Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 .).

Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis.

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 A1c [HbA1c] 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 HbA1c network and 16 in the SH network. All studies were of moderate quality. No network inconsistency was evident in the HbA1c network. Of the seven regimens of interest, iDet (bid) had the highest probability of being best (mean change in HbA1c -0.48; 95% credible interval -0.69 to -0.29). In contrast, the SH network demonstrated both considerable uncertainty and significant network inconsistency (χ2 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 HbA1c. Ranking of the regimens in terms of the SH rate was highly uncertain and no clear conclusion could be made.

Endocuff-assisted vs. standard colonoscopy in the fecal occult blood test-based UK Bowel Cancer Screening Programme (E-cap study): a randomized trial.

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 < 0.005). The endocuff had to be removed in 17/266 patients (6.4 %) because of inability to pass through the sigmoid colon. 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).

Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Cost-Utility Analysis.

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.

GPs have key role in improving outcomes in acute asthma.

Asthma deaths in the UK remain among the highest in Europe. The 2014 National Review of Asthma Deaths looked at detailed data over a 12-month period assessing 195 patients who died from asthma and highlighted the avoidable factors in patient deaths. Although faults were found in secondary care, many of the problems related to poor management of patients in the community, both in terms of regular surveillance and assessment and treatment at the onset of attacks. Features which indicate a high risk of severe attacks include: previous admission to intensive care, particularly if requiring mechanical ventilation; previous admission with asthma especially in the past year or repeated emergency admissions; history of worsening asthma in January or February; use of three or more classes of asthma medication; heavy use of beta-2 agonists; anxiety traits; and marital stress. Peak expiratory flow improves the recognition of severity when compared with examination alone. Oxygen should be used to maintain oxygen saturation of 94-98% and it is recommended that GP surgeries have oxygen and an oximeter available. For anything other than life-threatening asthma, a standard metered dose inhaler administered with repeated actuations via a large volume spacer is as effective as a nebuliser. If a nebuliser is used it should ideally be driven with oxygen but nebulisers should not be withheld if oxygen is not available. Oral steroids are required for all patients experiencing attacks of moderate severity or worse as they improve symptoms and reduce mortality, hospital admissions and the need for beta-2 agonists.

Optimising the management of patients with difficult asthma.

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.

Improving the management of asthma in adults in primary care.

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.

Pilot cluster randomised controlled trial of flooring to reduce injuries from falls in wards for older people.

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.

A correlation of time with meniscal tears in anterior cruciate ligament deficiency: stratifying the risk of surgical delay.

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.

Acetic acid-guided biopsies in Barrett's surveillance for neoplasia detection versus non-targeted biopsies (Seattle protocol): A feasibility study for a randomized tandem endoscopy trial. The ABBA study.

BACKGROUND AND STUDY AIMS: Barrett's esophagus is a potentially pre-cancerous condition, affecting 375,000 people in the UK. Patients receive a 2-yearly endoscopy to detect cancerous changes, as early detection and treatment results in better outcomes. Current treatment requires random mapping biopsies along the length of Barrett's, in addition to biopsy of visible abnormalities. As only 13 % of pre-cancerous changes appear as visible nodules or abnormalities, areas of dysplasia are often missed. Acetic acid chromoendoscopy (AAC) has been shown to improve detection of pre-cancerous and cancerous tissue in observational studies, but no randomized controlled trials (RCTs) have been performed to date. PATIENTS AND METHODS: A "tandem" endoscopy cross-over design. Participants will be randomized to endoscopy using mapping biopsies or AAC, in which dilute acetic acid is sprayed onto the surface of the esophagus, highlighting tissue through an whitening reaction and enhancing visibility of areas with cellular changes for biopsy. After 4 to 10 weeks, participants will undergo a repeat endoscopy, using the second method. Rates of recruitment and retention will be assessed, in addition to the estimated dysplasia detection rate, effectiveness of the endoscopist training program, and rates of adverse events (AEs). Qualitative interviews will explore participant and endoscopist acceptability of study design and delivery, and the acceptability of switching endoscopic techniques for Barrett's surveillance. RESULTS: Endoscopists' ability to diagnose dysplasia in Barrett's esophagus can be improved. AAC may offer a simple, universally applicable, easily-acquired technique to improve detection, affording patients earlier diagnosis and treatment, reducing endoscopy time and pathology costs. The ABBA study will determine whether a crossover "tandem" endoscopy design is feasible and acceptable to patients and clinicians and gather outcome data to power a definitive trial.

Temporarily quadrupling the dose of inhaled steroid to prevent asthma exacerbations: FAST.

BACKGROUND: Asthma 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. OBJECTIVES: To 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. DESIGN: A multicentre, parallel-group, pragmatic randomised trial, with follow-up for 12 months. SETTING: Primary and secondary care across 207 sites in the UK. PARTICIPANTS: Asthma patients aged ≥ 16 years treated with an inhaled corticosteroid who had experienced at least one exacerbation in the previous 12 months. INTERVENTIONS: Participants 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 OUTCOME: The 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). RESULTS: A 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. LIMITATIONS: As 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. CONCLUSIONS: An 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 WORK: To effectively implement asthma self-management plans that advise a temporary quadrupling of inhaled steroid at asthma deterioration into routine practice. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15441965. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 70. See the NIHR Journals Library website for further project information.

An unusual cause of granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is an inherited disorder of phagocytic cells caused by an inability to generate active microbicidal oxygen species required kill certain types of fungi and bacteria. This leads to recurrent life-threatening bacterial and fungal infections with tissue granuloma formation. CASE PRESENTATION: We describe a case of X-linked Chronic granulomatous disease (CGD) diagnosed in an 18-year-old male. He initially presented with granulomatous disease mimicking sarcoidosis and was treated with corticosteroids. He subsequently developed Burkholderia cepacia complex pneumonia and further investigation confirmed a diagnosis of CGD. CONCLUSION: Milder phenotypes of CGD are now being recognised. CGD should be considered in patients of any age with granulomatous diseases, especially if there is a history of recurrent or atypical infection.

Pharmacological management of hypertension.

Hypertension is a major risk factor for cardiovascular disease, and is both common and amenable to treatment. Several major new studies have appeared recently and in response the National Institute for Health and Clinical Excellence and the British Hypertension Society have collaborated to update their respective guidelines on primary hypertension, and to agree joint recommendations. The update focuses only on pharmacological aspects of treatment. Wherever possible, the recommendations are based on the clinical outcomes of mortality, stroke, myocardial infarction, heart failure, and new onset diabetes mellitus, rather than on blood pressure lowering. A brief treatment algorithm is included. In summary, either calcium channel inhibitors or thiazide-type diuretics should be the preferred initial agent for use in primary hypertension in most patients, although angiotensin converting enzyme (ACE) inhibitors (including angiotensin-II receptor inhibitors if ACE-intolerant) are preferred in patients younger than 55.

Theobromine for the treatment of persistent cough: a randomised, multicentre, double-blind, placebo-controlled clinical trial.

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.

FourFold Asthma Study (FAST): a study protocol for a randomised controlled trial evaluating the clinical cost-effectiveness of temporarily quadrupling the dose of inhaled steroid to prevent asthma exacerbations.

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.

Azithromycin for Acute Exacerbations of Asthma : The AZALEA Randomized Clinical Trial.

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.

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma.

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centres.

High-definition vs. standard-definition endoscopy with indigo carmine for the in vivo diagnosis of colonic polyps.

BACKGROUND: There is growing evidence that indigo carmine chromoendoscopy is effective for the in vivo diagnosis of colonic polyps. However, the impact of colonoscope resolution on diagnostic accuracy has not been investigated. OBJECTIVE: We aimed to compare the effectiveness of in vivo diagnosis of small colonic polyps using indigo carmine dye spray with standard-definition and high-definition colonoscopes. METHODS: Procedures were performed using Fujinon colonoscopes and EPX 4400 processor. Fujinon standard-definition (SD) and high-definition (HD) colonoscopes were used, with the endoscopist blinded to colonoscope definition. Polyps <10 mm were assessed using 0.2% indigo carmine dye spray, with the predicted diagnosis recorded. In each case the kind of colonoscope (SD or HD) was recorded. Polyps were removed and sent for histological analysis, with the pathologist blinded to the diagnosis made by the endoscopist. The predicted diagnosis was compared with the true histology to calculate the accuracy, sensitivity and specificity of in vivo assessment using either SD or HD scopes. RESULTS: In total 237 polyps <10 mm in size were examined. There was no statistically significant difference for any of the measured parameters between SD and HD assessments, with an accuracy, sensitivity and specificity of 89%, 91% and 87% with SD colonoscopes and 92%, 96% and 84% with HD colonoscopes. CONCLUSIONS: The accuracy of in vivo assessment of small colonic polyps with indigo carmine dye spray is excellent with standard-definition colonoscopes and is not improved with high-definition colonoscopes.