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RationalePlatelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin's antiplatelet and immunomodulatory effects may be beneficial in ARDS.ObjectiveTo test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS.MethodsHealthy volunteers were randomised to receive placebo or aspirin 75  or 1200 mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6 hours after inhaling 50 µg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24 mg aspirin and injured with LPS. BAL was carried out 4 hours later. Inflammation was assessed by BAL differential cell counts and histological changes.ResultsIn the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor α and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage.ConclusionsThese are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the prevention and treatment of ARDS.Trial registration numberNCT01659307 Results.

A 2-arm parallel-group randomized controlled trial measured the cost-effectiveness of caries prevention in caries-free children aged 2 to 3 y attending general practice. The setting was 22 dental practices in Northern Ireland. Participants were centrally randomized into intervention (22,600 ppm fluoride varnish, toothbrush, a 50-mL tube of 1,450 ppm fluoride toothpaste, and standardized prevention advice) and control (advice only), both provided at 6-monthly intervals during a 3-y follow-up. The primary outcome measure was conversion from caries-free to caries-active states assessed by calibrated and blinded examiners; secondary outcome measures included decayed, missing, or filled teeth surfaces (dmfs); pain; and extraction. Cumulative costs were related to each of the trial's outcomes in a series of incremental cost effectiveness ratios (ICERs). Sensitivity analyses examined the impact of using dentist's time as measured by observation rather than that reported by the dentist. The costs of applying topical fluoride were also estimated assuming the work was undertaken by dental nurses or hygienists rather than dentists. A total of 1,248 children (624 randomized to each group) were recruited, and 1,096 (549 in the intervention group and 547 in the control group) were included in the final analyses. The mean difference in direct health care costs between groups was £107.53 (£155.74 intervention, £48.21 control, P < 0.05) per child. When all health care costs were compared, the intervention group's mean cost was £212.56 more than the control group (£987.53 intervention, £774.97 control, P < 0.05). Statistically significant differences in outcomes were only detected with respect to carious surfaces. The mean cost per carious surface avoided was estimated at £251 (95% confidence interval, £454.39-£79.52). Sensitivity analyses did not materially affect the study's findings. This trial raises concerns about the cost-effectiveness of a fluoride-based intervention delivered at the practice level in the context of a state-funded dental service (EudraCT No: 2009-010725-39; ISRCTN: ISRCTN36180119). [ABSTRACT FROM AUTHOR]

Aims To determine the symptomatic and prognostic differences resulting from a novel diagnostic pathway based on cardiac computerized tomography (CT) compared with the traditional exercise stress electrocardiography test (EST) in stable chest pain patients. Methods and results A prospective randomized controlled trial compared selected patient outcomes in EST and cardiac CT coronary angiography groups. Five hundred patients with troponin-negative stable chest pain and without known coronary artery disease were recruited. Patients completed the Seattle Angina Questionnaires (SAQ) at baseline, 3, and 12 months to assess angina symptoms. Patients were also followed for management strategies and clinical events. Over the year 12 patients withdrew, resulting in 245 in the EST cohort and 243 in the CT cohort. There was no significant difference in baseline demographics. The CT arm had a statistical difference in angina stability and quality-of-life domains of the SAQ at 3 and 12 months, suggesting less angina compared with the EST arm. In the CT arm, there was more significant disease identified and more revascularizations. Significantly, more inconclusive results were seen in the EST arm with a higher number of additional investigations ordered. There was also a longer mean time to management. There were no differences in major adverse cardiac events between the cohorts. At 1 year in the EST arm, there were more Accident and Emergency (A&E) attendances and cardiac admission. Conclusion Cardiac CT as an index investigation for stable chest pain improved angina symptoms and resulted in fewer investigations and re-hospitalizations compared with EST. Clinical trial registration http://www.controlled-trials.com/ISRCTN52480460 [ABSTRACT FROM AUTHOR]

Background: The choice of outcome measure is a critical decision in the design of any clinical trial, but many Phase III clinical trials in critical care fail to detect a difference between the interventions being compared. This may be because the surrogate outcomes used to show beneficial effects in early phase trials (which informed the design of the subsequent Phase III trials) are not valid guides to the differences between the interventions for the main outcomes of the Phase III trials. We undertook a systematic review (1) to generate a list of outcome measures used in critical care trials, (2) to determine the variability in the outcome reporting in the respiratory subgroup and (3) to create a smaller list of potential early phase endpoints in the respiratory subgroup., Methods: Data related to outcomes were extracted from studies published in the six top-ranked critical care journals between 2010 and 2020. Outcomes were classified into subcategories and categories. A subset of early phase endpoints relevant to the respiratory subgroup was selected for further investigation. The variability of the outcomes and the variability in reporting was investigated., Results: A total of 6905 references were retrieved and a total of 294 separate outcomes were identified from 58 studies. The outcomes were then classified into 11 categories and 66 subcategories. A subset of 22 outcomes relevant for the respiratory group were identified as potential early phase outcomes. The summary statistics, time points and definitions show the outcomes are analysed and reported in different ways., Conclusion: The outcome measures were defined, analysed and reported in a variety of ways. This creates difficulties for synthesising data in systematic reviews and planning definitive trials. This review once again highlights an urgent need for standardisation and validation of surrogate outcomes reported in critical care trials. Future work should aim to validate and develop a core outcome set for surrogate outcomes in critical care trials.

Background: There is no pharmacologic treatment for ARDS. Platelets play an important role in the pathophysiology of ARDS. Preclinical, observational, and clinically relevant models of ARDS indicate aspirin as a potential therapeutic option., Research Question: Is enteral aspirin (75 mg, once daily) safe and effective in improving surrogate outcomes in adult patients with ARDS?, Study Design and Methods: This randomized, double-blind (patient and investigator), allocation-concealed, placebo-controlled phase 2 trial was conducted in five UK ICUs. Patients fulfilling the Berlin definition of ARDS were randomly assigned at a 1:1 ratio to receive enteral aspirin (75 mg) or placebo, for a maximum of 14 days, using a computer-generated randomization schedule, with variable block size, stratified by vasopressor requirement. The primary end point was oxygenation index (OI) on day 7. Secondary outcomes included safety parameters and other respiratory physiological markers. Analyses were by intention to treat., Results: The trial was stopped early, due to slow recruitment, after 49 of a planned 60 patients were recruited. Twenty-four patients were allocated to aspirin and 25 to placebo. There was no significant difference in day 7 OI [aspirin group: unadjusted mean, 54.4 (SD 26.8); placebo group: 42.4 (SD 25); mean difference, 12.0; 95% CI, -6.1 to 30.1; P = .19]. Aspirin did not significantly impact the secondary outcomes. There was no difference in the number of adverse events between the groups (13 in each; OR, 1.04; 95% CI, 0.56-1.94; P = .56)., Interpretation: Aspirin was well tolerated but did not improve OI or other physiological outcomes; a larger trial is not feasible in its current design., Trial Registration: ClinicalTrials.gov; No.: NCT02326350; URL: www., Clinicaltrials: gov., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background : Shoulder pain is common in primary care. The management of subacromial impingement (SAI) can include corticosteroid injections and physiotherapy. Physiotherapy can be on an individual or group basis. Aim : To examine the clinical effectiveness and make an economic analysis of individual versus group physiotherapy, following corticosteroid injection for SAI. Design and Setting : A single-blind, open-label, randomised equivalence study comparing group and individual physiotherapy. Patients referred by local general practitioners and physiotherapists were considered for inclusion. Method : Patients were randomised to individual or group physiotherapy groups, and all received corticosteroid injection before physiotherapy. The primary outcome measure was shoulder pain and disability index (SPADI) at 26 weeks. An economic analysis was conducted. Results and Conclusion : 136 patients were recruited, 68 randomised to each group. Recruitment was 68% of the target 200 participants. SPADI (from baseline to 26 weeks) demonstrated a difference (SE) in mean change between groups of -0.43 (5.7) ( p -value = 0.050001), and the TOST (two-one-sided test for equivalence) 90% CI for this difference was (-10.0 to 9.14). This was borderline. In a secondary analysis using inputted data, patients without SPADI at week 26 were analysed by carrying forward scores at week 12 (mean difference (95% CI) = -0.14 (-7.5 to 7.3), p -value = 0.014). There is little difference in outcome at 26 weeks. Group physiotherapy was cheaper to deliver per patient (£252 versus £84). Group physiotherapy for SAI produces similar clinical outcomes to individual physiotherapy with potential cost savings. Due to low recruitment to our study, firm conclusions are difficult and further research is required to give a definitive answer to this research question. (NCT Clinical Trial Registration Number NCT04058522).

Background/aims: To report the protocol of a trial designed to evaluate the efficacy, safety and mechanism of action of low-dose atropine (0.01%) eye-drops for reducing progression of myopia in UK children., Methods: Multicentre, double-masked, superiority, placebo-controlled, randomised trial. We will enrol children aged 6-12 years with myopia of -0.50 dioptres or worse in both eyes.We will recruit 289 participants with an allocation ratio of 2:1 (193 atropine; 96 placebo) from five centres. Participants will instil one drop in each eye every day for 2 years and attend a research centre every 6 months. The vehicle and preservative will be the same in both study arms.The primary outcome is SER of both eyes measured by autorefractor under cycloplegia at 2 years (adjusted for baseline). Secondary outcomes include axial length, best corrected distance visual acuity, near visual acuity, reading speed, pupil diameter, accommodation, adverse event rates and allergic reactions, quality of life (EQ-5D-Y) and tolerability at 2 years. Mechanistic evaluations will include: peripheral axial length, peripheral retinal defocus, anterior chamber depth, iris colour, height and weight, activities questionnaire, ciliary body biometry and chorioretinal thickness. Endpoints from both eyes will be pooled in combined analysis using generalised estimating equations to allow for the correlation between eyes within participant. Three years after cessation of treatment, we will also evaluate refractive error and adverse events., Conclusions: The Childhood Atropine for Myopia Progression in the UK study will be the first randomised trial reporting outcomes of low-dose atropine eye-drops for children with myopia in a UK population., Trial Registration Number: ISRCTN99883695, NCT03690089., Competing Interests: Competing interests: NL: research funding from CooperVision, Essilor and Zeiss., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Children and young people (CYP) with chronic rheumatic conditions; Juvenile Idiopathic Arthritis, Juvenile Systemic Lupus Erythematosus, Juvenile Dermatomyositis and Juvenile Vasculitis, treated with steroids, have low bone density, increased fracture risk and are likely to have suboptimal peak bone mass. There is currently no evidence base for the management of steroid-induced bone loss in children with rheumatic diseases., Methods: We undertook a multi-centre double dummy double-blind randomised placebo controlled trial to investigate whether the bisphosphonate risedronate was superior to alfacalcidol or calcium and vitamin D supplementation in the prevention and treatment of steroid-induced osteopaenia in these children. Patients were stratified and randomised in a 1:1 ratio, into: placebo; alfacalcidol; risedronate. The primary outcome was the change in lumbar spine bone mineral density z score (LSaBMDz) measured by dual energy x-ray absorptiometry at one year. Secondary outcome was fracture rate., Results: Two hundred and seventeen patients were recruited to the study. Seventy seven placebo, 71 alfacalcidol, and 69 risedronate. Highly statistically significant differences were observed in the change in LSaBMDz between the placebo and risedronate groups; 0.274, 95% CI (0.061, 0.487) (p < 0.001) and between the risedronate and the alfacalcidol groups; 0.326 95% CI (0.109, 0.543) (p < 0.001). The difference observed between the alfacalcidol and placebo group was not statistically significant.Highly statistically significant differences were seen in the change in Total Body Less Head aBMD-Z Score between the placebo and risedronate groups (p < 0.01) but not between the alfacalcidol and risedronate groups. No significant differences in fracture frequency, adverse or serious adverse reactions were observed between the groups., Conclusions: Children and adolescents receiving steroids for rheumatic diseases benefit from prophylactic treatment with bisphosphonates to increase LSaBMD. Alfacalcidol is ineffective.

Purpose: To evaluate the effect of non-pharmacological interventions versus standard care on incidence and duration of delirium in critically ill patients., Methods: We searched electronic and grey literature for randomised clinical trials up to March 2018. Two reviewers independently screened, selected and extracted data. Meta-analysis was undertaken using random effects modelling., Results: We identified 15 trials (2812 participants). Eleven trials reported incidence of delirium. Pooled data from four trials of bright light therapy showed no significant effect between groups (n = 829 participants, RR 0.45, 99% CI 0.10-2.13, P = 0.19, very low quality evidence). Seven trials of various individual interventions also failed to report any significant effects. A total of eight trials reported duration of delirium. Pooled data from two trials of multicomponent physical therapy showed no significant effect [n = 404 participants, MD (days) - 0.65, 99% CI - 2.73 to 1.44, P = 0.42, low quality of evidence]. Four trials of various individual interventions also reported no significant effects. A trial of family voice reorientation showed a beneficial effect [n = 30, MD (days) - 1.30, 99% CI - 2.41 to - 0.19, P = 0.003, very low quality evidence]., Conclusions: Current evidence does not support the use of non-pharmacological interventions in reducing incidence and duration of delirium in critically ill patients. Future research should consider well-designed and well-described multicomponent interventions and include adequately defined outcome measures.

Objectives: The NICPIP trial evaluated the costs and effects of a caries prevention intervention delivered to 2- to 3-year-old children attending dental practices in Northern Ireland. This supplementary study explored the oral health behaviours of children and their parents to help understand the reasons for the trial's findings., Methods: A mixed methods study that included a questionnaire completed by all parents (n = 1058) at the time they brought their child for the NICPIP final clinical assessment. The questionnaire collected data on frequency of toothbrushing and sugar consumption. Questionnaire data were analysed by trial group and caries status. Parents of trial participants (n = 42) were invited to take part in telephone interviews. Parents were purposively sampled according to trial group and whether or not their child developed caries. The interviews explored how and why oral health behaviours happened. Interview data were audio-recorded, transcribed verbatim and analysed thematically., Results: The questionnaire data indicated that toothbrushing and between-meal sugar snacking were common in the majority of children. The children of parents who automatically reminded their child to brush their teeth were more likely to remain caries-free (Odds Ratio 1.24; 95% CI 1.08, 1.41; P = .002). Frequency of sweet drink consumption was associated with the child developing caries (Odds Ratio 0.88; 95% CI 0.79, 0.98; P = .021). The interview data showed that parents had positive attitudes towards brushing both in terms of perceived importance and expected outcomes. Attitudes towards sugar snacking were more complex, with parents reporting difficulties in controlling this behaviour. Sugar was described as being something that was "ever present" in children's lives., Conclusions: Toothbrushing was widely adopted from a young age, but between-meal sugar consumption was highly prevalent. The results suggest that effective family-level and population-level interventions are needed to reduce sugar consumption if substantial improvements in caries prevention are to be achieved., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Dental caries is the most common disease of childhood. The NHS guidelines promote preventative care in dental practices, particularly for young children. However, the cost-effectiveness of this policy has not been established., Objective: To measure the effects and costs of a composite fluoride intervention designed to prevent caries in young children attending dental services., Design: The study was a two-arm, parallel-group, randomised controlled trial, with an allocation ratio of 1 : 1. Randomisation was by clinical trials unit, using randomised permuted blocks. Children/families were not blinded; however, outcome assessment was blinded to group assessment., Setting: The study took place in 22 NHS dental practices in Northern Ireland, UK., Participants: The study participants were children aged 2-3 years, who were caries free at baseline., Interventions: The intervention was composite in nature, comprising a varnish containing 22,600 parts per million (p.p.m.) fluoride, a toothbrush and a 50-ml tube of toothpaste containing 1450 p.p.m. fluoride; plus standardised, evidence-based prevention advice provided at 6-monthly intervals over 3 years. The control group received the prevention advice alone., Main Outcome Measures: The primary outcome measure was conversion from caries-free to caries-active states. Secondary outcome measures were the number of decayed, missing or filled tooth surfaces in primary dentition (dmfs) in caries-active children, the number of episodes of pain, the number of extracted teeth and the costs of care. Adverse reactions (ARs) were recorded., Results: A total of 1248 children (624 randomised to each group) were recruited and 1096 (549 in the intervention group and 547 in the control group) were included in the final analyses. A total of 87% of the intervention children and 85% of control children attended every 6-month visit (p = 0.77). In total, 187 (34%) children in the intervention group converted to caries active, compared with 213 (39%) in the control group [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.64 to 1.04; p = 0.11]. The mean number of tooth surfaces affected by caries was 7.2 in the intervention group, compared with 9.6 in the control group (p = 0.007). There was no significant difference in the number of episodes of pain between groups (p = 0.81). However, 164 out of the total of 400 (41%) children who converted to caries active reported toothache, compared with 62 out of 696 (9%) caries-free children (OR 7.1 95% CI 5.1 to 9.9; p < 0.001). There was no statistically significant difference in the number of teeth extracted in caries-active children (p = 0.95). Ten children in the intervention group had ARs of a minor nature. The average direct dental care cost was £155.74 for the intervention group and £48.21 for the control group over 3 years (p < 0.05). The mean cost per carious surface avoided over the 3 years was estimated at £251.00., Limitations: The usual limitations of a trial such as generalisability and understanding the underlying reasons for the outcomes apply. There is no mean willingness-to-pay threshold available to enable assessment of value for money., Conclusions: A statistically significant effect could not be demonstrated for the primary outcome. Once caries develop, pain is likely. There was a statistically significant difference in dmfs in caries-active children in favour of the intervention. Although adequately powered, the effect size of the intervention was small and of questionable clinical and economic benefit., Future Work: Future work should assess the caries prevention effects of interventions to reduce sugar consumption at the population and individual levels. Interventions designed to arrest the disease once it is established need to be developed and tested in practice., Trial Registration: Current Controlled Trials ISRCTN36180119 and EudraCT 2009-010725-39., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 71. See the NIHR Journals Library website for further project information.

Aims: To determine the symptomatic and prognostic differences resulting from a novel diagnostic pathway based on cardiac computerized tomography (CT) compared with the traditional exercise stress electrocardiography test (EST) in stable chest pain patients., Methods and Results: A prospective randomized controlled trial compared selected patient outcomes in EST and cardiac CT coronary angiography groups. Five hundred patients with troponin-negative stable chest pain and without known coronary artery disease were recruited. Patients completed the Seattle Angina Questionnaires (SAQ) at baseline, 3, and 12 months to assess angina symptoms. Patients were also followed for management strategies and clinical events. Over the year 12 patients withdrew, resulting in 245 in the EST cohort and 243 in the CT cohort. There was no significant difference in baseline demographics. The CT arm had a statistical difference in angina stability and quality-of-life domains of the SAQ at 3 and12 months, suggesting less angina compared with the EST arm. In the CT arm, there was more significant disease identified and more revascularizations. Significantly, more inconclusive results were seen in the EST arm with a higher number of additional investigations ordered. There was also a longer mean time to management. There were no differences in major adverse cardiac events between the cohorts. At 1 year in the EST arm, there were more Accident and Emergency (A&E) attendances and cardiac admission., Conclusion: Cardiac CT as an index investigation for stable chest pain improved angina symptoms and resulted in fewer investigations and re-hospitalizations compared with EST., Clinical Trial Registration: http://www.controlled-trials.com/ISRCTN52480460., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Purpose: To evaluate a sector analysis program in the assessment and comparison of pre- and post-implant dosimetric parameters during the development of an (125)I permanent prostate brachytherapy service., Methods and Materials: A total of 50 consecutive men being treated with permanent prostate brachytherapy had dose-volume analysis in 12 sectors of their pre-implant ultrasound (USpre) and post-implant CT (CTpost) studies. Individual sectors were created by dividing prostate into three equal lengths, namely base, midgland, and apex. Each of these volumes was then divided into four axial sectors. Dosimetric parameters were compared in adjoining sectors within each study and between studies., Results: There were statistically significant differences between individual sectors on USpre and CTpost volumes with CTpost higher than USpre (p=0.001). Statistically significant differences were found in corresponding sectors on USpre and CTpost for all dosimetric parameters. The dosimetric parameters were significantly lower on CTpost in the anterior base and midgland (p=0.001) and significantly higher at the posterior apex and midgland (p=0.05). Dose homogeneity was demonstrated in adjoining sectors in all USpre and most adjoining sectors on CTpost., Conclusions: Sector analysis allows rapid assessment of USpre and CTpost dosimetry. It offers a scientific method of identifying areas of increased and reduced dosing on CTpost when compared with USpre, providing a learning tool to refine dosimetric analysis and highlight sectors where implant quality could be improved., (Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)