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Background Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting UK general practices. Participants Children aged 1–12 years with acute uncomplicated lower respiratory tract infections. Outcomes The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2–4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child’s cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when ‘necessary’, and clinicians noted a reduction in parents’ expectations for antibiotics. Limitations The study was underpowered to detect small benefits in key subgroups. Conclusion Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child’s illness and safety-netting. Future work The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration This trial is registered as ISRCTN79914298. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information. Plain language summary Background Children are commonly prescribed antibiotics for chest infections, but such infections are becoming resistant to antibiotics, and it is not clear if antibiotics work in treating them. Methods A total of 432 children who saw their general practitioner with a chest infection were given either an antibiotic (amoxicillin) or a placebo (no antibiotic) for 7 days. Symptom diaries documented the infection’s duration and its side effects. Children not in the placebo study were able to participate in another study that documented the same outcomes (an ‘observational study’). We interviewed parents, doctors and nurses about their observations and concerns. Our patient and public involvement and engagement work with parents indicated that a 3-day symptom reduction was required to justify giving antibiotics. Results After seeing the doctor, parents whose children received antibiotics rated infective symptoms as moderately bad or worse for 5 days, and parents whose children received the placebo rated these for 6 days. Side effects and complications were similar in the two groups. Findings were similar when including the results of the observational study, and for children in whose chest the doctor could hear wheeze or rattles; who had fever; who were rated by the doctor as more unwell, who were short of breath, or who had had bacteria detected in the throat. The costs to the NHS per child were similar (antibiotics, £29; placebo, £26), and the wider costs to society were the same (antibiotics, £33; placebo, £33). Parents found it difficult to interpret their child’s symptoms, and commonly used the sound of the cough to judge severity. Parents commonly consulted to receive an examination and reassurance, and accepted that antibiotics should be used only when ‘necessary’. Clinicians noted a reduction in parents’ expectations for antibiotics. Conclusion Amoxicillin for chest infections in children is unlikely to be effective. General practitioners should support parents to self-manage at home and give clear communication about when and how to seek medical help if they continue to be concerned. Scientific summary Background Antimicrobial resistance (AMR) is a global public health threat. Antibiotics are very commonly prescribed for children presenting with uncomplicated lower respiratory tract infection, but there is little randomised evidence of the effectiveness of antibiotics for treating these, either overall or among key clinical subgroups. Objective The objective was to undertake a trial of antibiotics for children presenting with lower respiratory tract infection in primary care, with a parallel observational study. Aims The aims were to: 1.estimate the effectiveness of amoxicillin overall and in key clinical subgroups of children presenting with uncomplicated (non-pneumonic) lower respiratory tract infection in primary care 2.estimate the cost-effectiveness of antibiotics overall in children presenting with uncomplicated (non-pneumonic) lower respiratory tract infection in primary care 3.explore the estimates of effectiveness according to key pathophysiological subgroups (the presence of bacterial pathogens) 4.explore which variables predict poor prognosis and develop a prediction model for poor prognosis 5.explore the views of parents and clinicians regarding management of children and participation in the trial. Design This was a placebo-controlled trial with qualitative research and health economic analysis, and a parallel observational cohort. Setting UK general practices. Participants Participants were children aged between 6 months and 12 years presenting to primary care with an acute lower respiratory tract infection, defined as one in which an acute cough is the predominant symptom and judged by the general practitioner (GP) to be infective in origin, lasting < 21 days, and with other symptoms or signs localising to the lower respiratory tract (shortness of breath, sputum, pain), and in whom pneumonia was not suspected clinically. Outcomes The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). The secondary outcomes were symptom severity on days 2–4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; progression of illness sufficient to require hospital assessment; side effects; and resource use. Ethics The protocol was approved by the South West – Central Bristol Research Ethics Committee (reference 15/SW/0300). Methods Children were randomised to receive 50 mg/kg/day oral amoxicillin in divided doses for 7 days, or placebo, using pre-prepared packs randomised by an independent statistician using computer-generated random numbers. Children whom clinicians were unwilling to randomise or parents who were unwilling for their child to be randomised were invited to participate in an observational study in which the same data as in the trial were collected. The revised target sample size (agreed with the Trial Steering Committee, the Data Monitoring and Ethics Committee and the funder) to detect an important clinical difference of 3 days in symptoms duration was 298 participants for 80% power and 398 participants for 90% power. Semistructured interviews were used to explore the views of management and the decisions to participate in the trial. Parents were purposefully sampled by whether they took part in the trial or the observational study, and by practice. Clinicians who recruited participants into the study were also invited to take part in a telephone interview. The interviews were analysed using thematic analysis. Throat swabs were analysed for the presence of bacteria and viruses by multiplex polymerase chain reaction. Statistical analysis Cox regression was used for the primary outcome and for total symptom duration, adjusting for age, baseline symptom severity, prior duration of illness and comorbidity. Linear regression was used for symptom severity, and logistic regression was used for reconsultation, progression of illness and side effects, adjusting for the same baseline covariates as in the primary analysis. Analysis was by intention to treat, as randomised regardless of non-adherence or protocol deviations. Multiple imputation was used as the primary analysis, comprising all variables from the analysis model and any predictors of missingness, and using 100 imputations. Prespecified subgroup analyses were carried out on chest signs, sputum/rattly chest, history of fever, physician rating of unwell, shortness of breath, oxygen saturation below 95%, and STARWAVe clinical prediction rule for hospitalisation. For the observational data set, stratification by propensity scores was used to control for confounding by indication, and the data were merged with the trial data set to facilitate more powerful analyses. A logistic regression model was built to predict the progression of illness, and discrimination was assessed using estimates of area under the receiver operator curve that were bootstrapped for internal validation. Health economic analysis Both cost-effectiveness (in GBP per unit of primary outcome) and cost per quality-adjusted life-year (QALY) were estimated. The base case took an NHS perspective, but some non-NHS costs were also included (remedies and time off work). Resource use data were collected by a notes review in primary care supplemented by the diary. Unit costs of primary care consultation, community services, outpatient visits and accident and emergency attendances were costed based on the Personal Social Services Research Unit. National reference costs were used to cost hospital stay based on corresponding diagnostic categories. Medications were priced based on the British National Formulary. All costs were based on 2019 prices. QALYs were based on the EQ-5D-Y (EuroQol-5 Dimensions Youth), collected weekly, and on the recommended national tariff. Trial results A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The duration of moderately bad symptoms was similar in the two groups [median 5 vs. 6 days, respectively; hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.90 to 1.42]. Return with new or worsening symptoms (29.7% vs. 38.2%; risk ratio 0.80, 95% CI 0.58 to 1.05), progression of illness requiring hospital assessment (2.4% vs 2.0%) and side effects (38% vs. 34%) were also similar in the two groups. A small difference in mean symptom severity on days 2–4 (1.8 vs. 2.1 points; difference 0.28 points, 95% CI 0.04 to 0.51) is unlikely to be clinically meaningful. No differences were seen for the primary outcome in the five prespecified clinical subgroups in which antibiotic prescribing is common: chest signs subgroup (antibiotics 6 days vs. placebo 6 days; HR 0.97, 95% CI 0.65 to 1.43), sputum/rattly chest (5 vs. 7 days; 1.16, 95% CI 0.83 to 1.64), fever (5 vs. 6 days; 1.23, 95% CI 0.88 to 1.73), physician rating of unwell (5 vs. 6 days; 1.25, 95% CI 0.85 to 1.83) and shortness of breath (5 vs. 6 days; 1.13, 95% CI 0.72 to 1.77). There was also no evidence that the presence of bacteria in the throat swab mediated antibiotic effectiveness. Estimates from complete cases (n = 317) were very similar, as were estimates from a per-protocol analysis for children taking 11 or more of the of 15 doses in the first 5 days. NHS costs per child were slightly higher with antibiotics (antibiotic, £29; placebo, £26) and non-NHS costs were the same (antibiotics, £33; placebo, £33), but QALY data were too incomplete for robust imputation. The incremental cost per QALY (incremental cost-effectiveness ratio) was £30,851 (95% CI –£73,639 to £109,429) based on estimates from the means of complete cases and £6417 (95% CI –£12,240 to £20,535) based on the estimates using imputed data. Observational study A total of 326 children were recruited to the observational study. The estimate of benefit of antibiotics for the primary outcome was similar to that in the trial (HR 1.16, 95% CI 0.95 to 1.41). A prognostic model to predict the progression of illness consisting of seven variables (baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.85) and calibration, and a three-item model (respiratory rate, oxygen saturation, sputum/rattly chest) also performed well (area under the receiver operator curve 0.81). Qualitative results Thirty semistructured telephone interviews were conducted with 16 parents and 14 clinicians. Parents found it difficult to interpret the symptoms and signs, and commonly used the sounds of the cough to judge severity, which highlights the need to provide better information to support parents. Many parents said that the main reason for consulting was to receive a clinical examination and reassurance regarding illness severity. Parents acknowledged that antibiotics should be used only when ‘necessary’, and many of the clinicians also noted a shift in parents’ expectations about antibiotics and that they were satisfied with a clinical assessment, reassurance and advice. Decisions to take part in the trial were influenced by the perceived risks associated with taking a placebo compared with immediate antibiotics, and with taking antibiotics unnecessarily. Clear communication about the self-management of their child’s illness and ‘safety-netting’ (information on the natural course of the illness and advice about when it might be necessary to reconsult) were identified as important when implementing ‘no antibiotic’ prescribing strategies to reassure parents and to support prescribing decisions. Limitations The study was underpowered to detect small benefits in the key clinical subgroups. The trial included children who were more unwell than those in recent large generalisable cohorts, which suggests that, if anything, the benefit of antibiotics has been overestimated. Given the very large numbers of missing data, the imputed estimates in the economic analysis must be viewed with caution. If the costs of AMR were included, then these estimates of cost-effectiveness would worsen. Conclusions Implications for clinical care Amoxicillin for uncomplicated chest infections in children makes little difference to symptom burden or to health or societal costs. Better access to information is needed to support parents’ decision-making, as is clear clinician communication about the self-management of their child’s illness and safety-netting. A prognostic score using variables that can be collected very easily during consultations can be used to identify children who are at low risk of illness progression. Implications for future research •The data can be incorporated in a Cochrane review and an individual patient data meta-analysis. •Further work on the incremental QALY gain from antibiotics is needed, assessing a range of models and their implications when imputing missing QALY data, and better evidence is needed about how to incorporate AMR resource implications in modelling. •The prognostic score should be externally validated and could be developed as an app with automated outputs, and thereafter used as a tool to reduce antibiotic prescribing for antimicrobial stewardship interventions. Trial registration This trial is registered as ISRCTN79914298. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.

Abstract Background Dental caries remains a significant public health problem, prevalence being linked to social and economic deprivation. Occlusal surfaces of first permanent molars are the most susceptible site in the developing permanent dentition. Cochrane reviews have shown pit and fissure sealants (PFS) and fluoride varnish (FV) to be effective over no intervention in preventing caries. However, the comparative cost and effectiveness of these treatments is uncertain. The primary aim of the trial described in this protocol is to compare the clinical effectiveness of PFS and FV in preventing dental caries in first permanent molars in 6-7 year-olds. Secondary aims include: establishing the costs and the relative cost-effectiveness of PFS and FV delivered in a community/school setting; examining the impact of PFS and FV on children and their parents/carers in terms of quality of life/treatment acceptability measures; and examining the implementation of treatment in a community setting. Methods/design The trial design comprises a randomised, assessor-blinded, two-arm, parallel group trial in 6–7 year old schoolchildren. Clinical procedures and assessments will be performed at 66 primary schools, in deprived areas in South Wales. Treatments will be delivered via a mobile dental clinic. In total, 920 children will be recruited (460 per trial arm). At baseline and annually for 36 months dental caries will be recorded using the International Caries Detection and Assessment System (ICDAS) by trained and calibrated dentists. PFS and FV will be applied by trained dental hygienists. The FV will be applied at baseline, 6, 12, 18, 24 and 30 months. The PFS will be applied at baseline and re-examined at 6, 12, 18, 24, and 30 months, and will be re-applied if the existing sealant has become detached/is insufficient. The economic analysis will estimate the costs of providing the PFS versus FV. The process evaluation will assess implementation and acceptability through acceptability scales, a schools questionnaire and interviews with children, parents, dentists, dental nurses and school staff. The primary outcome measure will be the proportion of children developing new caries on any one of up to four treated first permanent molars. Discussion The objectives of this study have been identified by the National Institute for Health Research as one of importance to the National Health Service in the UK. The results of this trial will provide guidance on which of these technologies should be adopted for the prevention of dental decay in the most susceptible tooth-surface in the most at risk children. Trial registrations ISRCTN ref: ISRCTN17029222 EudraCT: 2010-023476-23 UKCRN ref: 9273

Abstract Background Urinary tract infection (UTI) is common in children, and may cause serious illness and recurrent symptoms. However, obtaining a urine sample from young children in primary care is challenging and not feasible for large numbers. Evidence regarding the predictive value of symptoms, signs and urinalysis for UTI in young children is urgently needed to help primary care clinicians better identify children who should be investigated for UTI. This paper describes the protocol for the Diagnosis of Urinary Tract infection in Young children (DUTY) study. The overall study aim is to derive and validate a cost-effective clinical algorithm for the diagnosis of UTI in children presenting to primary care acutely unwell. Methods/design DUTY is a multicentre, diagnostic and prospective observational study aiming to recruit at least 7,000 children aged before their fifth birthday, being assessed in primary care for any acute, non-traumatic, illness of ≤ 28 days duration. Urine samples will be obtained from eligible consented children, and data collected on medical history and presenting symptoms and signs. Urine samples will be dipstick tested in general practice and sent for microbiological analysis. All children with culture positive urines and a random sample of children with urine culture results in other, non-positive categories will be followed up to record symptom duration and healthcare resource use. A diagnostic algorithm will be constructed and validated and an economic evaluation conducted. The primary outcome will be a validated diagnostic algorithm using a reference standard of a pure/predominant growth of at least >103, but usually >105 CFU/mL of one, but no more than two uropathogens. We will use logistic regression to identify the clinical predictors (i.e. demographic, medical history, presenting signs and symptoms and urine dipstick analysis results) most strongly associated with a positive urine culture result. We will then use economic evaluation to compare the cost effectiveness of the candidate prediction rules. Discussion This study will provide novel, clinically important information on the diagnostic features of childhood UTI and the cost effectiveness of a validated prediction rule, to help primary care clinicians improve the efficiency of their diagnostic strategy for UTI in young children.

Abstract Background Implementing a primary care clinical research study in several countries can make it possible to recruit sufficient patients in a short period of time that allows important clinical questions to be answered. Large multi-country studies in primary care are unusual and are typically associated with challenges requiring innovative solutions. We conducted a multi-country study and through this paper, we share reflections on the challenges we faced and some of the solutions we developed with a special focus on the study set up, structure and development of Primary Care Networks (PCNs). Method GRACE-01 was a multi-European country, investigator-driven prospective observational study implemented by 14 Primary Care Networks (PCNs) within 13 European Countries. General Practitioners (GPs) recruited consecutive patients with an acute cough. GPs completed a case report form (CRF) and the patient completed a daily symptom diary. After study completion, the coordinating team discussed the phases of the study and identified challenges and solutions that they considered might be interesting and helpful to researchers setting up a comparable study. Results The main challenges fell within three domains as follows: i) selecting, setting up and maintaining PCNs; ii) designing local context-appropriate data collection tools and efficient data management systems; and iii) gaining commitment and trust from all involved and maintaining enthusiasm. The main solutions for each domain were: i) appointing key individuals (National Network Facilitator and Coordinator) with clearly defined tasks, involving PCNs early in the development of study materials and procedures. ii) rigorous back translations of all study materials and the use of information systems to closely monitor each PCNs progress; iii) providing strong central leadership with high level commitment to the value of the study, frequent multi-method communication, establishing a coherent ethos, celebrating achievements, incorporating social events and prizes within meetings, and providing a framework for exploitation of local data. Conclusions Many challenges associated with multi-country primary care research can be overcome by engendering strong, effective communication, commitment and involvement of all local researchers. The practical solutions identified and the lessons learned in implementing the GRACE-01 study may assist in establishing other international primary care clinical research platforms. Trial registration ClinicalTrials.gov Identifier: NCT00353951

Abstract Background Cognitive behaviour therapy (CBT) is the treatment of choice for common mental health problems, but this approach has only recently been adapted for people with learning disabilities, and there is a limited evidence base for the use of CBT with this client group. Anger treatment is the one area where there exists a reasonable number of small controlled trials. This study will evaluate the effectiveness of a manualized 12-week CBT intervention for anger. The intervention will be delivered by staff working in the day services that the participants attend, following training to act as 'lay therapists' by a Clinical Psychologist, who will also provide supervision. Methods/Design This is a multi-centre cluster randomized controlled trial of a group intervention versus a 'support as usual' waiting-list control group, with randomization at the level of the group. Outcomes will be assessed at the end of the intervention and again 6-months later. After completion of the 6-month follow-up assessments, the intervention will also be delivered to the waiting-list groups. The study will include a range of anger/aggression and mental health measures, some of which will be completed by service users and also by their day service key-workers and by home carers. Qualitative data will be collected to assess the impact of the intervention on participants, lay therapists, and services, and the study will also include a service-utilization cost and consequences analysis. Discussion This will be the first trial to investigate formally how effectively staff working in services providing day activities for people with learning disabilities are able to use a therapy manual to deliver a CBT based anger management intervention, following brief training by a Clinical Psychologist. The demonstration that service staff can successfully deliver anger management to people with learning disabilities, by widening the pool of potential therapists, would have very significant benefits in relation to the current policy of improving access to psychological therapies, in addition to addressing more effectively an important and often unmet need of this vulnerable client group. The economic analysis will identify the direct and indirect costs (and/or savings) of the intervention and consider these in relation to the range of observed effects. The qualitative analyses will enhance the interpretation of the quantitative data, and if the study shows positive results, will inform the roll-out of the intervention to the wider community. Trial registration ISRCTN: ISRCTN37509773

Abstract Background There is increased incidence of new cases of type 1 diabetes in children younger than 15 years. The debate concerning where best to manage newly diagnosed children continues. Some units routinely admit children to hospital whilst others routinely manage children at home. A Cochrane review identified the need for a large well-designed randomised controlled trial to investigate any significant differences in comprehensive short and long-term outcomes between the two approaches. The DECIDE study will address these knowledge gaps, providing high quality evidence to inform national and international policy and practice. Methods/Design This is a multi-centre randomised controlled trial across eight UK paediatric diabetes centres. The study aims to recruit 240 children newly diagnosed with type 1 diabetes and their parents/carers. Eligible patients (aged 0-17 years) will be remotely randomised to either 'hospital' or 'home' management. Parents/carers of patients will also be recruited. Nursing management of participants and data collection will be co-ordinated by a project nurse at each centre. Data will be collected for 24 months after diagnosis; at follow up appointments at 3, 12 and 24 months and every 3-4 months at routine clinic visits. The primary outcome measure is patients' glycosylated haemoglobin (HbA1c) at 24 months after diagnosis. Additional measurements of HbA1c will be made at diagnosis and 3 and 12 months later. HbA1c concentrations will be analysed at a central laboratory. Secondary outcome measures include length of stay at diagnosis, growth, adverse events, quality of life, anxiety, coping with diabetes, diabetes knowledge, home/clinic visits, self-care activity, satisfaction and time off school/work. Questionnaires will be sent to participants at 1, 12 and 24 months and will include a questionnaire, developed and validated to measure impact of the diagnosis on social activity and independence. Additional qualitative outcome measures include the experience of both approaches by a subgroup of participants (n = 30) and health professionals. Total health service costs will be evaluated. A cost effectiveness analysis will assess direct and indirect health service costs against the primary outcome (HbA1c). Discussion This will be the first randomised controlled trial to evaluate hospital and home management of children newly diagnosed with type 1 diabetes and the findings should provide important evidence to inform practice and national guidelines. Trial registration number ISRCTN: ISRCTN78114042

Abstract Background Hundreds of thousands of volunteers take part in medical research, but many will never hear from researchers about what the study revealed. There is a growing demand for the results of randomised trials to be fed back to research participants both for ethical research practice and for ensuring their co-operation in a trial. This study aims to determine participants' preferences for type of leaflet (short versus long) used to summarise the findings of a randomised trial; and to test whether certain characteristics explained participants' preferences. Methods 553 participants in a randomised trial about General Practitioners' access to Magnetic Resonance Imaging for patients presenting with suspected internal derangement of the knee were asked in the final follow-up questionnaire whether they would like to be fed back the results of the trial. Participants who agreed to this were included in a postal questionnaire survey asking about their preference, if any, between a short and a long leaflet and what it was about the leaflet that they preferred. Multinomial logistic regression was used to test whether certain demographics of responding participants along with treatment group explained whether a participant had a preference for type of leaflet or no preference. Results Of the participants who returned the final follow-up questionnaire, 416 (88%) agreed to receive the results of the trial. Subsequently 132 (32%) participants responded to the survey. Most participants preferred the longer leaflet (55%) and the main reasons for this were the use of technical information (94%) and diagrams (89%). There was weak evidence to suggest that gender might explain whether participants have a preference for type of leaflet or not (P = 0.084). Conclusions Trial participants want to receive feed back about the results and appear to prefer a longer leaflet. Males and females might require information to be communicated to them differently and should be the focus of further research. Trial registration The trial is registered with http://www.isrctn.org/ and ID is ISRCTN76616358.

Abstract Background Over the last 30 years options for collecting self-reported data in health surveys and questionnaires have increased with technological advances. However, mode of data collection such as face-to-face interview or telephone interview can affect how individuals respond to questionnaires. This paper adapts a framework for understanding mode effects on response quality and applies it to a health research context. Discussion Data collection modes are distinguished by key features (whether the survey is self- or interviewer-administered, whether or not it is conducted by telephone, whether or not it is computerised, whether it is presented visually or aurally). Psychological appraisal of the survey request will initially entail factors such as the cognitive burden upon the respondent as well as more general considerations about participation. Subsequent psychological response processes will further determine how features of the data collection mode impact upon the quality of response provided. Additional antecedent factors which may further interact with the response generation process are also discussed. These include features of the construct being measured such as sensitivity, and of the respondent themselves (e.g. their socio-demographic characteristics). How features of this framework relate to health research is illustrated by example. Summary Mode features can affect response quality. Much existing evidence has a broad social sciences research base but is of importance to health research. Approaches to managing mode feature effects are discussed. Greater consideration must be given to how features of different data collection approaches affect response from participants in studies. Study reports should better clarify such features rather than rely upon global descriptions of data collection mode.

Abstract Background Diabetes is the third most common chronic condition in childhood and poor glycaemic control leads to serious short-term and life-limiting long-term complications. In addition to optimal medical management, it is widely recognised that psychosocial and educational factors play a key role in improving outcomes for young people with diabetes. Recent systematic reviews of psycho-educational interventions recognise the need for new methods to be developed in consultation with key stakeholders including patients, their families and the multidisciplinary diabetes healthcare team. Methods/design Following a development phase involving key stakeholders, a psychosocial intervention for use by paediatric diabetes staff and not requiring input from trained psychologists has been developed, incorporating a communication skills training programme for health professionals and a shared agenda-setting tool. The effectiveness of the intervention will be evaluated in a cluster-randomised controlled trial (RCT). The primary outcome, to be measured in children aged 4-15 years diagnosed with type 1 diabetes for at least one year, is the effect on glycaemic control (HbA1c) during the year after training of the healthcare team is completed. Secondary outcomes include quality of life for patients and carers and cost-effectiveness. Patient and carer preferences for service delivery will also be assessed. Twenty-six paediatric diabetes teams are participating in the trial, recruiting a total of 700 patients for evaluation of outcome measures. Half the participating teams will be randomised to receive the intervention at the beginning of the trial and remaining centres offered the training package at the end of the one year trial period. Discussion The primary aim of the trial is to determine whether a communication skills training intervention for specialist paediatric diabetes teams will improve clinical and psychological outcomes for young people with type 1 diabetes. Previous research indicates the effectiveness of specialist psychological interventions in achieving sustained improvements in glycaemic control. This trial will evaluate an intervention which does not require the involvement of trained psychologists, maximising the potential feasibility of delivery in a wider NHS context. Trial registration Current Controlled Trials ISRCTN61568050.

Abstract Background Hip and knee osteoarthritis is a common cause of pain and disability, which can be improved by exercise interventions. However, regular exercise is uncommon in this group because the low physical activity level in the general population is probably reduced even further by pain related fear of movement. The best method of encouraging increased activity in this patient group is not known. A booklet has been developed for patients with hip or knee osteoarthritis. It focuses on changing disadvantageous beliefs and encouraging increased physical activity. Methods/Design This paper describes the design of a Phase II randomised controlled trial (RCT) to test the effectiveness of this new booklet for patients with hip and knee osteoarthritis in influencing illness and treatment beliefs, and to assess the feasibility of conducting a larger definitive RCT in terms of health status and exercise behaviour. A computerised search of four general medical practice patients' record databases will identify patients older than 50 years of age who have consulted with hip or knee pain in the previous twelve months. A random sample of 120 will be invited to participate in the RCT comparing the new booklet with a control booklet, and we expect 100 to return final questionnaires. This trial will assess the feasibility of recruitment and randomisation, the suitability of the control intervention and outcome measurement tools, and will provide an estimate of effect size. Outcomes will include beliefs about hip and knee pain, beliefs about exercise, fear avoidance, level of physical activity, health status and health service costs. They will be measured at baseline, one month and three months. Discussion We discuss the merits of testing effectiveness in a phase II trial, in terms of intermediate outcome measures, whilst testing the processes for a larger definitive trial. We also discuss the advantages and disadvantages of testing the psychometric properties of the primary outcome measures concurrently with the trial. Trial registration Current Controlled Trials ISRCTN24554946

Abstract Background Within cluster randomized trials no algorithms exist to generate a full enumeration of a block randomization, balancing for covariates across treatment arms. Furthermore, often for practical reasons multiple blocks are required to fully randomize a study, which may not have been well balanced within blocks. Results We present a convenient and easy to use randomization tool to undertake allocation concealed block randomization. Our algorithm highlights allocations that minimize imbalance between treatment groups across multiple baseline covariates. We demonstrate the algorithm using a cluster randomized trial in primary care (the PRE-EMPT Study) and show that the software incorporates a trade off between independent random allocations that were likely to be imbalanced, and predictable deterministic approaches that would minimise imbalance. We extend the methodology of single block randomization to allocate to multiple blocks conditioning on previous allocations. Conclusion The algorithm is included as Additional file 1 and we advocate its use for robust randomization within cluster randomized trials. Additional File 1 Cluster randomization allocation algorithm version 1. Algorithms scripted in R to provide robust cluster randomization. Click here for file

Abstract Background Respiratory tract infections in children result in more primary care consultations than any other acute condition, and are the most common reason for prescribing antibiotics (which are largely unnecessary). About a fifth of children consult again for the same illness episode. Providing parents with written information on respiratory tract infections may result in a reduction in re-consultation rates and antibiotic prescribing for these illnesses. Asking clinicians to provide and discuss the information during the consultation may enhance effectiveness. This paper outlines the protocol for a study designed to evaluate the use of a booklet on respiratory tract infections in children within primary care consultations. Methods/Design This will be a cluster randomised controlled trial. General practices will be randomised to provide parents consulting because their child has an acute respiratory tract infection with either an interactive booklet, or usual care. The booklet provides information on the expected duration of their child's illness, the likely benefits of various treatment options, signs and symptoms that should prompt re-consultation, and symptomatic treatment advice. It has been designed for use within the consultation and aims to enhance communication through the use of specific prompts. Clinicians randomised to using the interactive booklet will receive online training in its use. Outcomes will be assessed via a telephone interview with the parent two weeks after first consulting. The primary outcome will be the proportion of children who re-consult for the same illness episode. Secondary outcomes include: antibiotic use, parental satisfaction and enablement, and illness costs. Consultation rates for respiratory tract infections for the subsequent year will be assessed by a review of practice notes. Discussion Previous studies in adults and children have shown that educational interventions can result in reductions in re-consultation rates and use of antibiotics for respiratory tract infections. This will be the first study to determine whether providing parents with a booklet on respiratory tract infections in children, and discussing it with them during the consultation, reduces re-consultations and antibiotic use for the same illness without reducing satisfaction with care. Trial registration Current Controlled Trials ISRCTN46104365

Abstract Background There is no validated way of measuring diagnostic delay in cancer, especially covering patient and primary care delays. An instrument is needed in order to determine the effect of potential interventions to reduce delay and improve cancer morbidity and mortality. Methods Development of a postal questionnaire tool to measure patient and primary care time responses to key symptoms and signs. The pilot questionnaire was sent to 184 patients with suspected cancer. Results The response rate was only 85/184 (46.2%). Anxiety was cited as one reason for this low response. Patients returning questionnaires were more likely to be women and more likely to be younger. 84/85 (98.8%) provided consent to access medical records, and questions regarding health profile, smoking and socio-economic profile were answered adequately. Outcome data on their cancer diagnosis was linked satisfactorily and the question about GP-initiated investigations was answered well. Estimated dates for symptom duration were preferred for patient delays, but exact dates were preferred for primary care delays; however there was a significant amount of missing data. Conclusion A more personal approach to the collection of data about the duration of symptoms in this group of people is needed other than a postal questionnaire. However elements of this piloted questionnaire are likely to figure strongly in future development and evaluation of this tool.

Abstract Background Most antibiotic prescriptions for acute cough due to lower respiratory tract infections (LRTI) in primary care are not warranted. Diagnostic uncertainty and patient expectations and worries are major drivers of unnecessary antibiotic prescribing. A C-reactive protein (CRP) point of care test may help GPs to better guide antibiotic treatment by ruling out pneumonia in cases of low test results. Alternatively, enhanced communication skills training to help clinicians address patients' expectations and worries could lead to a decrease in antibiotic prescribing, without compromising clinical recovery, while enhancing patient enablement. The aim of this paper is to describe the design and methods of a study to assess two interventions for improving LRTI management in general practice. Methods/Design This cluster randomised controlled, factorial trial will introduce two interventions in general practice; point of care CRP testing and enhanced communication skills training for LRTI. Twenty general practices with two participating GPs per practice will recruit 400 patients with LRTI during two winter periods. Patients will be followed up for at least 28 days. The primary outcome measure is the antibiotic prescribing rate. Secondary outcomes are clinical recovery, cost-effectiveness, use of other diagnostic tests and medical services (including reconsultation), and patient enablement. Discussion This trial is the first cluster randomised trial to evaluate the influence of point of care CRP testing in the hands of the general practitioner and enhanced communication skills, on the management of LRTI in primary care. The pragmatic nature of the study, which leaves treatment decisions up to the responsible clinicians, will enhance the applicability and generalisability of findings. The factorial design will allow conclusion to be made about the value of CRP testing on its own, communication skills training on its own, and the two combined. Evaluating a biomedical and communication based intervention ('hard' and 'soft' technologies) together in this way makes this trial unique in its field.

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

Abstract Background Though new technologies like Magnetic Resonance Imaging (MRI) may be accurate, they often diffuse into practice before thorough assessment of their value in diagnosis and management, and of their effects on patient outcome and costs. MRI of the knee is a common investigation despite concern that it is not always appropriate. There is wide variation in general practitioners (GPs) access to, and use of MRI, and in the associated costs. The objective of this study was to resolve uncertainty whether GPs should refer patients with suspected internal derangement of the knee for MRI or to an orthopaedic specialist in secondary care. Methods/Design The design consisted of a pragmatic multi-centre randomised trial with two parallel groups and concomitant economic evaluation. Patients presenting in general practice with suspected internal derangement of the knee and for whom their GP was considering referral to an orthopaedic specialist in secondary care were eligible for inclusion. Within practices, GPs or practice nurses randomised eligible and consenting participants to the local radiology department for an MRI examination, or for consultation with an orthopaedic specialist. To ensure that the waiting time from GP consultation to orthopaedic appointment was similar for both trial arms, GPs made a provisional referral to orthopaedics when requesting the MRI examination. Thus we evaluated the more appropriate sequence of events independent of variations in waiting times. Follow up of participants was by postal questionnaires at six, twelve and 24 months after randomisation. This was to ensure that the evaluation covered all events up to and including arthroscopy. Discussion The DAMASK trial should make a major contribution to the development of evidence-based partnerships between primary and secondary care professionals and inform the debate when MRI should enter the diagnostic pathway.

Abstract Background Although there is published research on the methods markers use in marking various types of assessment, there is relatively little information on the processes markers use in approaching a marking exercise. This qualitative paper describes the preparation and experiences of general practice (GP) teachers who undertake marking a written assessment in an undergraduate medical course. Methods Semi-structured interviews were conducted with seven of the 16 GP tutors on an undergraduate course. The purposive sample comprised two new markers, two who had marked for a couple of years and three experienced markers. Each respondent was interviewed twice, once following a formative assessment of a written case study, and again after a summative assessment. All interviews were audio-taped and analysed for emerging themes. A respondent validation exercise was conducted with all 16 GP tutors. Results Markers had internal concerns about their ability to mark fairly and made considerable efforts to calibrate their marking. They needed guidance and coaching when marking for the first time and adopted a variety of marking styles, reaching a decision through a number of routes. Dealing with pass/fail borderline scripts and the consequences of the mark on the student were particular concerns. Even experienced markers felt the need to calibrate their marks both internally and externally Conclusion Previous experience of marking appears to improve markers' confidence and is a factor in determining the role which markers adopt. Confidence can be improved by giving clear instructions, along with examples of marking. The authors propose that one method of providing this support and coaching could be by a process of peer review of a selection of papers prior to the main marking. New markers in particular would benefit from further guidance, however they are influenced by others early on in their marking career and course organisers should be mindful of this when arranging double marking.

Background Underrepresentation of care home residents in research has resulted in a poorer evidence base for health care in care homes. Fewer opportunities to take part in research, as well as assumptions made by others about their interest or wishes, creates challenges for residents' inclusion in research. Early discussions about research preferences and wishes may be beneficial. This qualitative study aimed to explore stakeholders' views about how care home residents can be supported to communicate their wishes about research participation. Method Semi-structured interviews were conducted with 25 stakeholders: care home residents (n = 5), relatives (n = 5), care home staff (n = 5), other health and social care professionals who work with care homes (n = 6), and care home researchers (n = 4). Interviews were conducted virtually or face-to-face and data were analysed using thematic analysis. Results Views about resident research participation, the barriers and facilitators to their inclusion, and the role of advance research planning were iteratively organized into three themes: (i) We're of no value to research; (ii) Research is difficult; and (iii) Advance research planning: good in theory, challenging in practice. Subthemes were also identified, and findings were discussed with a Patient and Public Involvement group for additional reflections. Conclusions Stakeholders identified a number of barriers to including care home residents in research, including knowing their preferences about research. The development of interventions to facilitate communication that can be adapted to individuals' requirements are needed to support discussions and decision-making with care home residents about wishes and preferences for future research participation. [ABSTRACT FROM AUTHOR]

Introduction: The impact of multiple health conditions on bowel cancer screening is currently unknown. We explored the impact of multiple health conditions on bowel cancer screening perceptions, experience and clinical management decisions following a positive stool test. Methods: Semi‐structured qualitative interviews were conducted remotely with Bowel Screening Wales staff (n = 16) stratified by regional location and role and with screening participants (n = 19) stratified by age, gender and comorbidity. Interview topics were guided by the Common‐Sense Model. Results: Screening participants, regardless of comorbidity status, placed great emphasis on the importance of early detection of cancer and completing the bowel screening process. Screening staff emphasised comorbidities in the clinical decision‐making process; however, screening participants had low awareness of the impact that comorbidities can have on bowel screening. Participants describe how the presence of multiple health conditions can mask potential bowel symptoms and influence beliefs about follow‐up. Conclusion: Bowel screening staff try to individualise the service to meet participant needs. The potential mismatch in screening staff and participant awareness and expectations of the bowel screening and diagnostic process needs to be addressed. Clearer and more regular communication with screening participants could support the screening process, particularly for those with significant coexisting health conditions or facing time delays. The possible masking effects and misattribution of symptoms because of comorbidities highlight an opportunity for education and raising awareness for screening participants and a potential area of focus for discussions in clinical consultations and staff training. Patient and Public Contribution: Project funding included costs for patients and public contributors to be compensated for their contributions to the project, in line with current standards. A patient and public contributor was involved in the design of the study, including protocol development, and the interpretation of key findings and implications for patients, which are subsequently reflected within the manuscript. [ABSTRACT FROM AUTHOR]

Background: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. Aim: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over 6 months. Design and setting: An economic evaluation of the PANORAMIC trial in the UK. Method: A cost-utility analysis that adopted a UK NHS and personal social services perspective and a 6-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. Results: In the base-case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] = 445 to 453) and higher mean QALYs of 0.0055 (95% CI = 0.0044 to 0.0067) than usual care (mean incremental cost per QALY of £81 190). Sensitivity and subgroup analyses showed similar results, except for those aged ≥75 years, with a 55% probability of being cost-effective at a £30 000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15 000 per QALY threshold. Conclusion: At the current cost of £513 per course, molnupiravir is unlikely to be cost-effective relative to usual care over a 6-month time horizon among mainly vaccinated patients with COVID-19 at increased risk of adverse outcomes, except those aged ≥75 years. [ABSTRACT FROM AUTHOR]

Background/Aims: Older adults living in care homes are underrepresented in research, resulting in a poorer evidence base for their care. Increasing opportunities and ability for care home residents to be included in research is urgently needed. This survey explored the views and experiences of relevant stakeholders in the UK about opportunities for residents to participate in research, decisions about participation, and the barriers and facilitators to their involvement. Methods: The survey was conducted from September to December 2022 using an online survey tool or paper-based format. Participants were recruited via multiple routes, including social media and contact with care homes. Quantitative data were analysed using descriptive statistics and free-text responses were analysed using content analysis. Results: A total of 80 participants responded to the survey, of which 46 were suitable for analysis from care home residents (n=6), relatives (n=11), care home staff (n=14), other health and social care professionals who work with care homes (n=7), and researchers (n=8). The main barriers identified were the discordance between stakeholders' awareness of research opportunities and difficulties with residents' communication needs. Facilitators included effective communication between stakeholders, positive staff engagement and researchers' flexibility. Conclusions: There are a number of barriers to the inclusion of care home residents in research. There is a need to develop strategies to improve communication and relationships between stakeholders, as well as training programmes to educate stakeholders about care home-based research and its benefits. Implications for practice: These findings can support the development of strategies to improve communication and relationships between stakeholders, training programmes to educate stakeholders about care home research and its benefits, and targeted interventions to improve research inclusion for UK care home residents. [ABSTRACT FROM AUTHOR]