BACKGROUND:Bronchiolitis is a common viral respiratory disease of infants, with severity ranging from mild symptoms, such as coryza and feeding difficulties, to fulminant respiratory failure. Endotracheal administration of exogenous surfactant has been shown in small studies to improve gas exchange in critically ill infants with bronchiolitis. We aimed to investigate the safety and efficacy of endotracheal poractant alfa for treating critical bronchiolitis compared with a sham procedure. METHODS:BESS was a multicentre, blinded, randomised, sham-controlled, parallel-group, phase 2, superiority trial with exploratory mechanism evaluation studies. The trial was done in 15 paediatric intensive care units in the devolved National Health Service (NHS) of England, Scotland, and Northern Ireland. Preterm and term-born infants younger than 26 weeks of gestationally corrected age admitted to hospitals with bronchiolitis requiring invasive mechanical ventilation (IMV) were randomly assigned (1:1) to receive up to three doses of endotracheal poractant alfa (Curosurf) or sham intervention, allocated through web-based randomisation. Randomisation was stratified by duration of IMV before randomisation (<24 h and ≥24 h) and by site. The infants and their families, clinical care staff, Liverpool Clinical Trial Centre staff, and members of the site research teams were masked to treatment allocations. Endotracheal poractant alfa was given initially at 200 mg/kg, followed by 100 mg/kg at 12 h intervals. The primary endpoint was the duration of IMV from randomisation to final successful extubation. All infants who were successfully extubated were included in the intention-to-treat analysis. Safety outcomes were analysed in infants who had received at least one trial intervention. This trial was registered prospectively with ISRCTN (ISRCTN11746266) and EudraCT (2018-001169-18), and is completed. FINDINGS:The trial was completed after six recruitment seasons. Between Dec 18, 2018, to March 31, 2024, 1009 infants were assessed for eligibility, 232 of whom were randomly assigned to receive either endotracheal poractant alfa (n=115) or a sham intervention (n=117). 130 (56%) of 232 infants were male and 102 (44%) were female. Three infants were withdrawn from the study. None were lost to follow-up. The median duration of IMV was 64·9 h (IQR 43·2-92·1) in the endotracheal poractant alfa group and 62·0 h (39·3-95·1) in the sham intervention group. The geometric mean ratio was 1·02 (95% CI 0·84-1·24; t-test p=0·86). No clinically significant safety issues were associated with endotracheal poractant alfa and there were no deaths. INTERPRETATION:Poractant alfa, administered endotracheally to infants with early critical bronchiolitis, although safe, did not reduce the duration of IMV compared with the sham intervention. Therefore, our findings suggest that it should not be used for this indication at this dose and administration method. FUNDING:UK National Institute for Health and Care Research, UK Research and Innovation Medical Research Council, Chief Scientist Office Scotland, Health and Social Care Research and Development Division Northern Ireland, and Chiesi Farmaceutici, Italy.

Background Immunoglobulin E-mediated (immediate) cow’s milk allergy is one of the most frequent food allergies in infants, with a significant adverse impact on quality of life. There is no satisfactory treatment for cow’s milk allergy, and guidelines recommend milk avoidance, feeding with ‘hypoallergenic’ formulas (extensively hydrolysed formulas), emergency management of accidental reactions and waiting for the allergy to resolve spontaneously. Currently, the only potentially curative regimen is oral immunotherapy, that is, exposing patients to increasing doses of cow’s milk using a strictly controlled dose schedule. However, milk immunotherapy is not used in clinical practice due to risk of reactions. DREAM’s intention was to explore whether oral immunotherapy with a partially hydrolysed cow’s milk formula would be able to provide a safe and effective means of oral immunotherapy for milk-allergic infants. Limitations The trial was affected by a serious breach that led most of the participants to receive partially hydrolysed formula, even if randomised to extensively hydrolysed formula. It also ended prematurely due to unsatisfactory recruitment, and the main outcomes were not reached. Methods DREAM was a two-arm, parallel-group, double-blind randomised controlled trial. Eligible patients were infants aged 6–12 months with convincing medical history of immunoglobulin E-mediated allergy to cow’s milk formula. Inclusion criteria included a titre of cow’s milk-specific immunoglobulin E equal or higher to 2 kU/l, or wheal equal or over 5 mm to skin prick test to milk. Additionally, for the infants to be randomised, they needed to have a positive result to an open oral challenge either to partially hydrolysed formula or to milk. Participants were randomised to extensively hydrolysed formula or partially hydrolysed formula with a 1 : 1 ratio. Following randomisation, participants commenced free-feeding with the blinded product (or strict dose-based oral immunotherapy if they were not tolerant of the blinded product). The main outcome was the result of a double-blind, placebo-controlled food challenge to cow’s milk at the end of 1 year of free-feeding (or of dose-based immunotherapy) to establish if infants had become tolerant. As the trial was discontinued early on account of poor recruitment, no infant progressed to the double-blind, placebo-controlled food challenge. Results Out of 16 randomised participants who underwent an initial partially hydrolysed formula challenge, only 1 (6.25%) reacted to it (95% confidence interval 00.0 to 19.6). Hence, 93.75% of the allergic infants randomised in the trial tolerated partially hydrolysed formula. All fifteen infants that were found to be partially hydrolysed formula-tolerant also received partially hydrolysed formula free-feeding at home, on account of the serious breach. As per the trial’s criteria, these infants (and all randomised participants) were shown to be allergic to cow’s milk via either a positive open challenge to it (for the 15 partially hydrolysed formula-tolerant infants) or a positive open challenge to partially hydrolysed formula (for the single partially hydrolysed formula-reactive infant). Conclusions Partially hydrolysed formula was tolerated by the majority of well-characterised and confirmed cow’s milk-allergic infants in the DREAM trial. Future work Our findings demonstrate that partially hydrolysed formula holds promise as a potential oral immunotherapy medium in free-feeding oral immunotherapy regimens in future research. Further trials designed on the premise of partially hydrolysed formula oral immunotherapy are needed. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 17/60/44. Plain language summary Cow’s milk allergy is one of the most frequent food allergies in infants. There is no known cure for cow’s milk allergy, and allergic infants need to avoid cow’s milk, feed with ‘hypoallergenic’ formulas (if not solely breastfeeding) and wait for the allergy to go away on its own. The only potentially helpful management is oral immunotherapy, where some infants eat very low regular doses of milk under close doctor follow-up. However, immunotherapy is risky, and many reactions can happen; therefore, it is not normally advised to patients. DREAM was designed to show whether using a particular formula (partially hydrolysed cow’s milk formula) would be safe for immunotherapy. Milk-allergic infants aged 6–12 months were recruited and started to be fed on either extensively hydrolysed formula (safe formula used normally for allergic infants) or partially hydrolysed formula. These infants could also be breastfed, if their mother wanted to. The mother’s diet was not changed. After a year of feeding, also including several visits at the hospital, infants would be given cow’s milk at the hospital to see if they have managed to tolerate cow’s milk after having these formulas for a whole year. Unfortunately, the trial was stopped early due to not managing to recruit as many infants as needed, and therefore no infant reached the end of the trial. Out of 16 infants which did enter the trial, 15 (close to 94% of all infants) were able to have partially hydrolysed formula with no major problems. These infants were shown through the trial’s tests to be very allergic to cow’s milk; therefore, being able to have partially hydrolysed formula with little problem is very important. The trial managed to show that partially hydrolysed formula is promising for future immunotherapy management, because many milk-allergic infants were able to feed on it. More research is needed to show if this formula can be used in the future to help infants grow out of their allergy.

Background Systematic annual screening for sight-threatening diabetic retinopathy is established in several countries but is resource intensive. Personalised (individualised) medicine offers the opportunity to extend screening intervals for people at low risk of progression and to target high-risk groups. However, significant concern exists among all stakeholders around the safety of changing programmes. Evidence to guide decisions is limited, with, to the best of our knowledge, no randomised controlled trials to date. Objectives To develop an individualised approach to screening for sight-threatening diabetic retinopathy and test its acceptability, safety, efficacy and cost-effectiveness. To estimate the changing incidence of patient-centred outcomes. Design A risk calculation engine; a randomised controlled trial, including a within-trial cost-effectiveness study; a qualitative acceptability study; and an observational epidemiological cohort study were developed. A patient and public group was involved in design and interpretation. Setting A screening programme in an English health district of around 450,000 people. Participants People with diabetes aged ≥ 12 years registered with primary care practices in Liverpool. Interventions The risk calculation engine estimated each participant’s risk at each visit of progression to screen-positive diabetic retinopathy (individualised intervention group) and allocated their next appointment at 6, 12 or 24 months (high, medium or low risk, respectively). Main outcome measures The randomised controlled trial primary outcome was attendance at first follow-up assessing the safety of individualised compared with usual screening. Secondary outcomes were overall attendance, rates of screen-positive and sight-threatening diabetic retinopathy, and measures of visual impairment. Cost-effectiveness outcomes were cost/quality-adjusted life year and incremental cost savings. Cohort study outcomes were rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy. Data sources Local screening programme (retinopathy), primary care (demographic, clinical) and hospital outcomes. Methods A seven-person patient and public involvement group was recruited. Data were linked into a purpose-built dynamic data warehouse. In the risk assessment, the risk calculation engine used patient-embedded covariate data, a continuous Markov model, 5-year historical local population data, and most recent individual demographic, retina and clinical data to predict risk of future progression to screen-positive. The randomised controlled trial was a masked, two-arm, parallel assignment, equivalence randomised controlled trial, with an independent trials unit and 1 : 1 allocation to individualised screening (6, 12 or 24 months, determined by risk calculation engine at each visit) or annual screening (control). Cost-effectiveness was assessed using a within-trial analysis over a 2-year time horizon, including NHS and societal perspectives and costs directly observed within the randomised controlled trial. Acceptability was assessed by purposive sampling of 60 people with diabetes and 21 healthcare professionals with semistructured interviews analysed thematically; this was a constant comparative method until saturation. The cohort was an 11-year retrospective/prospective screening population data set. Results In the randomised controlled trial, 4534 participants were randomised: 2097 out of 2265 in the individualised arm (92.6%) and 2224 out of 2269 in the control arm (98.0%) remained after withdrawals. Attendance rates at first follow-up were equivalent (individualised 83.6%, control 84.7%) (difference –1.0%, 95% confidence interval –3.2% to 1.2%). Sight-threatening diabetic retinopathy detection rates were non-inferior: individualised 1.4%, control 1.7% (difference –0.3%, 95% confidence interval –1.1% to 0.5%). In the cost-effectiveness analysis, the mean differences in complete-case quality-adjusted life years (EuroQol-5 Dimensions, five-level version, and Health Utilities Index Mark 3) did not significantly differ from zero. Incremental cost savings per person not including treatment costs were from the NHS perspective £17.34 (confidence interval £17.02 to £17.67) and the societal perspective £23.11 (confidence interval £22.73 to £23.53). In the individualised arm, 43.2% fewer screening appointments were required. In terms of acceptability, changing to variable intervals was acceptable for the majority of people with diabetes and health-care professionals. Annual screening was perceived as unsustainable and an inefficient use of resources. Many people with diabetes and healthcare professionals expressed concerns that 2-year screening intervals may detect referable eye disease too late and might have a negative effect on perceptions about the importance of attendance and diabetes care. The 6-month interval was perceived positively. Among people with dementia, there was considerable misunderstanding about eye-related appointments and care. In the cohort study, the numbers of participants (total 28,384) rose over the 11 years (2006/7, n = 6637; 2016/17, n = 14,864). Annual incidences ranged as follows: screen-positive 4.4–10.6%, due to diabetic retinopathy 2.3–4.6% and sight-threatening diabetic retinopathy 1.3–2.2%. The proportions of screen-positive fell steadily but sight-threatening diabetic retinopathy rates remained stable. Limitations Our findings apply to a single city-wide established English screening programme of mostly white people with diabetes. The cost-effectiveness analysis was over a short timeline for a long-standing disease; the study, however, was designed to test the safety and effectiveness of the screening regimen, not the cost-effectiveness of screening compared with no screening. Cohort data collection was partly retrospective: data were unavailable on people who had developed sight-threatening diabetic retinopathy or died prior to 2013. Conclusions Our randomised controlled trial can reassure stakeholders involved in diabetes care that extended intervals and personalised screening is feasible, where data linkage is possible, and can be safely introduced in established screening programmes with potential cost savings compared with annual screening. Rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy are low and show consistent falls over time. Involvement of patients in research is crucial to success. Future work Future work could include external validation with other programmes followed by scale-up of individualised screening outside a research setting and economic modelling beyond the 2-year time horizon. Trial registration This trial is registered as ISRCTN87561257. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research ; Vol. 11, No. 6. See the NIHR Journals Library website for further project information.

BackgroundThe prevalence of psychological morbidity among asylum seekers and refugees is high, but these groups encounter extensive barriers to accessing health and social care. The aim of the PROSPER study was to assess the feasibility of conducting a randomised controlled trial in the UK of Problem Management Plus (PM+), an evidence-based psychosocial intervention delivered by lay therapists for distressed and functionally impaired asylum seekers and refugees.DesignWe undertook a feasibility study of PM+, which included a pilot study of the design features of a future definitive randomised controlled trial and economic evaluation. The feasibility study involved the adaptation of PM+ based on evidence drawn from literature synthesis and local stakeholder engagement, and a two-stage training procedure for lay therapists. These were followed by a pilot trial designed to assess the feasibility of conducting a three-arm randomised controlled trial of five 90-minute sessions of PM+, delivered individually or in groups, with 105 participants randomised 1 : 1 : 1 to individual PM+, group PM+ or a control intervention. Primary health outcomes were anxiety and depressive symptoms at 3 months; other outcomes included post-traumatic stress disorder symptoms, quality of life, progress with identified goals and service use.FindingsWe demonstrated that the form and content of PM+ could be adapted to meet the needs of asylum seekers and refugees. Twelve people with lived experience of the asylum process were successfully trained as lay therapists to deliver this targeted, low-intensity psychosocial intervention in local asylum seeker and refugee communities. The pilot trial was affected by governance issues. It began in December 2019 and was cut short by the COVID-19 pandemic. We were not able to complete recruitment and follow-up as planned; 11 out of 105 (10%) participants were recruited to the pilot trial (individual PM+,n = 4; group PM+,n = 3; control,n = 4); 8 out of 11 participants were followed up at 13 weeks and 7 out of 11 participants were followed up at 26 weeks. (Preliminary data were gathered on recruitment and retention, intervention fidelity and acceptability of study measures, including service use measures.)LimitationsProtracted delays due to governance issues, followed by the COVID-19 pandemic, meant that we were unable to complete the pilot trial or to provide evidence regarding the feasibility of group PM+. The complexities of working with multiple languages and cultural groups were noted. There were mixed views on how successful PM+ might prove, and we had insufficient evidence to provide clear conclusions.Future workFuture research could explore how technology can be used to improve the acceptability, feasibility, efficacy and potential cost-effectiveness of scalable mental health interventions and well-being support for distressed asylum seekers and refugees. The use of mobile phone and/or app-based forms of support may help to increase asylum seekers’ and refugees’ willingness to engage in research of this type.ConclusionsAlthough it was not possible to specify the parameters for a full randomised controlled trial of PM+ for asylum seekers and refugees in the UK, our findings offer guidance on strategies that may be of value in future studies of this nature.Trial registrationThis trial is registered as ISRCTN15214107.FundingThis project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full inPublic Health Research; Vol. 10, No. 10. See the NIHR Journals Library website for further project information.

Introduction The emergence and rapid spread of COVID-19 have caused widespread and catastrophic public health and economic impact, requiring governments to restrict societal activity to reduce the spread of the disease. The role of household transmission in the population spread of SARS-CoV-2, and of host immunity in limiting transmission, is poorly understood. This paper describes a protocol for a prospective observational study of a cohort of households in Liverpool City Region, UK, which addresses the transmission of SARS-CoV-2 between household members and how immunological response to the infection changes over time. Methods and analysis Households in the Liverpool City Region, in which members have not previously tested positive for SARS-CoV-2 with a nucleic acid amplification test, are followed up for an initial period of 12 weeks. Participants are asked to provide weekly self-throat and nasal swabs and record their activity and presence of symptoms. Incidence of infection and household secondary attack rates of COVID-19 are measured. Transmission of SARS-CoV-2 will be investigated against a range of demographic and behavioural variables. Blood and faecal samples are collected at several time points to evaluate immune responses to SARS-CoV-2 infection and prevalence and risk factors for faecal shedding of SARS-CoV-2, respectively. Ethics and dissemination The study has received approval from the National Health Service Research Ethics Committee; REC Reference: 20/HRA/2297, IRAS Number: 283 464. Results will be disseminated through scientific conferences and peer-reviewed open access publications. A report of the findings will also be shared with participants. The study will quantify the scale and determinants of household transmission of SARS-CoV-2. Additionally, immunological responses before and during the different stages of infection will be analysed, adding to the understanding of the range of immunological response by infection severity.

Using variable diabetic retinopathy screening intervals, informed by personal risk levels, offers improved engagement of people with diabetes and reallocation of resources to high-risk groups, while addressing the increasing prevalence of diabetes. However, safety data on extending screening intervals are minimal. The aim of this study was to evaluate the safety and cost-effectiveness of individualised, variable-interval, risk-based population screening compared with usual care, with wide-ranging input from individuals with diabetes. This was a two-arm, parallel-assignment, equivalence RCT (minimum 2 year follow-up) in individuals with diabetes aged 12 years or older registered with a single English screening programme. Participants were randomly allocated 1:1 at baseline to individualised screening at 6, 12 or 24 months for those at high, medium and low risk, respectively, as determined at each screening episode by a risk-calculation engine using local demographic, screening and clinical data, or to annual screening (control group). Screening staff and investigators were observer-masked to allocation and interval. Data were collected within the screening programme. The primary outcome was attendance (safety). A secondary safety outcome was the development of sight-threatening diabetic retinopathy. Cost-effectiveness was evaluated within a 2 year time horizon from National Health Service and societal perspectives. A total of 4534 participants were randomised. After withdrawals, there were 2097 participants in the individualised screening arm and 2224 in the control arm. Attendance rates at first follow-up were equivalent between the two arms (individualised screening 83.6%; control arm 84.7%; difference −1.0 [95% CI −3.2, 1.2]), while sight-threatening diabetic retinopathy detection rates were non-inferior in the individualised screening arm (individualised screening 1.4%, control arm 1.7%; difference −0.3 [95% CI −1.1, 0.5]). Sensitivity analyses confirmed these findings. No important adverse events were observed. Mean differences in complete case quality-adjusted life-years (EuroQol Five-Dimension Questionnaire, Health Utilities Index Mark 3) did not significantly differ from zero; multiple imputation supported the dominance of individualised screening. Incremental cost savings per person with individualised screening were £17.34 (95% CI 17.02, 17.67) from the National Health Service perspective and £23.11 (95% CI 22.73, 23.53) from the societal perspective, representing a 21% reduction in overall programme costs. Overall, 43.2% fewer screening appointments were required in the individualised arm. Stakeholders involved in diabetes care can be reassured by this study, which is the largest ophthalmic RCT in diabetic retinopathy screening to date, that extended and individualised, variable-interval, risk-based screening is feasible and can be safely and cost-effectively introduced in established systematic programmes. Because of the 2 year time horizon of the trial and the long time frame of the disease, robust monitoring of attendance and retinopathy rates should be included in any future implementation. ISRCTN 87561257 The study was funded by the UK National Institute for Health Research.

Background Insertion of a ventriculoperitoneal shunt to treat hydrocephalus is one of the most common neurosurgical procedures worldwide. Shunt infection affects up to 15% of patients, resulting in long hospital stays, multiple surgeries and reduced cognition and quality of life. Objectives The aim of this trial was to determine whether or not antibiotic-impregnated ventriculoperitoneal shunts (hereafter referred to as antibiotic shunts) (e.g. impregnated with rifampicin and clindamycin) or silver-impregnated ventriculoperitoneal shunts (hereafter referred to as silver shunts) reduce infection compared with standard ventriculoperitoneal shunts (hereafter referred to as standard shunts). Design This was a three-arm, superiority, multicentre, parallel-group randomised controlled trial. Patients and a central primary outcome review panel, but not surgeons or operating staff, were blinded to the type of ventriculoperitoneal shunt inserted. Setting The trial was set in 21 neurosurgical wards across the UK and the Republic of Ireland. Participants Participants were patients with hydrocephalus of any aetiology who were undergoing insertion of their first ventriculoperitoneal shunt. Interventions Participants were allocated 1 : 1 : 1 by pressure-sealed envelope to receive a standard non-impregnated, silver-impregnated or antibiotic-impregnated ventriculoperitoneal shunt at the time of insertion. Ventriculoperitoneal shunts are medical devices, and were used in accordance with the manufacturer’s instructions for their intended purpose. Main outcome measures The primary outcome was time to ventriculoperitoneal shunt failure due to infection. Secondary outcomes were time to failure for any cause, reason for failure (infection, mechanical), types of ventriculoperitoneal shunt infection, rate of infection after first clean (non-infected) revision and health economics. Outcomes were analysed by intention to treat. Results Between 26 June 2013 and 9 October 2017, 1605 patients from neonate to 91 years of age were randomised to the trial: n = 36 to the standard shunt, n = 538 to the antibiotic shunt and n = 531 to the silver shunt. Patients who did not receive a ventriculoperitoneal shunt ( n = 4) or who had an infection at the time of insertion ( n = 7) were not assessed for the primary outcome. Infection occurred in 6.0% ( n = 32/533) of those who received the standard shunt, in 2.2% ( n = 12/535) of those who received the antibiotic shunt and in 5.9% ( n = 31/526) of those who received the silver shunt. Compared with the standard shunt, antibiotic shunts were associated with a lower rate of infection (cause-specific hazard ratio 0.38, 97.5% confidence interval 0.18 to 0.80) and a decreased probability of infection (subdistribution hazard ratio 0.38, 97.5% confidence interval 0.18 to 0.80). Silver shunts were not associated with a lower rate of infection than standard shunts (cause-specific hazard ratio 0.99, 97.5% confidence interval 0.56 to 1.74). The ventriculoperitoneal shunt failure rate attributable to any cause was 25.0% overall and did not differ between arms. Antibiotic shunts save £135,753 per infection avoided. There were no serious adverse events. Limitations It was not possible to blind treating neurosurgeons to the ventriculoperitoneal shunt type. The return rate for patient-reported outcomes was low. Limitations to the economic evaluation included failure to obtain Hospital Episode Statistics data from NHS Digital, as per protocol. Reliance on patient-level information and costing systems data mitigated these limitations. Conclusions Antibiotic shunts have a reduced infection rate compared with standard shunts, whereas silver shunts do not. Antibiotic shunts are cost-saving. Future work A sample collection has been established that will enable the study of surrogate markers of ventriculoperitoneal shunt infection in cerebrospinal fluid or blood using molecular techniques. A post hoc analysis to study factors related to shunt failure will be performed as part of a future study. An impact analysis to assess change in practice is planned. Trial registration Current Controlled Trials ISRCTN49474281. 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. 24, No. 17. See the NIHR Journals Library website for further project information.

Background Clinical trials show that antimicrobial-impregnated central venous catheters reduce catheter-related bloodstream infection in adults and children receiving intensive care, but there is insufficient evidence for use in newborn babies. Objectives The objectives were (1) to determine clinical effectiveness by conducting a randomised controlled trial comparing antimicrobial-impregnated peripherally inserted central venous catheters with standard peripherally inserted central venous catheters for reducing bloodstream or cerebrospinal fluid infections (referred to as bloodstream infections); (2) to conduct an economic evaluation of the costs, cost-effectiveness and value of conducting additional research; and (3) to conduct a generalisability analysis of trial findings to neonatal care in the NHS. Design Three separate studies were undertaken, each addressing one of the three objectives. (1) This was a multicentre, open-label, pragmatic randomised controlled trial; (2) an analysis was undertaken of hospital care costs, lifetime cost-effectiveness and value of information from an NHS perspective; and (3) this was a retrospective cohort study of bloodstream infection rates in neonatal units in England. Setting The randomised controlled trial was conducted in 18 neonatal intensive care units in England. Participants Participants were babies who required a peripherally inserted central venous catheter (of 1 French gauge in size). Interventions The interventions were an antimicrobial-impregnated peripherally inserted central venous catheter (coated with rifampicin–miconazole) or a standard peripherally inserted central venous catheter, allocated randomly (1 : 1) using web randomisation. Main outcome measure Study 1 – time to first bloodstream infection, sampled between 24 hours after randomisation and 48 hours after peripherally inserted central venous catheter removal. Study 2 – cost-effectiveness of the antimicrobial-impregnated peripherally inserted central venous catheter compared with the standard peripherally inserted central venous catheters. Study 3 – risk-adjusted bloodstream rates in the trial compared with those in neonatal units in England. For study 3, the data used were as follows: (1) case report forms and linked death registrations; (2) case report forms and linked death registrations linked to administrative health records with 6-month follow-up; and (3) neonatal health records linked to infection surveillance data. Results Study 1, clinical effectiveness – 861 babies were randomised (antimicrobial-impregnated peripherally inserted central venous catheter, n = 430; standard peripherally inserted central venous catheter, n = 431). Bloodstream infections occurred in 46 babies (10.7%) randomised to antimicrobial-impregnated peripherally inserted central venous catheters and in 44 (10.2%) babies randomised to standard peripherally inserted central venous catheters. No difference in time to bloodstream infection was detected (hazard ratio 1.11, 95% confidence interval 0.73 to 1.67; p = 0.63). Secondary outcomes of rifampicin resistance in positive blood/cerebrospinal fluid cultures, mortality, clinical outcomes at neonatal unit discharge and time to peripherally inserted central venous catheter removal were similar in both groups. Rifampicin resistance in positive peripherally inserted central venous catheter tip cultures was higher in the antimicrobial-impregnated peripherally inserted central venous catheter group (relative risk 3.51, 95% confidence interval 1.16 to 10.57; p = 0.02) than in the standard peripherally inserted central venous catheter group. Adverse events were similar in both groups. Study 2, economic evaluation – the mean cost of babies’ hospital care was £83,473. Antimicrobial-impregnated peripherally inserted central venous catheters were not cost-effective. Given the increased price, compared with standard peripherally inserted central venous catheters, the minimum reduction in risk of bloodstream infection for antimicrobial-impregnated peripherally inserted central venous catheters to be cost-effective was 3% and 15% for babies born at 23–27 and 28–32 weeks’ gestation, respectively. Study 3, generalisability analysis – risk-adjusted bloodstream infection rates per 1000 peripherally inserted central venous catheter days were similar among babies in the trial and in all neonatal units. Of all bloodstream infections in babies receiving intensive or high-dependency care in neonatal units, 46% occurred during peripherally inserted central venous catheter days. Limitations The trial was open label as antimicrobial-impregnated and standard peripherally inserted central venous catheters are different colours. There was insufficient power to determine differences in rifampicin resistance. Conclusions No evidence of benefit or harm was found of peripherally inserted central venous catheters impregnated with rifampicin–miconazole during neonatal care. Interventions with small effects on bloodstream infections could be cost-effective over a child’s life course. Findings were generalisable to neonatal units in England. Future research should focus on other types of antimicrobial impregnation of peripherally inserted central venous catheters and alternative approaches for preventing bloodstream infections in neonatal care. Trial registration Current Controlled Trials ISRCTN81931394. Funding This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 57. See the NIHR Journals Library website for further project information.

BACKGROUND In the UK, juvenile idiopathic arthritis is the most common inflammatory disorder in childhood, affecting 10 : 100,000 children and young people aged < 16 years each year, with a population prevalence of around 1 : 1000. Corticosteroids are commonly used to treat juvenile idiopathic arthritis; however, there is currently a lack of consensus as to which corticosteroid induction regimen should be used with various disease subtypes and severities of juvenile idiopathic arthritis. OBJECTIVE The main study objective was to determine the feasibility of conducting a randomised controlled trial to compare the different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis. DESIGN This was a mixed-methods study. Work packages included a literature review; qualitative interviews with children and young people with juvenile idiopathic arthritis and their families; a questionnaire survey and screening log to establish current UK practice; a consensus meeting with health-care professionals, children and young people with juvenile idiopathic arthritis, and their families to establish the primary outcome; a feasibility study to pilot data capture and to collect data for future sample size calculations; and a final consensus meeting to establish the final protocol. SETTING The setting was rheumatology clinics across the UK. PARTICIPANTS Children, young people and their families who attended clinics and health-care professionals took part in this mixed-methods study. INTERVENTIONS This study observed methods of prescribing corticosteroids across the UK. MAIN OUTCOME MEASURES The main study outcomes were the acceptability of a future trial for children, young people, their families and health-care professionals, and the feasibility of delivering such a trial. RESULTS Qualitative interviews identified differences in the views of children, young people and their families on a randomised controlled trial and potential barriers to recruitment. A total of 297 participants were screened from 13 centres in just less than 6 months. In practice, all routes of corticosteroid administration were used, and in all subtypes of juvenile idiopathic arthritis. Intra-articular corticosteroid injection was the most common treatment. The questionnaire surveys showed the varying clinical practice across the UK, but established intra-articular corticosteroids as the treatment control for a future trial. The primary outcome of choice for children, young people, their families and health-care professionals was the Juvenile Arthritis Disease Activity Score, 71-joint count. However, results from the feasibility study showed that, owing to missing blood test data, the clinical Juvenile Arthritis Disease Activity Score should be used. The Juvenile Arthritis Disease Activity Score, 71-joint count, and the clinical Juvenile Arthritis Disease Activity Score are composite disease activity scoring systems for juvenile arthritis. Two final trial protocols were established for a future randomised controlled trial. LIMITATIONS Fewer clinics were included in this feasibility study than originally planned, limiting the ability to draw strong conclusions about these units to take part in future research. CONCLUSIONS A definitive randomised controlled trial is likely to be feasible based on the findings from this study; however, important recommendations should be taken into account when planning such a trial. FUTURE WORK This mixed-methods study has laid down the foundations to develop the evidence base in this area and conducting a randomised control trial to compare different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis is likely to be feasible. STUDY REGISTRATION Current Controlled Trials ISRCTN16649996. 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. 24, No. 36. See the NIHR Journals Library website for further project information.

Background: Printed participant information about trials is often technical, long and difficult to navigate. Optimisation and user testing can improve information materials, and may improve participant understanding and rates of recruitment. Methods: A study within a trial (SWAT) was undertaken within the ISDR trial. Potential participants in the ISDR trial were randomised to receive either the standard trial information or revised information that had been optimised through information design and user testing. Results: A total of 3,169 patients were randomised in the SWAT. Recruitment rates to the ISDR trial were 25.3% in the optimised information group and 26.1% in the standard information group (odds ratio 0.951; 95% CI 0.752 to 1.201; p=0.672). Clinic attendance rates were 71.6% in the optimised information group and 69.3% in the standard information group (OR 1.145; 95% CI 0.885 to 1.480; p=0.304). Conclusions: Optimisation of participant information through information design and user testing did not affect rate of recruitment to the host ISDR trial. Registration: ISRCTN ID ISRCTN87561257 ; registered on 08 May 2014.

Background Juvenile idiopathic arthritis (JIA) is an umbrella term for seven relapsing-remitting inflammatory conditions in children and young people (CYP). Early, intensive treatment can prevent long-term damage; however, established drugs exhibit a delayed response, prompting the need for rapid-onset treatment in the form of corticosteroids. Given a lack of consensus as to which corticosteroid induction regimen should be used for CYP with JIA, a feasibility trial of different regimens is needed. Objectives The aim was to achieve consensus among CYP, families, and healthcare professionals (HCPs) about the primary outcome measures and protocol components to include in a prospective feasibility study. Methods A modified Nominal Group Technique was used to achieve consensus on the most appropriate primary outcome measure to be included in a prospective feasibility study, in addition to other protocol components such as inclusion/exclusion criteria. Fifteen participants participated in the process, including a combination of CYP with JIA, families (n=9) and HCPs (n=6). Results In the first vote, participants agreed that ‘Juvenile Arthritis Disease Activity Score (JADAS)’ and ‘Physician Global Assessment Score’ were most meaningful. During sub-group discussions, the need for a composite score which captured the voice of CYP and families was emphasised. In the second vote, ‘JADAS’ and the ‘JIA Core Set’ were identified as the most important. Further discussions led to the results of the third vote, agreeing ‘JADAS’ as the primary outcome measure of choice being measured at 6 weeks after commencement of treatment. The majority of HCPs, CYP and families voted for all JIA sub-types to be included in a prospective feasibility study, with some queries about the inclusion of systemic JIA given its unique presentation. Participants also identified the need for more frequent data collection time points to capture the rapid onset of corticosteroid action, while CYP and families opted for accessible mechanisms for participation, such as digital follow-up strategies. Conclusion It is feasible to include CYP, families and HCPs in synthesising complex concepts to agree by consensus the design components of clinical research. The primary outcome measure for inclusion in a prospective feasibility study of corticosteroid regimens in CYP with JIA was co-prioritised, with CYP and families taking a leading role in the ultimate selection of an appropriate outcome measure and other study protocol components. Using consensus methods with CYP, families and HCPs is a systematic and rigorous way in which to select outcome measures that are both meaningful and relevant to everyone involved in the care and treatment of CYP with JIA. References [1] Sherratt F, et al. Family perspectives on the feasibility of a corticosteroid induction regimen trial in juvenile idiopathic arthritis. In: International Clinical Trials Methodology Conference: 2017; Liverpool, UK: Trials; 2017 Acknowledgement This consensus meeting was funded as part of the SIRJIA study, funded by the NIHR Health Technology Assessment Programme (14/167/01). The funders did not have a role in the design, collection, analysis, or interpretation of the data Disclosure of Interests Simon Stones Consultant for: SS has provided consultancy services to Envision Pharma Group, though this is not related to the contents of this abstract., Speakers bureau: SS has undertaken speaking engagements for Actelion, eyeforpharma, Four Health, Janssen and Roche, though these are not related to the contents of this abstract., Heather Bagley: None declared, Ashley Jones: None declared, Flora McErlane: None declared, Tracy Moitt: None declared, Gloria Nkhoma: None declared, Frances Sherratt: None declared, Bridget Young: None declared, Michael Beresford: None declared, Eileen Baildam Consultant for: EB has received one paid consultancy for Pfizer in the last 12 months, but this was not related to this study.

Introduction Currently, all people with diabetes (PWD) aged 12 years and over in the UK are invited for screening for diabetic retinopathy (DR) annually. Resources are not increasing despite a 5% increase in the numbers of PWD nationwide each year. We describe the rationale, design and methodology for a randomised controlled trial (RCT) evaluating the safety, acceptability and cost-effectiveness of personalised variable-interval risk-based screening for DR. This is the first randomised trial of personalised screening for DR and the largest ophthalmic RCT in the UK. Methods and analysis PWD attending seven screening clinics in the Liverpool Diabetic Eye Screening Programme were recruited into a single site RCT with a 1:1 allocation to individualised risk-based variable-interval or annual screening intervals. A risk calculation engine developed for the trial estimates the probability that an individual will develop referable disease (screen positive DR) within the next 6, 12 or 24 months using demographic, retinopathy and systemic risk factor data from primary care and screening programme records. Dynamic, secure, real-time data connections have been developed. The primary outcome is attendance for follow-up screening. We will test for equivalence in attendance rates between the two arms. Secondary outcomes are rates and severity of DR, visual outcomes, cost-effectiveness and health-related quality of life. The required sample size was 4460 PWD. Recruitment is complete, and the trial is in follow-up. Ethics and dissemination Ethical approval was obtained from National Research Ethics Service Committee North West – Preston, reference 14/NW/0034. Results will be presented at international meetings and published in peer-reviewed journals. This pragmatic RCT will inform screening policy in the UK and elsewhere. Trial registration number ISRCTN87561257 ; Pre-results.

Abstract Background Background Corticosteroids (CS) are widely used for rapid-action or induction treatment in children and young people (CYP) with juvenile idiopathic arthritis (JIA). Given a lack of evidence base on CS induction regimen for CYP with JIA, and since criteria for choosing CS are based on healthcare professional (HCP) preference, further research is needed (1). Methods A national electronic survey was undertaken among HCPs across the UK as part of the Steroid Induction Regimen for Juvenile Idiopathic Arthritis (SIRJIA) study. We aimed to establish the opinions of HCPs current practice regarding the clinical criteria for commencing CS treatment Results A total of 39 (24%) responses were received from 162 HCPs. These included 22 (56%) NHS consultants, five (13%) grid trainees, eight (21%) clinical nurse specialists and four other HCPs (10%). The most common treatments newly diagnosed JIA or a disease flare were intra-articular IACS or a combination of DMARDs and IAS (except for systemic JIA and oligoarticular JIA). The majority of HCPs 17 would treat new and flaring CYP the same with 53% choosing a different regime or not answering. The key criteria HCPs used for commencing CS and choosing route of administration were rapid induction of remission (31 (89%)), high disease activity (31 (89%)), severity of systemic JIA (30 (86%)) and level of inflammation (28 (80%)), see Table 1. The main determinants of route of administration was disease severity disease subtype. The majority of HCPs (52-72%) would consider entering CYP with JIA into a trial randomising to modes of administration. P14 Table 1 Reasons of CS Choice Number N = 39 Percentage % High Disease Activity 35 89.7 Rapid induction of remission 34 87.18 Severity of Systemic JIA 34 87.18 Level of inflammation 32 82.5 Severe Uveitis 30 76.92 JIA subtype 27 68.21 Targeting Specific Joints 26 66.67 Level of Disability 18 46.15 Level of pain 16 41.03 Long-standing Disease 11 28.1 Patient reluctance to take DMARDS 8 20.5 Conclusion The results from this national survey of clinical practice showed varying practices in the management of new CYP with JIA and those that are flaring. The majority of HCPs who completed this survey, indicated that they would be prepared to consider entering CYP into a trial that randomised to the four CS delivery methods. Conflicts of Interest The authors declare no conflicts of interest.

Juvenile idiopathic arthritis (JIA) is an umbrella term for seven relapsing-remitting inflammatory conditions in children and young people (CYP). Early, intensive treatment can prevent long-term damage; however, established drugs exhibit a delayed response, prompting the need for rapid-onset treatment in the form of corticosteroids. Given a lack of consensus as to which corticosteroid induction regimen should be used for CYP with JIA, a feasibility trial of different regimens is needed. The aim was to achieve consensus among CYP, families, and healthcare professionals (HCPs) about the primary outcome measures and protocol components to include in a prospective feasibility study. A modified Nominal Group Technique was used to achieve consensus on the most appropriate primary outcome measure to be included in a prospective feasibility study, in addition to other protocol components such as inclusion/exclusion criteria. Fifteen participants participated in the process, including a combination of CYP with JIA, families (n = 9) and HCPs (n = 6). In the first vote, participants agreed that Juvenile Arthritis Disease Activity Score (JADAS) and Physician Global Assessment Score were most meaningful. During sub-group discussions, the need for a composite score which captured the voice of CYP and families was emphasised. In the second vote, JADAS and the JIA Core Set were identified as the most important. Further discussions led to the results of the third vote, agreeing JADAS as the primary outcome measure of choice being measured at 6 weeks after commencement of treatment. The majority of HCPs, CYP and families voted for all JIA sub-types to be included in a prospective feasibility study, with some queries about the inclusion of systemic JIA given its unique presentation. Participants also identified the need for more frequent data collection time points to capture the rapid onset of corticosteroid action, while CYP and families opted for accessible mechanisms for participation, such as digital follow-up strategies. It is feasible to include CYP, families and HCPs in synthesising complex concepts to agree by consensus the design components of clinical research. The primary outcome measure for inclusion in a prospective feasibility study of corticosteroid regimens in CYP with JIA was co-prioritised, with CYP and families taking a leading role in the ultimate selection of an appropriate outcome measure and other study protocol components. Using consensus methods with CYP, families and HCPs is a systematic and rigorous way in which to select outcome measures that are both meaningful and relevant to everyone involved in the care and treatment of CYP with JIA. The authors declare no conflicts of interest.

BACKGROUND:Impregnated central venous catheters (CVCs) are recommended for adults to reduce bloodstream infection (BSI) but not for children. OBJECTIVE:To determine the effectiveness of impregnated compared with standard CVCs for reducing BSI in children admitted for intensive care. DESIGN:Multicentre randomised controlled trial, cost-effectiveness analysis from a NHS perspective and a generalisability analysis and cost impact analysis. SETTING:14 English paediatric intensive care units (PICUs) in England. PARTICIPANTS:Children aged < 16 years admitted to a PICU and expected to require a CVC for ≥ 3 days. INTERVENTIONS:Heparin-bonded, antibiotic-impregnated (rifampicin and minocycline) or standard polyurethane CVCs, allocated randomly (1 : 1 : 1). The intervention was blinded to all but inserting clinicians. MAIN OUTCOME MEASURE:Time to first BSI sampled between 48 hours after randomisation and 48 hours after CVC removal. The following data were used in the trial: trial case report forms; hospital administrative data for 6 months pre and post randomisation; and national-linked PICU audit and laboratory data. RESULTS:In total, 1859 children were randomised, of whom 501 were randomised prospectively and 1358 were randomised as an emergency; of these, 984 subsequently provided deferred consent for follow-up. Clinical effectiveness - BSIs occurred in 3.59% (18/502) of children randomised to standard CVCs, 1.44% (7/486) of children randomised to antibiotic CVCs and 3.42% (17/497) of children randomised to heparin CVCs. Primary analyses comparing impregnated (antibiotic and heparin CVCs) with standard CVCs showed no effect of impregnated CVCs [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.37 to 1.34]. Secondary analyses showed that antibiotic CVCs were superior to standard CVCs (HR 0.43, 95% CI 0.20 to 0.96) but heparin CVCs were not (HR 1.04, 95% CI 0.53 to 2.03). Time to thrombosis, mortality by 30 days and minocycline/rifampicin resistance did not differ by CVC. Cost-effectiveness - heparin CVCs were not clinically effective and therefore were not cost-effective. The incremental cost of antibiotic CVCs compared with standard CVCs over a 6-month time horizon was £1160 (95% CI -£4743 to £6962), with an incremental cost-effectiveness ratio of £54,057 per BSI avoided. There was considerable uncertainty in costs: antibiotic CVCs had a probability of 0.35 of being dominant. Based on index hospital stay costs only, antibiotic CVCs were associated with a saving of £97,543 per BSI averted. The estimated value of health-care resources associated with each BSI was £10,975 (95% CI -£2801 to £24,751). Generalisability and cost-impact - the baseline risk of BSI in 2012 for PICUs in England was 4.58 (95% CI 4.42 to 4.74) per 1000 bed-days. An estimated 232 BSIs could have been averted in 2012 using antibiotic CVCs. The additional cost of purchasing antibiotic CVCs for all children who require them (£36 per CVC) would be less than the value of resources associated with managing BSIs in PICUs with standard BSI rates of > 1.2 per 1000 CVC-days. CONCLUSIONS:The primary outcome did not differ between impregnated and standard CVCs. However, antibiotic-impregnated CVCs significantly reduced the risk of BSI compared with standard and heparin CVCs. Adoption of antibiotic-impregnated CVCs could be beneficial even for PICUs with low BSI rates, although uncertainty remains whether or not they represent value for money to the NHS. Limitations - inserting clinicians were not blinded to allocation and a lower than expected event rate meant that there was limited power for head-to-head comparisons of each type of impregnation. Future work - adoption of impregnated CVCs in PICUs should be considered and could be monitored through linkage of electronic health-care data and clinical data on CVC use with laboratory surveillance data on BSI. TRIAL REGISTRATION:ClinicalTrials.gov NCT01029717. FUNDING:This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 18. See the NIHR Journals Library website for further project information.

ISDR is a 5 year NIHR funded programme of applied research aiming to introduce a step-change in screening for sight threatening diabetic retinopathy utilising personalised risk based intervals. The research programme includes a Randomised Controlled Trial (RCT) to assess the validity of these intervals. The RCT aims to recruit 4400 participants from a pool of 18,000 subjects in Liverpool. Due to the size of the cohort and that much of the data required for the study is collected routinely in multiple NHS organisations, the RCT relies heavily on the integration of multiple databases/data sources and automated systems across multiple networks to reduce the workload on the study team and medical practitioners and to maintain data quality. Data for the RCT is obtained from the following systems: EMIS Web (GP Data), OptoMize (screening software provided by Digital Healthcare), OpenClinica (study database), randomisation system (bespoke system), risk engine (a bespoke application to calculate personalised screening intervals) and a record of those subjects who have consented for their data to be used by the ISDR programme. This paper will present the processes and solutions undertaken to automate, test and validate the import/export of data, create bespoke systems to clean these data and integrate the different data sources. Thereby ensuring the timely transfer and format of data minimise the disruption to patient care while ensuring integrity of the trials data. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.