Background The most common cause of preventable death after injury is haemorrhage. Resuscitative endovascular balloon occlusion of the aorta is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis. Objective To compare standard care plus resuscitative endovascular balloon occlusion of the aorta versus standard care in patients with exsanguinating haemorrhage in the emergency department. Design Pragmatic, multicentre, Bayesian, group-sequential, registry-enabled, open-label, parallel-group randomised controlled trial to determine the clinical and cost-effectiveness of standard care plus resuscitative endovascular balloon occlusion of the aorta, compared to standard care alone. Setting United Kingdom Major Trauma Centres. Participants Trauma patients aged 16 years or older with confirmed or suspected life-threatening torso haemorrhage deemed amenable to adjunctive treatment with resuscitative endovascular balloon occlusion of the aorta. Interventions Participants were randomly assigned 1 : 1 to: standard care, as expected in a major trauma centre standard care plus resuscitative endovascular balloon occlusion of the aorta. Main outcome measures Primary: Mortality at 90 days. Secondary: Mortality at 6 months, while in hospital, and within 24, 6 and 3 hours; need for haemorrhage control procedures, time to commencement of haemorrhage procedure, complications, length of stay (hospital and intensive care unit-free days), blood product use. Health economic: Expected United Kingdom National Health Service perspective costs, life-years and quality-adjusted life-years, modelled over a lifetime horizon. Data sources Case report forms, Trauma Audit and Research Network registry, NHS Digital (Hospital Episode Statistics and Office of National Statistics data). Results Ninety patients were enrolled: 46 were randomised to standard care plus resuscitative endovascular balloon occlusion of the aorta and 44 to standard care. Mortality at 90 days was higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group (54%) compared to the standard care group (42%). The odds ratio was 1.58 (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (indicating increased odds of death with resuscitative endovascular balloon occlusion of the aorta) was 86.9%. The overall effect did not change when an enthusiastic prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3, 6 and 24 hours mortality), the posterior probability that standard care plus resuscitative endovascular balloon occlusion of the aorta was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at any time point. Death due to haemorrhage was more common in the standard care plus resuscitative endovascular balloon occlusion of the aorta group than in the standard care group. There were no serious adverse device effects. Resuscitative endovascular balloon occlusion of the aorta is less costly (probability 99%), due to the competing mortality risk but also substantially less effective in terms of lifetime quality-adjusted life-years (probability 91%). Limitations The size of the study reflects the relative infrequency of exsanguinating traumatic haemorrhage in the United Kingdom. There were some baseline imbalances between groups, but adjusted analyses had little effect on the estimates. Conclusions This is the first randomised trial of the addition of resuscitative endovascular balloon occlusion of the aorta to standard care in the management of exsanguinating haemorrhage. All the analyses suggest that a strategy of standard care plus resuscitative endovascular balloon occlusion of the aorta is potentially harmful. Future work The role (if any) of resuscitative endovascular balloon occlusion of the aorta in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required. Trial registration This trial is registered as ISRCTN16184981. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and is published in full in Health Technology Assessment; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information.

Objective To estimate the cost of paediatric asthma from a UK National Health Service (NHS) and societal perspective and explore determinants of these costs. Design Cost analysis based on data from a large clinical trial between 2017 and 2019. Case report forms recorded healthcare resource use and productivity losses attributable to asthma over a 12-month period. These were combined with national unit cost data to generate estimates of health service and indirect costs. Setting Asthma clinics in primary and secondary care in England and Scotland. Main outcome measures Cost per asthma attack stratified by highest level of care received. Total annual health service and indirect costs. Modelled effect of sex, age, severity, number of attacks and adherence on total annual costs. Results Of 506 children included in the analysis, 252 experienced at least one attack. The mean (SD) cost per attack was £297 (806) (median £46, IQR 40–138) and the mean total annual cost to the NHS was £1086 (2504) (median £462, IQR 296–731). On average, children missed 6 days of school and their carers missed 13 hours of paid work, contributing to a mean annual indirect cost of £412 (879) (median £30, IQR 0–477). Health service costs increased significantly with number of attacks and participant age (>11 years). Indirect costs increased with asthma severity and number of attacks but were found to be lower in older children. Conclusions Paediatric asthma imparts a significant economic burden on the health service, families and society. Efforts to improve asthma control may generate significant cost savings. Trial registration number ISRCTN 67875351.

Background:Low levels of testosterone cause male hypogonadism, which is associated with sexual dysfunction, tiredness and reduced muscle strength and quality of life. Testosterone replacement therapy is commonly used for ameliorating symptoms of male hypogonadism, but there is uncertainty about the magnitude of its effects and its cardiovascular and cerebrovascular safety. Aims of the research:The primary aim was to evaluate the safety of testosterone replacement therapy. We also assessed the clinical and cost-effectiveness of testosterone replacement therapy for men with male hypogonadism, and the existing qualitative evidence on men's experience and acceptability of testosterone replacement therapy. Design:Evidence synthesis and individual participant data meta-analysis of effectiveness and safety, qualitative evidence synthesis and model-based cost-utility analysis. Data sources:Major electronic databases were searched from 1992 to February 2021 and were restricted to English-language publications. Methods:We conducted a systematic review with meta-analysis of individual participant data according to current methodological standards. Evidence was considered from placebo-controlled randomised controlled trials assessing the effects of any formulation of testosterone replacement therapy in men with male hypogonadism. Primary outcomes were mortality and cardiovascular and cerebrovascular events. Data were extracted by one reviewer and cross-checked by a second reviewer. The risk of bias was assessed using the Cochrane Risk of Bias tool. We performed one-stage meta-analyses using the acquired individual participant data and two-stage meta-analyses to integrate the individual participant data with data extracted from eligible studies that did not provide individual participant data. A decision-analytic Markov model was developed to evaluate the cost per quality-adjusted life-years of the use of testosterone replacement therapy in cohorts of patients of different starting ages. Results:We identified 35 trials (5601 randomised participants). Of these, 17 trials (3431 participants) provided individual participant data. There were too few deaths to assess mortality. There was no difference between the testosterone replacement therapy group (120/1601, 7.5%) and placebo group (110/1519, 7.2%) in the incidence of cardiovascular and/or cerebrovascular events (13 studies, odds ratio 1.07, 95% confidence interval 0.81 to 1.42; p = 0.62). Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups. In the testosterone replacement therapy group, serum testosterone was higher while serum cholesterol, triglycerides, haemoglobin and haematocrit were all lower. We identified several themes from five qualitative studies showing how symptoms of low testosterone affect men's lives and their experience of treatment. The cost-effectiveness of testosterone replacement therapy was dependent on whether uncertain effects on all-cause mortality were included in the model, and on the approach used to estimate the health state utility increment associated with testosterone replacement therapy, which might have been driven by improvements in symptoms such as sexual dysfunction and low mood. Limitations:A meaningful evaluation of mortality was hampered by the limited number of defined events. Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials. Conclusions:Our findings do not support a relationship between testosterone replacement therapy and cardiovascular/cerebrovascular events in the short-to-medium term. Testosterone replacement therapy improves sexual function and quality of life without adverse effects on blood pressure, serum lipids or glycaemic markers. Future work:Rigorous long-term evidence assessing the safety of testosterone replacement therapy and subgroups most benefiting from treatment is needed. Study registration:The study is registered as PROSPERO CRD42018111005. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/68/01) and is published in full in Health Technology Assessment; Vol. 28, No. 43. See the NIHR Funding and Awards website for further award information.

Background: Peripheral artery disease is a common condition caused by narrowing/blockage of the arteries, resulting in reduced blood supply. Peripheral artery disease is associated with an increased risk of vascular complications, but early treatment reduces mortality and morbidity. Leg ulcers are long-lasting wounds, usually treated by compression therapy. Compression therapy is not suitable for people with peripheral artery disease, as it can affect the arterial blood supply. In clinical practice, people with peripheral artery disease are identified by measurement of the ankle-brachial pressure index using a sphygmomanometer and manual Doppler device. However, this method can be uncomfortable for people with leg ulcers and automated devices have been proposed as a more acceptable alternative. The objective of this appraisal was to summarise the clinical and cost-effectiveness evidence on the use of automated devices to detect peripheral artery disease in people with leg ulcers. Methods: Clinical effectiveness: To identify reports of relevant studies, we searched major electronic databases and scrutinised the information supplied by the manufacturers of the automated devices under investigation. Due to the lack of evidence on people with leg ulcers, we considered evidence from studies of any design assessing automated devices versus an acceptable reference device in any population receiving ankle-brachial pressure index assessment. We summarised information on diagnostic accuracy of the automated devices and level of agreement with the reference device. For each device, when data permit, we pooled data across studies by conducting random-effects meta-analyses using a Hierarchical Summary Receiving Operating Characteristics model. Cost-effectiveness: An economic model comprising a decision tree (24 weeks) and Markov models to capture lifetime costs and quality-adjusted life-years associated with venous, arterial and mixed aetiology disease in leg ulcer patients. Analyses were conducted from a United Kingdom National Health Service and Personal Social Services perspective. Costs and quality-adjusted life-years were discounted at 3.5% per year. Deterministic and several probabilistic analyses were used to capture uncertainty surrounding a range of optimistic and pessimistic assumptions about the impact of automated tests on health outcomes (ulcer healing and requirement for invasive management of arterial disease). Results: Clinical effectiveness: From the 116 records retrieved by the electronic searches, we included 24 studies evaluating five devices (BlueDop Vascular Expert, BOSO ABI-System 100, Dopplex Ability, MESI ankle-brachial pressure index MD and WatchBP Office ABI). Two studies assessing people with leg ulcers found that automated devices often gave higher ankle-brachial pressure index readings than manual Doppler (underestimation of arterial disease). In the 22 studies involving people without leg ulcers, automated devices generally demonstrated good specificity and moderate specificity. Meta-analysis of 12 studies showed a pooled sensitivity of 64% (95% confidence interval 57% to 71%) and a pooled specificity of 96% (95% confidence interval 92% to 98%) for detection of peripheral artery disease.Cost-effectiveness: Automated devices cost less than manual Doppler to deliver. However, increased risks of invasive treatment requirements for inappropriately compressed arterial/mixed ulcers due to false-negative results, and increased healing times due to delayed compression of false-positive test results mean that in most scenarios manual Doppler was less costly and had slightly higher quality-adjusted life-years than automated devices. Results are highly uncertain, dependent on many assumptions and should be interpreted cautiously. Limitations and conclusions: The limited evidence identified for each automated device, especially in people with leg ulcers, and its clinical heterogeneity precludes any firm conclusions on the diagnostic performance and cost-effectiveness of these devices in clinical practice

Importance:Bleeding is the most common cause of preventable death after trauma.Objective:To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage.Design, Setting, and Participants:Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days.Intervention:Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44).Main Outcomes and Measures:The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death.Results:Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours.Conclusions and Relevance:In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone.Trial Registration:isrctn.org Identifier: ISRCTN16184981.

IntroductionLeg ulcers are usually treated with compression therapy unless there is evidence of peripheral arterial disease (PAD). Compression may lead to vascular complications in people with PAD. Timely diagnosis and appropriate treatment are important to ensure the best patient outcomes. PAD is usually assessed using a manual ankle brachial pressure index (ABPI). Automated devices may reduce time to diagnosis and treatment of leg ulcers. This study investigated the diagnostic accuracy, clinical effectiveness, and cost effectiveness of automated ABPI measurement, compared with manual doppler testing, to detect PAD in people with leg ulcers.MethodsWe conducted a systematic review of studies of any design assessing automated devices in any population. Meta-analyses were conducted where possible. A decision tree and Markov model was used to capture lifetime costs, quality-adjusted life-years (QALYs), and cost effectiveness from a UK National Health Service perspective. Sensitivity analyses captured the uncertainty surrounding model assumptions and probabilistic sensitivity analyses described parameter uncertainty. Value of information analysis was conducted to identify future research priorities.ResultsA total of 22 studies provided diagnostic accuracy data for five automated devices, but there were no studies in people with leg ulcers. Meta-analysis of 12 studies demonstrated a pooled sensitivity of 64 percent (95% confidence interval [CI]: 57, 71) and a specificity of 96 percent (95% CI: 92, 98) for detecting PAD. Automated devices were cheaper to complete due to shorter test times, but the increased risk of inappropriate or delayed treatment due to inaccurate test results offset the cost savings and reduced the QALYs for automated devices.ConclusionsGiven the current limited evidence base, automated devices would only be cost effective if they can demonstrate substantial reductions in time to diagnosis in clinical practice. Value of information analysis identified the following research priorities: (i) to determine diagnostic accuracy in a population with leg ulcers; (ii) to determine the impact of test results on ulcer healing times, and (iii) to determine the risk of providing inappropriate treatment based on inaccurate test results.

Background/aims To evaluate the cost-effectiveness of non-invasive monitoring tests to detect the onset of neovascular age-related macular degeneration (nAMD) in the unaffected second eye of patients receiving treatment for unilateral nAMD in a UK National Health Service (NHS) hospital outpatient setting. Methods A patient-level state transition model was constructed to simulate the onset, detection, and treatment of nAMD in the second eye. Five index tests were compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity from baseline, fundus assessment by clinical examination or colour photography, and spectral domain optical coherence tomography (SD-OCT). Diagnosis of nAMD was confirmed by fundus fluorescein angiography (FFA) before prompt initiation of antivascular endothelial growth factor treatment. Quality-adjusted life-years (QALYs) and costs of health and social care were modelled over a 25-year time horizon. Results SD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient’s subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient’s subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests. Probabilistic sensitivity analysis indicated a high probability (97%–99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000–£30 000) applied in the UK NHS. Conclusions Early treatment of the second eye following FFA confirmation of SD-OCT positive findings is expected to maintain better visual acuity and health-related quality of life and may reduce costs of health and social care over the lifetime of patients.

Background: The role of fractional exhaled nitric oxide in guiding asthma treatment in children is uncertain. Objective: To compare treatment guided by both fractional exhaled nitric oxide and symptoms (intervention) with treatment guided by symptoms alone (standard care) in children with asthma who are at risk of an asthma exacerbation, in terms of the number of asthma exacerbations over 12 months. Design: This was a pragmatic, multicentre, randomised controlled trial with embedded cost-effectiveness and qualitative process evaluations. Randomisation (1 : 1) was carried out using a remote web-based system and was minimised on recruitment centre, age, sex and British Thoracic Society treatment step. Clinical teams and participants were not blind to treatment allocation. Setting: The trial took place in 35 hospitals and seven primary care practices in the UK. Participants: Children aged 6–15 years with a diagnosis of asthma who were currently prescribed inhaled corticosteroids and who had one or more parent-/patient-reported asthma exacerbation treated with oral corticosteroids in the 12 months prior to recruitment. Interventions: Asthma treatment guided by symptoms alone (standard care) and asthma treatment guided by symptoms plus fractional exhaled nitric oxide (intervention). Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic logging device) and current treatment. Main outcome measures: The primary outcome measure was asthma exacerbations treated with oral corticosteroids in the year post randomisation. Secondary outcomes included time to first exacerbation, number of exacerbations, lung function, fractional exhaled nitric oxide, daily dose of inhaled corticosteroid, asthma control and quality of life. Results: In total, 509 eligible participants were recruited and the primary outcome was available for 506 participants. The primary outcome occurred in 123 out of 255 (48.2%) participants in the intervention group and 129 out of 251 (51.4%) participants in the standard-care group (adjusted odds ratio 0.88, 95% confidence interval 0.61 to 1.27). There was algorithm non-compliance on 21% of assessments. Per-protocol and complier-average causal effect analysis did not change the interpretation. This non-statistically significant estimate was consistent across predefined subgroups. There were no differences between the groups in secondary outcomes. There were no serious adverse events or deaths. No meaningful differences in health service costs, direct patient costs or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide and wariness around extreme step ups/downs in treatment in the light of contextual factors not being taken into account by the algorithm. Limitations: Potential limitations included the choice of cut-off point to define uncontrolled asthma and the change in fractional exhaled nitric oxide to trigger a change in treatment. Furthermore, the treatment decisions in the two groups may not have been sufficiently different to create a difference in outcomes. Conclusions: The RAACENO (Reducing Asthma Attacks in Children using Exhaled Nitric Oxide) trial findings do not support the routine use of fractional exhaled nitric oxide measurements as part of asthma management in a secondary care setting. The potential for other objective markers to guide asthma management in children needs to be evaluated. Trial registration: This trial was registered as ISRCTN67875351. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 4. See the NIHR Journals Library website for further project information.

Background Neovascular age-related macular degeneration is a leading cause of sight loss, and early detection and treatment is important. For patients with neovascular age-related macular degeneration in one eye, it is usual practice to monitor the unaffected eye. The test used to diagnose neovascular age-related macular degeneration, fundus fluorescein angiography, is an invasive test. Non-invasive tests are available, but their diagnostic accuracy is unclear. Objectives The primary objective was to determine the diagnostic monitoring performance of tests for neovascular age-related macular degeneration in the second eye of patients with unilateral neovascular age-related macular degeneration. The secondary objectives were the cost-effectiveness of tests and to identify predictive factors of developing neovascular age-related macular degeneration. Design This was a multicentre, prospective, cohort, comparative diagnostic accuracy study in a monitoring setting for up to 3 years. A Cox regression risk prediction model and a Markov microsimulation model comparing cost-effectiveness of the index tests over 25 years were used. Setting This took place in hospital eye services. Participants Participants were adults (aged 50–95 years) with newly diagnosed (within the previous 6 weeks) neovascular age-related macular degeneration in one eye and an unaffected second (study) eye who were attending for treatment injections in the first eye and who had a study eye baseline visual acuity of ≥ 68 Early Treatment Diabetic Retinopathy Study letters. Interventions The index tests were Amsler chart (completed by participants), fundus clinical examination, optical coherence tomography, self-reported vision assessment (completed by participants) and visual acuity. The reference standard was fundus fluorescein angiography. Main outcome measures The main outcome measures were sensitivity and specificity; the performance of the risk predictor model; and costs and quality-adjusted life-years. Results In total, 552 out of 578 patients who consented from 24 NHS hospitals ( n = 16 ineligible; n = 10 withdrew consent) took part. The mean age of the patients was 77.4 years (standard deviation 7.7 years) and 57.2% were female. For the primary analysis, 464 patients underwent follow-up fundus fluorescein angiography and 120 developed neovascular age-related macular degeneration on fundus fluorescein angiography. The diagnostic accuracy [sensitivity (%) (95% confidence interval); specificity (%) (95% confidence interval)] was as follows: optical coherence tomography 91.7 (85.2 to 95.6); 87.8 (83.8 to 90.9)], fundus clinical examination [53.8 (44.8 to 62.5); 97.6 (95.3 to 98.9)], Amsler [33.7 (25.1 to 43.5); 81.4 (76.4 to 85.5)], visual acuity [30.0 (22.5 to 38.7); 66.3 (61.0 to 71.1)] and self-reported vision [4.2 (1.6 to 9.8); 97.0 (94.6 to 98.5)]. Optical coherence tomography had the highest sensitivity across all secondary analyses. The final prediction model for neovascular age-related macular degeneration in the non-affected eye included smoking status, family history of neovascular age-related macular degeneration, the presence of nodular drusen with or without reticular pseudodrusen, and the presence of pigmentary abnormalities [ c -statistic 0.66 (95% confidence interval 0.62 to 0.71)]. Optical coherence tomography monitoring generated the greatest quality-adjusted life-years gained per patient (optical coherence tomography, 5.830; fundus clinical examination, 5.787; Amsler chart, 5.736, self-reported vision, 5.630; and visual acuity, 5.600) for the lowest health-care and social care costs (optical coherence tomography, £19,406; fundus clinical examination, £19,649; Amsler chart, £19,751; self-reported vision, £20,198; and visual acuity, £20,444) over the lifetime of the simulated cohort. Optical coherence tomography dominated the other tests or had an incremental cost-effectiveness ratio below the accepted cost-effectiveness thresholds (£20,000) across the scenarios explored. Limitations The diagnostic performance may be different in an unselected population without any history of neovascular age-related macular degeneration; the prediction model did not include genetic profile data, which might have improved the discriminatory performance. Conclusions Optical coherence tomography was the most accurate in diagnosing conversion to neovascular age-related macular degeneration in the fellow eye of patients with unilateral neovascular age-related macular degeneration. Economic modelling suggests that optical coherence tomography monitoring is cost-effective and leads to earlier diagnosis of and treatment for neovascular age-related macular degeneration in the second eye of patients being treated for neovascular age-related macular degeneration in their first eye. Future work Future works should investigate the role of home monitoring, improved risk prediction models and impact on long-term visual outcomes. Study registration This study was registered as ISRCTN48855678. 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. 26, No. 8. See the NIHR Journals Library website for further project information.

IntroductionSeveral diagnostic tests are often adopted into diagnostic pathways for specific indications without strong evidence to support their use. In this context, real-world prospective cohort studies in combination with decision modelling can generate evidence to support decision-making. The Early Detection of neovascular Age-Related Macular Degeneration (EDNA) study was a prospective cohort designed to assess the diagnostic accuracy and cost-effectiveness of several diagnostic monitoring tests used in routine practice for the detection of neovascular age-related macular degeneration (nAMD) in the second eye of patients being treated for unilateral disease.MethodsFive-hundred and fifty-two participants with newly diagnosed unilateral nAMD were monitored for up to 3 years in 24 UK eye clinics. The diagnostic monitoring performance of five index tests was compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity, fundus assessment by clinical examination or colour photography, and spectral-domain optical coherence tomography (SD-OCT). The reference standard was fundus fluorescein angiography (FFA). A patient-level state transition model was used to simulate the onset of nAMD in the second eye, and assess the impact of different tests on the timing of detection and treatment, and associated costs and quality adjusted life years (QALYs) over a 25-year time-horizon.ResultsOne hundred and forty-five (26.3%) patients developed active nAMD in the study eye, of whom 120 had an FFA at detection. SD-OCT had the highest sensitivity (91.7 percent (95% CI: 85.2-95.6) and provided high specificity (87.8% (95% CI: 83.8-90.9)). It generated more QALYs and lower health and personal social care costs compared to all other monitoring tests. The combination of SD-OCT with fundus-examination provided a marginal increase in sensitivity over OCT alone, but the associated incremental cost-effectiveness ratios was >GBP 100,000 per QALY.ConclusionsThe efficiency of diagnostic pathways for nAMD may be improved by using SD-OCT alone to monitor the second eye of people being treated for unilateral disease. Prospective cohort studies embedded into routine practice offer value for informing decisions surrounding the use of technologies already in routine use.

Background The benefit of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment is uncertain. We evaluated the efficacy of adding FeNO to symptom-guided treatment in children with asthma versus only symptom-guided treatment. Methods RAACENO was a multicentre, parallel, randomised, controlled, phase 3 trial done in 35 secondary care centres and 17 primary care recruitment sites (only seven primary care sites managed to recruit patients) in the UK. Patients with a confirmed asthma diagnosis, aged 6-15 years, prescribed inhaled corticosteroids, and who received a course of oral corticosteroids for at least one asthma exacerbation during the 12 months before recruitment were included. Participants were randomly assigned to either FeNO plus symptom-guided treatment (intervention) or symptom-guided treatment alone (standard care) using a 24 h in-house, web-based randomisation system. Participants and the clinical and research teams were not masked to the group allocation. A web-based algorithm gave treatment recommendations based on the Asthma Control Test (ACT) or Childhood ACT (CACT) score; current asthma treatment; adherence to study treatment in the past 3 months; and use of FeNO (in the intervention group). Follow-up occurred at 3-month intervals for 12 months. The primary outcome was any asthma exacerbation treated with oral corticosteroids in the 12 months after randomisation, assessed in the intention-to-treat population. This study is registered with the International Standard Randomised Controlled Trial Registry, ISRCTN67875351. Findings Between June 22, 2017, and Aug 8, 2019, 535 children were assessed for eligibility, 20 were ineligible and six were excluded post-randomisation. 509 children were recruited and at baseline, the mean age of participants was 10.1 years (SD 2.6), and 308 (60.5%) were male. The median FeNO was 21 ppb (IQR 10-48), mean predicted FEV1 was 89.6% (SD 18.0), and median daily dose of inhaled corticosteroids was 400 mu g budesonide equivalent (IQR 400-1000). Asthma was partly or fully controlled in 256 (50.3%) of 509 participants. The primary outcome, which was available for 506 (99%) of 509 participants, occurred in 123 (48.2%) of 255 participants in the intervention group and 129 (51.4%) of 251 in the standard care group, the intention-to-treat adjusted odds ratio (OR) was 0.88 (95% CI 0.61 to 1.27; p=0.49). The adjusted difference in the percentage of participants who received the intervention in whom the primary outcome occurred compared with those who received standard care was -3.1% (-11.9% to 5.6%). In 377 (21.3%) of 1771 assessments, the algorithm recommendation was not followed. Adverse events were reported by 27 (5.3%) of 509 participants (15 in the standard care group and 12 in the intervention group). The most common adverse event was itch after skin prick testing (reported by eight participants in each group). Interpretation We found that the addition of FeNO to symptom-guided asthma treatment did not lead to reduced exacerbations among children prone to asthma exacerbation. Asthma symptoms remain the only tool for guiding treatment decisions. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved.

Background: The benefit of Fractional Exhaled Nitric Oxide (FeNO) in guiding asthma treatment is uncertain. Our hypothesis was that FeNO plus symptom-guided treatment reduces exacerbations in children with asthma compared to symptom-guided treatment alone. Methods: A multicentre randomised controlled trial recruited 6-15 year olds with asthma treated with inhaled corticosteroids (ICS) with an exacerbation in the previous year. Randomisation was to asthma treatment guided by FeNO plus symptoms (intervention) or by symptoms only (standard care). A web-based algorithm using symptom control, ICS adherence, current treatment and (within the intervention group) FeNO gave treatment recommendations. Participants attended assessments 3, 6, 9 and 12-months post-randomisation. The primary outcome was exacerbation requiring oral corticosteroid over the 12 months post-randomisation. Findings: There were 509 children recruited. At randomisation, the mean (SD) age was 10∙1y (2.6), median (IQR) FeNO 21 ppb (10, 48), mean (SD) %FEV 1 90% (18), 56% received ≤400 microg budesonide equivalent ICS and 50% had controlled symptoms. The primary outcome occurred in 123/255 (48%) of the intervention group and 129/251 (51%) of the standard care group. The adjusted difference in percentage of participants who received the intervention where the primary outcome occurred exacerbation compared to those receiving standard care was -3∙13% (95% CI: -11∙9% to 5∙6%).  In adjusted intention-to-treat analysis, the odds ratio (OR) for primary outcome was 0 ∙88 [95%CI 0∙61 to 1∙27]. In 377 of 1771 assessments, the algorithm recommendation was not followed. In complier average causal effect analysis, adjusting for algorithm adherence, the OR for those fully adherent was 0∙82 [95% CI 0∙48 to 1∙41]. There were no differences in secondary outcomes between groups. Interpretation: In this exacerbation-prone population, adding FeNO to symptom-guided treatment did not reduce exacerbations. Trial Registration: ISRCTN number #67875351. Funding: This study was funded by the Efficacy and Mechanisms Evaluation programme of the National Institute for Health Research (reference 15-18-14). Declaration of Interest: David Price has board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermofisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. Ethical Approval: The study was approved by the North of Scotland Research Ethics Committee (16/NS/0106).

BackgroundPaediatric head injury is common, yet 80% are mild and require no investigation or treatment. Decision-making around neuroimaging is guided by clinical decision rules. Whether parents and clinicians interpret questions within these algorithms in the same way is not known. Understanding this is fundamental for public facing algorithms and parental guidance.We aimed to determine the inter-observer reliability of Pediatric Emergency Care Applied Research Network (PECARN) head injury algorithm completion between clinicians and parents of head injured children.We conducted a prospective, observational, feasibility study. Children over 2 years old, presenting to the Royal Manchester Children’s Hospital within 24 hours of a head injury, were recruited. Children were excluded if they required immediate resuscitation or non-accidental injury was suspected. Parents were given a questionnaire to complete whilst awaiting assessment, with the PECARN criteria in lay-man’s language. Following assessment, the treating clinician completed a similar questionnaire, blinded to the parent’s answers.57 children were included. The mean age was 5.8 years (SD 4.07). The most common mechanism of injury was a fall from standing (46%), with only 6 parents reporting a dangerous mechanism. Arrival Glasgow Coma Scale (GCS) was 15/15 in 98% of children. The inter-rater reliability for individual PECARN criteria was highly variable, with kappa values ranging from −0.10 to 1.00. There was poor agreement on whether the child was alert and acting normally (K −0.10, SE 0.49) but perfect agreement on other features of altered mental state including agitation, repeated questioning and taking longer than normal to respond (all K 1.0).The high variability in agreement between clinicians and parents when assessing PECARN criteria highlights differences in how these groups evaluate head injured children. This has significant implications for public facing algorithms, such as those used by NHS 111.