Single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus umeclidinium using two inhalers for chronic obstructive pulmonary disease: A randomized non-inferiority study

Background: Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg has been shown to improve lung function and health status, and reduce exacerbations, versus budesonide/formoterol in patients with chronic obstructive pulmonary disease (COPD). We evaluated the non-inferiority of single-inhaler FF/UMEC/VI versus FF/VI + UMEC using two inhalers. Methods: Eligible patients with COPD (aged ≥40 years; ≥1 moderate/severe exacerbation in the 12 months before screening) were randomized (1:1; stratified by the number of long-acting bronchodilators [0, 1 or 2] per day during run-in) to receive 24-week FF/UMEC/VI 100/62.5/25 μg and placebo or FF/VI 100/25 μg + UMEC 62.5 μg; all treatments/placebo were delivered using the ELLIPTA inhaler once-daily in the morning. Primary endpoint: change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week 24. The non-inferiority margin for the lower 95% confidence limit was set at − 50 mL. Results: A total of 1055 patients (844 [80%] of whom were enrolled on combination maintenance therapy) were randomized to receive FF/UMEC/VI (n = 527) or FF/VI + UMEC (n = 528). Mean change from baseline in trough FEV1 at Week 24 was 113 mL (95% CI 91, 135) for FF/UMEC/VI and 95 mL (95% CI 72, 117) for FF/VI + UMEC; the between-treatment difference of 18 mL (95% CI -13, 50) confirmed FF/UMEC/VI’s was considered non-inferior to FF/ VI + UMEC. At Week 24, the proportion of responders based on St George’s Respiratory Questionnaire Total score was 50% (FF/UMEC/VI) and 51% (FF/VI + UMEC); the proportion of responders based on the Transitional Dyspnea Index focal score was similar (56% both groups). A similar proportion of patients experienced a moderate/severe exacerbation in the FF/UMEC/VI (24%) and FF/VI + UMEC (27%) groups; the hazard ratio for time to first moderate/ severe exacerbation with FF/UMEC/VI versus FF/VI + UMEC was 0.87 (95% CI 0.68, 1.12). The incidence of adverse events was comparable in both groups (48%); the incidence of serious adverse events was 10% (FF/UMEC/VI) and 11% (FF/VI + UMEC). Conclusions: Single-inhaler triple therapy (FF/UMEC/VI) is non-inferior to two inhalers (FF/VI + UMEC) on trough FEV1 change from baseline at 24 weeks. Results were similar on all other measures of efficacy, health-related quality of life, and safety. Trial registration: GSK study CTT200812; ClinicalTrials.gov NCT02729051 (submitted 31 March 2016)

Improving response rates using a monetary incentive for patient completion of questionnaires: an observational study

Background: Poor response rates to postal questionnaires can introduce bias and reduce the statistical power of a study. To improve response rates in our trial in primary care we tested the effect of introducing an unconditional direct payment of 5 pound for the completion of postal questionnaires. Methods: We recruited patients in general practice with knee problems from sites across the United Kingdom. An evidence-based strategy was used to follow-up patients at twelve months with postal questionnaires. This included an unconditional direct payment of 5 pound to patients for the completion and return of questionnaires. The first 105 patients did not receive the 5 pound incentive, but the subsequent 442 patients did. We used logistic regression to analyse the effect of introducing a monetary incentive to increase the response to postal questionnaires. Results: The response rate following reminders for the historical controls was 78.1% ( 82 of 105) compared with 88.0% ( 389 of 442) for those patients who received the 5 pound payment (diff = 9.9%, 95% CI 2.3% to 19.1%). Direct payments significantly increased the odds of response ( adjusted odds ratio = 2.2, 95% CI 1.2 to 4.0, P = 0.009) with only 12 of 442 patients declining the payment. The incentive did not save costs to the trial - the extra cost per additional respondent was almost 50 pound. Conclusion: The direct payment of 5 pound significantly increased the completion of postal questionnaires at negligible increase in cost for an adequately powered study

Surgical fixation compared with cast immobilisation for adults with a bicortical fracture of the scaphoid waist: the SWIFFT RCT

Background: Scaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. Immediate surgical fixation of this fracture has increased. Objective: To compare clinical and cost-effectiveness of surgical fixation with cast treatment and early fixation of those that fail to unite for scaphoid waist fractures in adults. Design: Multicentre, pragmatic, open-label, parallel two-arm randomised controlled trial with an economic evaluation and nested qualitative study. Setting: Orthopaedic departments of 31 hospitals in England and Wales recruited from July 2013 with final follow-up in September 2017. Participants: Adults (aged ≥ 16 years), presenting within two weeks of injury with a clear bicortical fracture of the scaphoid waist on plain radiographs. Interventions: Early surgical fixation using CE marked headless compression screws. Below elbow cast immobilisation for six to ten weeks, and urgent fixation of confirmed non-union. Main outcome measures: The primary outcome and end-point was the Patient Rated Wrist Evaluation (PRWE) total score at 52 weeks, with a clinically relevant difference of six points. Secondary outcomes included PRWE pain and function subscales, Short Form 12-item questionnaire (SF-12), bone union, range of movement, grip strength, complications and return to work. Results: The mean age of 439 participants was 33 years, 363 were male (83%) and 269 had an undisplaced fracture (61%). The primary analysis was on 408 participants providing valid PRWE outcome data for at least one post-randomisation time-point (surgery n=203 of 219; cast n=205 of 220). There was no clinically relevant difference in the total PRWE at 52 weeks: cast group mean 14.0 [95% confidence interval (CI) 11.3 to 16.6] and surgery group mean 11.9 (95% CI 9.2 to 14.5); adjusted mean difference of -2.1 in favour of surgery (95% CI -5.8 to 1.6, p=0.27). Non-union rate was low (surgery group n=1; cast group n=4). Eight participants in the surgery group had 11 re-operations, and one participant in the cast group required a re-operation for non-union. The base-case economic analysis at 52 weeks found the cost of surgery was £1,295 more per patient (95% CI £1,084 to £1,504) than cast treatment. The base-case analysis of a lifetime extrapolated model confirmed that the cast treatment pathway was the most cost-effective option. The nested qualitative study identified patients desire to have a “sense of recovering” which surgeons should address at the outset. Limitation: There were 17 participants who had initial cast treatment and surgery for confirmed non-union, 14 within six months from randomisation and three after six months. Three of four participants in the cast group, who had a non-union at 52 weeks, were not offered surgery. Conclusions: Adult patients with an undisplaced or minimally displaced scaphoid waist fracture should have cast immobilisation and suspected non-unions immediately confirmed and urgently fixed. Future work: Patients will be followed-up at five years to investigate the effect of partial union, degenerative arthritis, malunion and screw problems on their quality of life

Another nail in the hammer's coffin?

Blood pressure saggy? Cardiac output low? Oliguria? Increasing acidosis? Peripheries a bit cool? Poor cardiac history? No problem. Just start some dobutamine and watch the numbers improve. And if the patient happens to die, that is their fault. Or is it? Catecholamines are long-established drugs that have never undergone formal testing of long-term outcomes and safety. Their use requires re-evaluation in the light of a wide range of deleterious actions and retrospective studies suggesting harm

United Kingdom Frozen Shoulder Trial (UK FROST), multi-centre, randomised, 12 month, parallel group, superiority study to compare the clinical and cost-effectiveness of Early Structured Physiotherapy versus manipulation under anaesthesia versus arthroscopic capsular release for patients referred to secondary care with a primary frozen shoulder : study protocol for a randomised controlled trial

BACKGROUND: Frozen shoulder (also known as adhesive capsulitis) occurs when the capsule, or the soft tissue envelope around the ball and socket shoulder joint, becomes scarred and contracted, making the shoulder tight, painful and stiff. It affects around 1 in 12 men and 1 in 10 women of working age. Although this condition can settle with time (typically taking 1 to 3 years), for some people it causes severe symptoms and needs referral to hospital. Our aim is to evaluate the clinical and cost-effectiveness of two invasive and costly surgical interventions that are commonly used in secondary care in the National Health Service (NHS) compared with a non-surgical comparator of Early Structured Physiotherapy. METHODS: We will conduct a randomised controlled trial (RCT) of 500 adult patients with a clinical diagnosis of frozen shoulder, and who have radiographs that exclude other pathology. Early Structured Physiotherapy with an intra-articular steroid injection will be compared with manipulation under anaesthesia with a steroid injection or arthroscopic (keyhole) capsular release followed by manipulation. Both surgical interventions will be followed with a programme of post-procedural physiotherapy. These treatments will be undertaken in NHS hospitals across the United Kingdom. The primary outcome and endpoint will be the Oxford Shoulder Score (a patient self-reported assessment of shoulder function) at 12 months. This will also be measured at baseline, 3 and 6 months after randomisation; and on the day that treatment starts and 6 months later. Secondary outcomes include the Disabilities of Arm Shoulder and Hand (QuickDASH) score, the EQ-5D-5 L score, pain, extent of recovery and complications. We will explore the acceptability of the different treatments to patients and health care professionals using qualitative methods. DISCUSSION: The three treatments being compared are the most frequently used in secondary care in the NHS, but there is uncertainty about which one works best and at what cost. UK FROST is a rigorously designed and adequately powered study to inform clinical decisions for the treatment of this common condition in adults. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Register, ID: ISRCTN48804508 . Registered on 25 July 2014

Embedded point of care randomisation for evaluating comparative effectiveness questions: PROSPECTOR-critical care feasibility study protocol

INTRODUCTION: Many routinely administered treatments lack evidence as to their effectiveness. When treatments lack evidence, patients receive varying care based on the preferences of clinicians. Standard randomised controlled trials are unsuited to comparisons of different routine treatment strategies, and there remains little economic incentive for change.Integrating clinical trial infrastructure into electronic health record systems offers the potential for routine treatment comparisons at scale, through reduced trial costs. To date, embedded trials have automated data collection, participant identification and eligibility screening, but randomisation and consent remain manual and therefore costly tasks.This study will investigate the feasibility of using computer prompts to allow flexible randomisation at the point of clinical decision making. It will compare the effectiveness of two prompt designs through the lens of a candidate research question-comparing liberal or restrictive magnesium supplementation practices for critical care patients. It will also explore the acceptability of two consent models for conducting comparative effectiveness research. METHODS AND ANALYSIS: We will conduct a single centre, mixed-methods feasibility study, aiming to recruit 50 patients undergoing elective surgery requiring postoperative critical care admission. Participants will be randomised to either 'Nudge' or 'Preference' designs of electronic point-of-care randomisation prompt, and liberal or restrictive magnesium supplementation.We will judge feasibility through a combination of study outcomes. The primary outcome will be the proportion of prompts displayed resulting in successful randomisation events (compliance with the allocated magnesium strategy). Secondary outcomes will evaluate the acceptability of both prompt designs to clinicians and ascertain the acceptability of pre-emptive and opt-out consent models to patients. ETHICS AND DISSEMINATION: This study was approved by Riverside Research Ethics Committee (Ref: 21/LO/0785) and will be published on completion. TRIAL REGISTRATION NUMBER: NCT05149820

Interplay between antipredator behavior, parasitism, and gut microbiome in wild stickleback populations

The impact of microbial composition on stress-related behavior in aquatic organisms is poorly understood. This study explored the link between antipredator behavior, parasitism, and the gut microbiome in wild stickleback from two lakes: clear, spring-fed Galtaból and turbid, glacial-fed Þristikla. Behavioral analysis revealed differences between populations, with each exhibiting unique baseline behaviors. Microbiome analysis showed that a small proportion of its variation was explained by population, likely reflecting differences in lake environments. Only the marine genus Pseudoalteromonas abundance differed between populations. Our findings suggest that behavior and microbiome correlations may primarily reflect environmental adaptations and parasite status rather than direct gut-brain interactions. However, some tentative evidence suggests a potential innate connection between some antipredator behavior and microbiome composition. The study highlights the complexity of the gut-brain axis in wild populations and suggests future research directions, including experimental manipulations to uncover causal relationships between microbiome composition and behavior.publishedVersio

Funding issues in a major strategic project: A case of investment appraisal

This paper describes and allows interaction with the issues involved in a major investment decision. In the summer of 1997, UKH faced major decisions concerning the purchase and funding of new plant and equipment. The authors were given excellent access to the company and were able to document key steps in the decision process. The issues are set out in a case study format that allows the reader to retrace the analyses carried out within UKH. A number of tasks are suggested that should test, develop and enhance a range of analytical, social and negotiation skills. The case can be handled in a variety of ways and most of the suggested tasks can be undertaken or omitted depending on the pedagogical objectives of the course/ instructor