range and number of abnormal/high-risk pregnancies identified during an ultrasound scan at 12-14 weeks' gestation; range and number of abnormalities diagnosed during scans at later gestations; outcomes of the pregnancies; questionnaires assessing how the women viewed early pregnancy ultrasound as a method of screening. Nine hundred and eighty-four (99%) women accepted the offer of an early ultrasound scan at 12-14 weeks' gestation; of these 840(85%) women accepted screening for trisomy 21 (T21) by fetal nuchal translucency thickness (NT) and maternal age (fetal medicine foundation risk assessment programme) and this was completed successfully in 797(80%) of cases. Twenty-four women (2%) had a failed pregnancy and where necessary an ERPC was performed following a planned admission. Thirty pregnancies (3%) were diagnosed as abnormal or having high risk of abnormality at the early scan. A major abnormality was confirmed before the expected anomaly scan at 20 weeks in five (17%) pregnancies; all of these patients opted for an elective termination. Twenty-six (3%) pregnancies had a diagnosis of abnormality at their anomaly scan. Of these, three pregnancies were diagnosed as major abnormalities with two resulting in termination of the affected pregnancy before 24 weeks' gestation. Eight hundred and thirty-seven women (85%) completed questionnaires, 833 women (84.5%) were satisfied with the counselling they received before the ultrasound scan and 827 women (84%) answered that they would accept an early pregnancy scan if offered during their next pregnancy. Early pregnancy ultrasound at 12-14 weeks' gestation can be used as an effective method of identifying and screening for major abnormalities of pregnancy within a DGH setting, but it is appropriate to use this in conjunction with an anomaly scan at around 20 weeks' gestation. Women found this method of screening acceptable.