Talking in primary care (TIP): protocol for a cluster-randomised controlled trial in UK primary care to assess clinical and cost-effectiveness of communication skills e-learning for practitioners on patients' musculoskeletal pain and enablement.

INTRODUCTION: Effective communication can help optimise healthcare interactions and patient outcomes. However, few interventions have been tested clinically, subjected to cost-effectiveness analysis or are sufficiently brief and well-described for implementation in primary care. This paper presents the protocol for determining the effectiveness and cost-effectiveness of a rigorously developed brief eLearning tool, EMPathicO, among patients with and without musculoskeletal pain. METHODS AND ANALYSIS: A cluster randomised controlled trial in general practitioner (GP) surgeries in England and Wales serving patients from diverse geographic, socioeconomic and ethnic backgrounds. GP surgeries are randomised (1:1) to receive EMPathicO e-learning immediately, or at trial end. Eligible practitioners (eg, GPs, physiotherapists and nurse practitioners) are involved in managing primary care patients with musculoskeletal pain. Patient recruitment is managed by practice staff and researchers. Target recruitment is 840 adults with and 840 without musculoskeletal pain consulting face-to-face, by telephone or video. Patients complete web-based questionnaires at preconsultation baseline, 1 week and 1, 3 and 6 months later. There are two patient-reported primary outcomes: pain intensity and patient enablement. Cost-effectiveness is considered from the National Health Service and societal perspectives. Secondary and process measures include practitioner patterns of use of EMPathicO, practitioner-reported self-efficacy and intentions, patient-reported symptom severity, quality of life, satisfaction, perceptions of practitioner empathy and optimism, treatment expectancies, anxiety, depression and continuity of care. Purposive subsamples of patients, practitioners and practice staff take part in up to two qualitative, semistructured interviews. ETHICS APPROVAL AND DISSEMINATION: Approved by the South Central Hampshire B Research Ethics Committee on 1 July 2022 and the Health Research Authority and Health and Care Research Wales on 6 July 2022 (REC reference 22/SC/0145; IRAS project ID 312208). Results will be disseminated via peer-reviewed academic publications, conference presentations and patient and practitioner outlets. If successful, EMPathicO could quickly be made available at a low cost to primary care practices across the country. TRIAL REGISTRATION NUMBER: ISRCTN18010240.

Online behavioural interventions for children and young people with eczema: Quantitative evaluation.

BACKGROUND: Two online behavioural interventions (Eczema Care Online; one website for parents/carers of children with eczema; one for young people with eczema) have been shown in randomised controlled trials to facilitate a sustained improvement in eczema severity. AIM: To describe intervention use and examine potential mediators of intervention outcomes and contextual factors that may influence intervention delivery and outcomes. DESIGN AND SETTING: Quantitative process evaluation; UK primary care. METHOD: Parents/carers and young people were recruited through primary care. Intervention use was recorded and summarised descriptively. Logistic regression explored socio-demographic and other factors associated with intervention engagement. Mediation analysis investigated whether patient enablement (ability to understand and cope with health issues), treatment use, and barriers to adherence were mediators of intervention effect. Subgroup analysis compared intervention effects among pre-specified participants subsets. RESULTS: 340 parents/carers and 337 young people were recruited. 87% (148/171) parent/carers and 91% (153/168) young people in the intervention group completed the core introduction. At 24 weeks, users spent approximately 20 minutes on average on the interventions. Among parents/carers, greater intervention engagement was associated with higher education levels, uncertainty about carrying out treatments, and doubts about treatment efficacy at baseline. Among young people, higher intervention use was associated with higher baseline eczema severity. Patient enablement accounted for approximately 30% of the intervention effect among parents/carers and 50% among young people. CONCLUSION: Findings demonstrated that positive intervention outcomes depended on a modest time commitment from users. They provide further support that the wider implementation of Eczema Care Online is justified.

Cost-effectiveness of two online interventions supporting self-care for eczema for parents/carers and young people.

OBJECTIVE: To estimate the cost-effectiveness of online behavioral interventions (EczemaCareOnline.org.uk) designed to support eczema self-care management for parents/carers and young people from an NHS perspective. METHODS: Two within-trial economic evaluations, using regression-based approaches, adjusting for baseline and pre-specified confounder variables, were undertaken alongside two independent, pragmatic, parallel group, unmasked randomized controlled trials, recruiting through primary care. Trial 1 recruited 340 parents/carers of children aged 0-12 years and Trial 2 337 young people aged 13-25 years with eczema scored ≥ 5 on Patient-Oriented Eczema Measure (POEM). Participants were randomized (1:1) to online intervention plus usual care or usual care alone. Resource use, collected via medical notes review, was valued using published unit costs in UK £Sterling 2021. Quality-of-life was elicited using proxy CHU-9D in Trial 1 and self-report EQ-5D-5L in Trial 2. RESULTS: The intervention was dominant (cost saving and more effective) with a high probability of cost-effectiveness (> 68%) in most analyses. The exception was the complete case cost-utility analysis for Trial 1 (omitting participants with children aged < 2), with adjusted incremental cost savings of -£34.15 (95% CI - 104.54 to 36.24) and incremental QALYs of - 0.003 (95% CI - 0.021 to 0.015) producing an incremental cost per QALY of £12,466. In the secondary combined (Trials 1 and 2) cost-effectiveness analysis, the adjusted incremental cost was -£20.35 (95% CI - 55.41 to 14.70) with incremental success (≥ 2-point change on POEM) of 10.3% (95% CI 2.3-18.1%). CONCLUSION: The free at point of use online eczema self-management intervention was low cost to run and cost-effective. TRIAL REGISTRATION: This trial was registered prospectively with the ISRCTN registry (ISRCTN79282252). URL www.EczemaCareOnline.org.uk .

Internet Tool to Support Self-Assessment and Self-Swabbing of Sore Throat: Development and Feasibility Study.

BACKGROUND: Sore throat is a common problem and a common reason for the overuse of antibiotics. A web-based tool that helps people assess their sore throat, through the use of clinical prediction rules, taking throat swabs or saliva samples, and taking throat photographs, has the potential to improve self-management and help identify those who are the most and least likely to benefit from antibiotics. OBJECTIVE: We aimed to develop a web-based tool to help patients and parents or carers self-assess sore throat symptoms and take throat photographs, swabs, and saliva samples for diagnostic testing. We then explored the acceptability and feasibility of using the tool in adults and children with sore throats. METHODS: We used the Person-Based Approach to develop a web-based tool and then recruited adults and children with sore throats who participated in this study by attending general practices or through social media advertising. Participants self-assessed the presence of FeverPAIN and Centor score criteria and attempted to photograph their throat and take throat swabs and saliva tests. Study processes were observed via video call, and participants were interviewed about their views on using the web-based tool. Self-assessed throat inflammation and pus were compared to clinician evaluation of patients' throat photographs. RESULTS: A total of 45 participants (33 adults and 12 children) were recruited. Of these, 35 (78%) and 32 (71%) participants completed all scoring elements for FeverPAIN and Centor scores, respectively, and most (30/45, 67%) of them reported finding self-assessment relatively easy. No valid response was provided for swollen lymph nodes, throat inflammation, and pus on the throat by 11 (24%), 9 (20%), and 13 (29%) participants respectively. A total of 18 (40%) participants provided a throat photograph of adequate quality for clinical assessment. Patient assessment of inflammation had a sensitivity of 100% (3/3) and specificity of 47% (7/15) compared with the clinician-assessed photographs. For pus on the throat, the sensitivity was 100% (3/3) and the specificity was 71% (10/14). A total of 89% (40/45), 93% (42/45), 89% (40/45), and 80% (30/45) of participants provided analyzable bacterial swabs, viral swabs, saliva sponges, and saliva drool samples, respectively. Participants were generally happy and confident in providing samples, with saliva samples rated as slightly more acceptable than swab samples. CONCLUSIONS: Most adult and parent participants were able to use a web-based intervention to assess the clinical features of throat infections and generate scores using clinical prediction rules. However, some had difficulties assessing clinical signs, such as lymph nodes, throat pus, and inflammation, and scores were assessed as sensitive but not specific. Many participants had problems taking photographs of adequate quality, but most were able to take throat swabs and saliva samples.

Predicting illness progression for children with lower respiratory infections in primary care: a prospective cohort and observational study.

BACKGROUND: Antibiotics are commonly prescribed for children with lower respiratory tract infections (LRTIs), fuelling antibiotic resistance, and there are few prognostic tools available to inform management. AIM: To externally validate an existing prognostic model (STARWAVe) to identify children at low risk of illness progression, and if model performance was limited to develop a new internally validated prognostic model. DESIGN AND SETTING: Prospective cohort study with a nested trial in a primary care setting. METHOD: Children aged 6 months to 12 years presenting with uncomplicated LRTI were included in the cohort. Children were randomised to receive amoxicillin 50 mg/kg per day for 7 days or placebo, or if not randomised they participated in a parallel observational study to maximise generalisability. Baseline clinical data were used to predict adverse outcome (illness progression requiring hospital assessment). RESULTS: A total of 758 children participated (n = 432 trial, n = 326 observational). For predicting illness progression the STARWAVe prognostic model had moderate performance (area under the receiver operating characteristic [AUROC] 0.66, 95% confidence interval [CI] = 0.50 to 0.77), but a new, internally validated model (seven items: baseline severity; respiratory rate; duration of prior illness; oxygen saturation; sputum or a rattly chest; passing urine less often; and diarrhoea) had good discrimination (bootstrapped AUROC 0.83, 95% CI = 0.74 to 0.92) and calibration. A three-item model (respiratory rate; oxygen saturation; and sputum or a rattly chest) also performed well (AUROC 0.81, 95% CI = 0.70 to 0.91), as did a score (ranging from 19 to 102) derived from coefficients of the model (AUROC 0.78, 95% CI = 0.67 to 0.88): a score of <70 classified 89% (n = 600/674) of children having a low risk (<5%) of progression of illness. CONCLUSION: A simple three-item prognostic score could be useful as a tool to identify children with LRTI who are at low risk of an adverse outcome and to guide clinical management.

Using microbiological data to improve the use of antibiotics for respiratory tract infections: A protocol for an individual patient data meta-analysis.

BACKGROUND: Resistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence. AIM: To undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs. METHODS: A systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs. TRIAL REGISTRATION: PROSPERO Registration number: CRD42023376769.

Antibiotics for lower respiratory tract infection in children presenting in primary care: ARTIC-PC RCT.

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.

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. 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. 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. 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.

Non-pharmaceutical interventions and risk of COVID-19 infection: survey of U.K. public from November 2020 - May 2021.

INTRODUCTION: Non-pharmaceutical interventions (NPIs), such as handwashing, social distancing and face mask wearing, have been widely promoted to reduce the spread of COVID-19. This study aimed to explore the relationship between self-reported use of NPIs and COVID-19 infection. METHODS: We conducted an online questionnaire study recruiting members of the UK public from November 2020 to May 2021. The association between self-reported COVID-19 illness and reported use of NPIs was explored using logistic regression and controlling for participant characteristics, month of questionnaire completion, and vaccine status. Participants who had been exposed to COVID-19 in their household in the previous 2 weeks were excluded. RESULTS: Twenty-seven thousand seven hundred fifty-eight participants were included and 2,814 (10.1%) reported having a COVID-19 infection. The odds of COVID-19 infection were reduced with use of a face covering in unadjusted (OR 0.17 (95% CI: 0.15 to 0.20) and adjusted (aOR 0.19, 95% CI 0.16 to 0.23) analyses. Social distancing (OR 0.27, 95% CI: 0.22 to 0.31; aOR 0.35, 95% CI 0.28 to 0.43) and handwashing when arriving home (OR 0.57, 95% CI 0.46 to 0.73; aOR 0.63, 95% CI: 0.48 to 0.83) also reduced the odds of COVID-19. Being in crowded places of 10-100 people (OR 1.89, 95% CI: 1.70 to 2.11; aOR 1.62, 95% CI: 1.42 to 1.85) and > 100 people (OR 2.33, 95% CI: 2.11 to 2.58; aOR 1.73, 95% CI: 1.53 to 1.97) were both associated with increased odds of COVID-19 infection. Handwashing before eating, avoiding touching the face, and cleaning things with virus on were all associated with increased odds of COVID-19 infections. CONCLUSIONS: This large observational study found evidence for strong protective effects for individuals from use of face coverings, social distancing (including avoiding crowded places) and handwashing on arriving home on developing COVID-19 infection. We also found evidence for an increased risk associated with other behaviours, possibly from recall bias.

Antibiotic effectiveness for children with lower respiratory infections: prospective cohort and trial in primary care.

BACKGROUND: Antibiotics are commonly prescribed for children with chest infections but there is little randomised evidence and trials commonly recruit selected populations, which undermines their applicability. AIM: To document the effectiveness of antibiotics for chest infections in children. DESIGN AND SETTING: This was a prospective cohort study with nested trial in primary care. METHOD: Children aged 1-12 years presenting with uncomplicated lower respiratory tract infections were included in the cohort. Children were either randomised to receive amoxicillin 50 mg/kg per day for 7 days or placebo, or participated in a parallel observational study, where propensity scores controlled for confounding by indication. The outcomes were duration of symptoms rated moderately bad or worse (primary outcome) and illness progression requiring hospital assessment. RESULTS: A total of 764 children participated (438 trial, 326 observational), and children were more unwell than in previous cohorts (more sputum, fever, shortness of breath). Children had been unwell for a median of 5-6 days, and symptoms rated moderately bad or worse lasted another 6 days when no antibiotics were given.With antibiotics there was a non-significant reduction of approximately 1 day in duration of symptoms rated moderately bad or worse for the whole cohort (hazard ratio [HR] 1.16, 95% confidence interval [CI] = 0.95 to 1.41), similar to the trial alone (HR 1.13, 95% CI = 0.90 to 1.43). The effect of antibiotic treatment on secondary outcomes was also non-significant. CONCLUSION: Antibiotics for uncomplicated chest infections, even in a sample of more unwell children, are unlikely to be clinically very effective.

Post-consultation acute respiratory tract infection recovery: a latent class-informed analysis of individual patient data.

BACKGROUND: There is a lack of evidence regarding post-consultation symptom trajectories for patients with respiratory tract infections (RTIs) and whether patient characteristics can be used to predict illness duration. AIM: To describe symptom trajectories in patients with RTIs, and assess baseline characteristics and adverse events associated with trajectories. DESIGN AND SETTING: The study included data about 9103 adults and children from 12 primary care studies. METHOD: A latent class-informed regression analysis of individual patient data from randomised controlled trials and observational cohort studies was undertaken. Post-consultation symptom trajectory (severity and duration), re-consultation with same or worsening illness, and admission to hospital were assessed. RESULTS: In total, 90% of participants recovered from all symptoms by 28 days, regardless of antibiotic prescribing strategy (none, immediate, and delayed antibiotics). For studies of RTI with cough as a dominant symptom (n = 5314), four trajectories were identified: 'rapid (6 days)' (90% of participants recovered within 6 days) in 52.0%; 'intermediate (10 days)' (28.9%); 'slow progressive improvement (27 days)' (12.5%); and 'slow improvement with initial high symptom burden (27 days)' (6.6%). For cough, being aged 16-64 years (odds ratio [OR] 2.57, 95% confidence interval [CI] = 1.72 to 3.85 compared with <16 years), higher presenting illness baseline severity (OR 1.51, 95% CI = 1.12 to 2.03), presence of lung disease (OR 1.78, 95% CI = 1.44 to 2.21), and median and above illness duration before consultation (≥7 days) (OR 1.99, 95% CI = 1.68 to 2.37) were associated with slower recovery (>10 days) compared with faster recovery (≤10 days). Re-consultations and admissions to hospital for cough were higher in those with slower recovery (ORs: 2.15, 95% CI = 1.78 to 2.60 and 7.42, 95% CI = 3.49 to 15.78, respectively). CONCLUSION: Older patients presenting with more severe, longer pre-consultation symptoms and chronic lung disease should be advised they are more likely to experience longer post-consultation illness durations, and that recovery rates are similar with and without antibiotics.

Self-sampling to identify pathogens and inflammatory markers in patients with acute sore throat: Feasibility study.

Introduction: Sore throat is a common reason for overuse of antibiotics. The value of inflammatory or biomarkers in throat swab or saliva samples in predicting benefit from antibiotics is unknown. Methods: We used the 'person-based approach' to develop an online tool to support self-swabbing and recruited adults and children with sore throats through participating general practices and social media. Participants took bacterial and viral swabs and a saliva sponge swab and passive drool sample. Bacterial swabs were cultured for streptococcus (Group A, B, C, F and G). The viral swab and saliva samples were tested using a routine respiratory panel PCR and Covid-19 PCR testing. We used remaining viral swab and saliva sample volume for biomarker analysis using a panel of 13 biomarkers. Results: We recruited 11 asymptomatic participants and 45 symptomatic participants. From 45 symptomatic participants, bacterial throat swab, viral throat swab, saliva sponge and saliva drool samples were returned by 41/45 (91.1%), 43/45 (95.6%), 43/45 (95.6%) and 43/45 (95.6%) participants respectively. Three saliva sponge and 6 saliva drool samples were of insufficient quantity. Two adult participants had positive bacterial swabs. Six participants had a virus detected from at least one sample (swab or saliva). All of the biomarkers assessed were detectable from all samples where there was sufficient volume for testing. For most biomarkers we found higher concentrations in the saliva samples. Due to low numbers, we were not able to compare biomarker concentrations in those who did and did not have a bacterial pathogen detected. We found no evidence of a difference between biomarker concentrations between the symptomatic and asymptomatic participants but the distributions were wide. Conclusions: We have demonstrated that it is feasible for patients with sore throat to self-swab and provide saliva samples for pathogen and biomarker analysis. Typical bacterial and viral pathogens were detected but at low prevalence rates. Further work is needed to determine if measuring biomarkers using oropharyngeal samples can help to differentiate between viral and bacterial pathogens in patients classified as medium or high risk using clinical scores, in order to better guide antibiotic prescribing and reduce inappropriate prescriptions.

Parallel randomized controlled feasibility trials of the "Active Brains" digital intervention to protect cognitive health in adults aged 60-85.

Introduction: Multidomain interventions to address modifiable risk factors for dementia are promising, but require more cost-effective, scalable delivery. This study investigated the feasibility of the "Active Brains" digital behavior change intervention and its trial procedures. Materials and methods: Active Brains aims to reduce cognitive decline by promoting physical activity, healthy eating, and online cognitive training. We conducted 12-month parallel-design randomized controlled feasibility trials of "Active Brains" amongst "lower cognitive scoring" (n = 180) and "higher cognitive scoring" (n = 180) adults aged 60-85. Results: We collected 67.2 and 76.1% of our 12-month primary outcome (Baddeley verbal reasoning task) data for the "lower cognitive score" and "higher cognitive score" groups, respectively. Usage of "Active Brains" indicated overall feasibility and satisfactory engagement with the physical activity intervention content (which did not require sustained online engagement), but engagement with online cognitive training was limited. Uptake of the additional brief telephone support appeared to be higher in the "lower cognitive score" trial. Preliminary descriptive trends in the primary outcome data might indicate a protective effect of Active Brains against cognitive decline, but further investigation in fully-powered trials is required to answer this definitively. Discussion: Whilst initial uptake and engagement with the online intervention was modest, it was in line with typical usage of other digital behavior change interventions, and early indications from the descriptive analysis of the primary outcome and behavioral data suggest that further exploration of the potential protective benefits of Active Brains are warranted. The study also identified minor modifications to procedures, particularly to improve online primary-outcome completion. Further investigation of Active Brains will now seek to determine its efficacy in protecting cognitive performance amongst adults aged 60-85 with varied levels of existing cognitive performance.

Antibiotics for lower respiratory tract infection in children presenting in primary care (ARTIC-PC): the predictive value of molecular testing.

OBJECTIVES: This study aimed to assess whether the presence of bacteria or viruses in the upper airway of children presenting with uncomplicated lower respiratory tract infection (LRTI) predicts the benefit of antibiotics. METHODS: Children between 6 months and 12 years presenting to UK general practices with an acute LRTI were randomized to receive amoxicillin 50 mg/kg/d for 7 days or placebo. Children not randomized (ineligible or clinician/parental choice) could participate in a parallel observational study. The primary outcome was the duration of symptoms rated moderately bad or worse. Throat swabs were taken and analyzed for the presence of bacteria and viruses by multiplex PCR. RESULTS: Swab results were available for most participants in the trial (306 of 432; 71%) and in the observational (182 of 326; 59%) studies. Bacterial pathogens potentially sensitive to amoxicillin (Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae) were detected among 51% of the trial placebo group and 49% of the trial antibiotic group. The median difference in the duration of symptoms rated moderately bad or worse between antibiotic and placebo was similar when potentially antibiotic-susceptible bacteria were present (median: -1 day; 99% CI, -12.3 to 10.3) or not present (median: -1 day; 99% CI, -4.5 to 2.5). Furthermore, bacterial genome copy number did not predict benefit. There were similar findings for all secondary outcomes and when including the data from the observational study. DISCUSSION: There was no clear evidence that antibiotics improved clinical outcomes conditional on the presence or concentration of bacteria or viruses in the upper airway. Before deploying microbiologic point-of-care tests for children with uncomplicated LRTI in primary care, rigorous validating trials are needed.

Eczema Care Online behavioural interventions to support self-care for children and young people: two independent, pragmatic, randomised controlled trials.

OBJECTIVE: To determine the effectiveness of two online behavioural interventions, one for parents and carers and one for young people, to support eczema self-management. DESIGN: Two independent, pragmatic, parallel group, unmasked, randomised controlled trials. SETTING: 98 general practices in England. PARTICIPANTS: Parents and carers of children (0-12 years) with eczema (trial 1) and young people (13-25 years) with eczema (trial 2), excluding people with inactive or very mild eczema (≤5 on POEM, the Patient-Oriented Eczema Measure). INTERVENTIONS: Participants were randomised (1:1) using online software to receive usual eczema care or an online (www.EczemaCareOnline.org.uk) behavioural intervention for eczema plus usual care. MAIN OUTCOME MEASURES: Primary outcome was eczema symptoms rated using POEM (range 0-28, with 28 being very severe) every four weeks over 24 weeks. Outcomes were reported by parents or carers for children and by self-report for young people. Secondary outcomes included POEM score every four weeks over 52 weeks, quality of life, eczema control, itch intensity (young people only), patient enablement, treatment use, perceived barriers to treatment use, and intervention use. Analyses were carried out separately for the two trials and according to intention-to-treat principles. RESULTS: 340 parents or carers of children (169 usual care; 171 intervention) and 337 young people (169 usual care; 168 intervention) were randomised. The mean baseline POEM score was 12.8 (standard deviation 5.3) for parents and carers and 15.2 (5.4) for young people. Three young people withdrew from follow-up but did not withdraw their data. All randomised participants were included in the analyses. At 24 weeks, follow-up rates were 91.5% (311/340) for parents or carers and 90.2% (304/337) for young people. After controlling for baseline eczema severity and confounders, compared with usual care groups over 24 weeks, eczema severity improved in the intervention groups: mean difference in POEM score -1.5 (95% confidence interval -2.5 to -0.6; P=0.002) for parents or carers and -1.9 (-3.0 to -0.8; P<0.001) for young people. The number needed to treat to achieve a 2.5 difference in POEM score at 24 weeks was 6 in both trials. Improvements were sustained to 52 weeks in both trials. Enablement showed a statistically significant difference favouring the intervention group in both trials: adjusted mean difference at 24 weeks -0.7 (95% confidence interval -1.0 to -0.4) for parents or carers and -0.9 (-1.3 to -0.6) for young people. No harms were identified in either group. CONCLUSIONS: Two online interventions for self-management of eczema aimed at parents or carers of children with eczema and at young people with eczema provide a useful, sustained benefit in managing eczema severity in children and young people when offered in addition to usual eczema care. TRIAL REGISTRATION: ISRCTN registry ISRCTN79282252.

Antibiotics for lower respiratory tract infection in children presenting in primary care in England (ARTIC PC): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Antibiotic resistance is a global public health threat. Antibiotics are very commonly prescribed for children presenting with uncomplicated lower respiratory tract infections (LRTIs), but there is little evidence from randomised controlled trials of the effectiveness of antibiotics, both overall or among key clinical subgroups. In ARTIC PC, we assessed whether amoxicillin reduces the duration of moderately bad symptoms in children presenting with uncomplicated (non-pneumonic) LRTI in primary care, overall and in key clinical subgroups. METHODS: ARTIC PC was a double-blind, randomised, placebo-controlled trial done at 56 general practices in England. Eligible children were those aged 6 months to 12 years presenting in primary care with acute uncomplicated LRTI judged to be infective in origin, where pneumonia was not suspected clinically, with symptoms for less than 21 days. Patients were randomly assigned in a 1:1 ratio to receive amoxicillin 50 mg/kg per day or placebo oral suspension, in three divided doses orally for 7 days. Patients and investigators were masked to treatment assignment. The primary outcome was the duration of symptoms rated moderately bad or worse (measured using a validated diary) for up to 28 days or until symptoms resolved. The primary outcome and safety were assessed in the intention-to-treat population. The trial is registered with the ISRCTN Registry (ISRCTN79914298). FINDINGS: Between Nov 9, 2016, and March 17, 2020, 432 children (not including six who withdrew permission for use of their data after randomisation) were randomly assigned to the antibiotics group (n=221) or the placebo group (n=211). Complete data for symptom duration were available for 317 (73%) patients; missing data were imputed for the primary analysis. Median durations of moderately bad or worse symptoms were similar between the groups (5 days [IQR 4-11] in the antibiotics group vs 6 days [4-15] in the placebo group; hazard ratio [HR] 1·13 [95% CI 0·90-1·42]). No differences were seen for the primary outcome between the treatment groups in the five prespecified clinical subgroups (patients with chest signs, fever, physician rating of unwell, sputum or chest rattle, and short of breath). Estimates from complete-case analysis and a per-protocol analysis were similar to the imputed data analysis. INTERPRETATION: Amoxicillin for uncomplicated chest infections in children is unlikely to be clinically effective either overall or for key subgroups in whom antibiotics are commonly prescribed. Unless pneumonia is suspected, clinicians should provide safety-netting advice but not prescribe antibiotics for most children presenting with chest infections. FUNDING: National Institute for Health Research.

Diarrhoea Management using Over-the-counter Nutraceuticals in Daily practice (DIAMOND): a feasibility RCT on alternative therapy to reduce antibiotic use.

BACKGROUND: Although rarely indicated, antibiotics are commonly used for acute diarrhoea in China. We conducted a randomised, double blind exploratory clinical trial of loperamide, berberine and turmeric for treatment of acute diarrhoea. METHODS: Adults with acute uncomplicated diarrhoea aged 18 to 70 were randomised to 4 groups: (A) loperamide; (B) loperamide and berberine; (C) loperamide and turmeric; (D) loperamide, berberine and turmeric. All participants were given rescue ciprofloxacin for use after 48 h if symptoms worsened or were unimproved. Primary endpoints were feasibility and ciprofloxacin use during the 2-week follow-up period. Semi-structured interviews were conducted following recruitment and were analysed thematically. Recruiting doctors, delivery pharmacists and research assistants were blinded to treatment allocation. RESULTS: Only 21.5% (278/1295) of patients screened were deemed eligible, and 49% (136/278) of these consented and were entered into the final analysis. Most participants had mild symptoms, because most patients with moderate or severe symptoms wanted to be given antibiotics. Follow-up was good (94% at 2 weeks). Only three participants used rescue antibiotics compared to 67% of acute diarrhoea patients in the hospital during the recruitment period. The median symptom duration was 14 h in group B (interquartile range (IQR) 10-22), 16 h in group D (IQR 10-22), 18 h in group A (IQR 10-33) and 20 h in group C (IQR 16-54). Re-consultation rates were low. There were no serious treatment-related adverse events. Most interviewed participants said that although they had believed antibiotics to be effective for diarrhoea, they were surprised by their quick recovery without antibiotics in this trial. CONCLUSION: Although recruitment was challenging because of widespread expectations for antibiotics, patients with mild diarrhoea accepted trying an alternative. The three nutraceuticals therapy require further evaluation in a fully powered, randomised controlled trial among a broader sample. TRIAL REGISTRATION: ChiCTR-IPR-17014107.

Delayed antibiotic prescribing for respiratory tract infections: individual patient data meta-analysis.

OBJECTIVE: To assess the overall effect of delayed antibiotic prescribing on average symptom severity for patients with respiratory tract infections in the community, and to identify any factors modifying this effect. DESIGN: Systematic review and individual patient data meta-analysis. DATA SOURCES: Cochrane Central Register of Controlled Trials, Ovid Medline, Ovid Embase, EBSCO CINAHL Plus, and Web of Science. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials and observational cohort studies in a community setting that allowed comparison between delayed versus no antibiotic prescribing, and delayed versus immediate antibiotic prescribing. MAIN OUTCOME MEASURES: The primary outcome was the average symptom severity two to four days after the initial consultation measured on a seven item scale (ranging from normal to as bad as could be). Secondary outcomes were duration of illness after the initial consultation, complications resulting in admission to hospital or death, reconsultation with the same or worsening illness, and patient satisfaction rated on a Likert scale. RESULTS: Data were obtained from nine randomised controlled trials and four observational studies, totalling 55 682 patients. No difference was found in follow-up symptom severity (seven point scale) for delayed versus immediate antibiotics (adjusted mean difference -0.003, 95% confidence interval -0.12 to 0.11) or delayed versus no antibiotics (0.02, -0.11 to 0.15). Symptom duration was slightly longer in those given delayed versus immediate antibiotics (11.4 v 10.9 days), but was similar for delayed versus no antibiotics. Complications resulting in hospital admission or death were lower with delayed versus no antibiotics (odds ratio 0.62, 95% confidence interval 0.30 to 1.27) and delayed versus immediate antibiotics (0.78, 0.53 to 1.13). A significant reduction in reconsultation rates (odds ratio 0.72, 95% confidence interval 0.60 to 0.87) and an increase in patient satisfaction (adjusted mean difference 0.09, 0.06 to 0.11) were observed in delayed versus no antibiotics. The effect of delayed versus immediate antibiotics and delayed versus no antibiotics was not modified by previous duration of illness, fever, comorbidity, or severity of symptoms. Children younger than 5 years had a slightly higher follow-up symptom severity with delayed antibiotics than with immediate antibiotics (adjusted mean difference 0.10, 95% confidence interval 0.03 to 0.18), but no increased severity was found in the older age group. CONCLUSIONS: Delayed antibiotic prescribing is a safe and effective strategy for most patients, including those in higher risk subgroups. Delayed prescribing was associated with similar symptom duration as no antibiotic prescribing and is unlikely to lead to poorer symptom control than immediate antibiotic prescribing. Delayed prescribing could reduce reconsultation rates and is unlikely to be associated with an increase in symptoms or illness duration, except in young children. STUDY REGISTRATION: PROSPERO CRD42018079400.

Supporting self-care for eczema: protocol for two randomised controlled trials of ECO (Eczema Care Online) interventions for young people and parents/carers.

INTRODUCTION: Eczema care requires management of triggers and various treatments. We developed two online behavioural interventions to support eczema care called ECO (Eczema Care Online) for young people and ECO for families. This protocol describes two randomised controlled trials (RCTs) aimed to evaluate clinical and cost-effectiveness of the two interventions. METHODS AND ANALYSIS: Design: Two independent, pragmatic, unmasked, parallel group RCTs with internal pilots and nested health economic and process evaluation studies. Setting: Participants will be recruited from general practitioner practices in England. Participants: Young people aged 13-25 years with eczema and parents and carers of children aged 0-12 years with eczema, excluding inactive or very mild eczema (five or less on Patient-Oriented Eczema Measure (POEM)). Interventions: Participants will be randomised to online intervention plus usual care or to usual eczema care alone. Outcome measures: Primary outcome is eczema severity over 24 weeks measured by POEM. Secondary outcomes include POEM 4-weekly for 52 weeks, quality of life, eczema control, itch intensity (young people only), patient enablement, health service and treatment use. Process measures include treatment adherence, barriers to adherence and intervention usage. Our sample sizes of 303 participants per trial are powered to detect a group difference of 2.5 (SD 6.5) in monthly POEM scores over 24 weeks (significance 0.05, power 0.9), allowing for 20% loss to follow-up. Cost-effectiveness analysis will be from a National Health Service and personal social service perspective. Qualitative and quantitative process evaluation will help understand the mechanisms of action and participant experiences and inform implementation. ETHICS AND DISSEMINATION: The study has been approved by South Central Oxford A Research Ethics Committee (19/SC/0351). Recruitment is ongoing, and follow-up will be completed by mid-2022. Findings will be disseminated to participants, the public, dermatology and primary care journals, and policy makers. TRIAL REGISTRATION NUMBER: ISRCTN79282252.

Clustering of continuous and binary outcomes at the general practice level in individually randomised studies in primary care - a review of 10 years of primary care trials.

BACKGROUND: In randomised controlled trials, the assumption of independence of individual observations is fundamental to the design, analysis and interpretation of studies. However, in individually randomised trials in primary care, this assumption may be violated because patients are naturally clustered within primary care practices. Ignoring clustering may lead to a loss of power or, in some cases, type I error. METHODS: Clustering can be quantified by intra-cluster correlation (ICC), a measure of the similarity between individuals within a cluster with respect to a particular outcome. We reviewed 17 trials undertaken by the Department of Primary Care at the University of Southampton over the last ten years. We calculated the ICC for the primary and secondary outcomes in each trial at the practice level and determined whether ignoring practice-level clustering still gave valid inferences. Where multiple studies collected the same outcome measure, the median ICC was calculated for that outcome. RESULTS: The median intra-cluster correlation (ICC) for all outcomes was 0.016, with interquartile range 0.00-0.03. The median ICC for symptom severity was 0.02 (interquartile range (IQR) 0.01 to 0.07) and for reconsultation with new or worsening symptoms was 0.01 (IQR 0.00, 0.07). For HADS anxiety the ICC was 0.04 (IQR 0.02, 0.05) and for HADS depression was 0.02 (IQR 0.00, 0.05). The median ICC for EQ. 5D-3 L was 0.01 (IQR 0.01, 0.04). CONCLUSIONS: There is evidence of clustering in individually randomised trials primary care. The non-zero ICC suggests that, depending on study design, clustering may not be ignorable. It is important that this is fully considered at the study design phase.