Abstract\nBackground\nPeople with severe mental illnesses (SMI) such as schizophrenia die on average 15 to 20 years earlier than everyone else. Two thirds of these deaths are from preventable physical illnesses such as hypertension, cardiovascular disease, and diabetes, which are worsened by weight gain. Antipsychotics are associated with significant weight gain. In REalist Synthesis Of non-pharmacologicaL interVEntions (RESOLVE), a realist synthesis, combining primary and secondary data, will be used to understand and explain how, why, for whom, and in what contexts non-pharmacological interventions can help service users to manage antipsychotic-induced weight gain.\n\nMethods\nA five-step approach will be used to develop guidance:\n1. Developing the initial programme theory\nAn initial (candidate) programme theory, which sets out how and why outcomes occur within an intervention, will be developed.\n2. Developing the search\nThe initial programme theory will be refined using academic and grey literature. The proposed initial sampling frame are as follows:\nContext: people living with SMI, taking antipsychotics, different types of SMI.\nIntervention: non-pharmacological interventions.\nMechanisms: triggered by the intervention.\nOutcomes e.g. weight, metabolic adverse events, quality of life, adherence, burden, economic.\nSearching for relevant documents will continue until sufficient data is found to conclude that the refined programme theory is coherent and plausible. Lived experience (service users) and stakeholder (practitioners) groups will provide feedback.\n3. Selection, appraisal and data extraction\nDocuments will be screened against inclusion and exclusion criteria. The text extracted from these documents will be coded as contexts, mechanisms and their relationships to outcomes.\n4. Primary data collection\nRealist interviews with up to 30 service users and informal carers, and 20 practitioners will gather data to support, refute or refine the programme theory.\n5. Data analysis\nA realist logic of analysis will be used to develop and refine the programme theory from secondary and primary data. The analysis will aim to identify practical intervention strategies to change contexts so that key mechanisms are triggered to produce desired outcomes. Guidance will be produced based on these strategies.\n\nDiscussion\nThis realist synthesis aims to develop guidance for service users and practitioners on the most appropriate interventional strategies to manage and limit antipsychotic weight gain.\n\nSystematic review registration\nPROSPERO: CRD42021268697\n
\n \n\n \n \nBlood eosinophils are a potentially useful biomarker for guiding inhaled corticosteroid (ICS) treatment decisions in COPD. We investigated whether existing blood eosinophil counts predict benefit from initiation of ICS compared to bronchodilator therapy. We used routinely collected data from UK primary care in the Clinical Practice Research Datalink. Participants were aged \u2a7e40 years with COPD, were ICS-na\u00efve and starting a new inhaled maintenance medication (intervention group: ICS; comparator group: long-acting bronchodilator, non-ICS). Primary outcome was time to first exacerbation, compared between ICS and non-ICS groups, stratified by blood eosinophils (\u201chigh\u201d \u2a7e150 cells\u00b7\u00b5L\u22121 and \u201clow\u201d <150 cells\u00b7\u00b5L\u22121 ). Out of 9475 eligible patients, 53.9% initiated ICS and 46.1% non-ICS treatment with no difference in eosinophils between treatment groups ( p=0.71). Exacerbation risk was higher in patients prescribed ICS than those prescribed non-ICS treatment, but with a lower risk in those with high eosinophils (hazard ratio (HR) 1.04, 95% CI 0.98\u20131.10) than low eosinophils (HR 1.19, 95% CI 1.09\u20131.31) ( p-value for interaction 0.01). Risk of pneumonia hospitalisation with ICS was greatest in those with low eosinophils (HR 1.26, 95% CI 1.05\u20131.50; p-value for interaction 0.04). Results were similar whether the most recent blood eosinophil count or the mean of blood eosinophil counts was used. In a primary care population, the most recent blood eosinophil count could be used to guide initiation of ICS in COPD patients. We suggest that ICS should be considered in those with higher eosinophils and avoided in those with lower eosinophils (<150 cells\u00b7\u00b5L\u22121).
\n \n\n \n \nBackground: It remains unclear to what extent reductions in urgent referrals for suspected cancer during the COVID-19 pandemic were the result of fewer patients attending primary care compared to GPs referring fewer patients. Methods: Cohort study including electronic health records data from 8,192,069 patients from 663 English practices. Weekly consultation rates, cumulative consultations and referrals were calculated for 28 clinical features from the NICE suspected cancer guidelines. Clinical feature consultation rate ratios (CRR) and urgent referral rate ratios (RRR) compared time periods in 2020 with 2019. Findings: Consultations for cancer clinical features decreased by 24.19% (95% CI: 24.04\u201324.34%) between 2019 and 2020, particularly in the 6\u201312 weeks following the first national lockdown. Urgent referrals for clinical features decreased by 10.47% (95% CI: 9.82\u201311.12%) between 2019 and 2020. Overall, once patients consulted with primary care, GPs urgently referred a similar or greater proportion of patients compared to previous years. Conclusion: Due to the significant fall in patients consulting with clinical features of cancer there was a lower than expected number of urgent referrals in 2020. Sustained efforts should be made throughout the pandemic to encourage the public to consult their GP with cancer clinical features.
\n \n\n \n \nBACKGROUND: Urine collection devices (UCD) are being marketed and used in clinical settings to reduce urine sample contamination, despite inadequate supporting evidence. AIM: To determine whether UCDs, compared to standardised instructions for urine sample collection, reduce the proportion of contaminated samples. Design, Setting: Single blind randomised controlled trial in UK Primary care. METHOD: Women aged \u2265 18 years presenting to with symptoms attributable to urinary tract infection (UTI) were randomised (1:1:1) to use either a Peezy UCD, a Whizaway Midstream UCD, or standardised verbal instructions (SVI) for midstream sample collection. The primary outcome was the proportion of urine samples reported as contaminated by microbiology laboratory analysis. RESULTS: 1264 women (Peezy n=424; Whizaway n=421; SVI n=419) were randomised between 5/10/16 and 20/8/18. 90 women were excluded from the primary analysis due to ineligibility or lack of primary outcome data, leaving 1174 (n=381; n=390; n=403) for intention-to-treat analysis. The proportion of contaminated samples was 26.5% with the Peezy, 28.2% Whizaway, and 29% SVI (relative risk (RR) Peezy v SVI 0.91 [95% Confidence Interval (CI) 0.76 to 1.09] (P = 0.32); Whizaway v SI 0.98 [95% CI 0.97 to 1.20] (P = 0.82)). There were 100 (25.3%) device failures with Peezy and 35 (8.8%) with Whizaway UCDs; the proportion of contaminated samples was similar after device failure samples were excluded. CONCLUSION: Neither Peezy nor Whizaway UCDs reduced sample contamination when used by women presenting to primary care with suspected UTI. Their use cannot be recommended for this purpose in this setting.
\n \n\n \n \nINTRODUCTION: Clinical depression is usually treated in primary care with psychological therapies and antidepressant medication. However, when patients do not respond to at least two or more antidepressants within a depressive episode, they are considered to have treatment resistant depression (TRD). Previous small randomised controlled trials suggested that pramipexole, a dopamine D2/3 receptor agonist, may be effective for treating patients with unipolar and bipolar depression as it is known to influence motivational drive and reward processing. PAX-D will compare the effects of pramipexole vs placebo when added to current antidepressant medication for people with TRD. Additionally, PAX-D will investigate the mechanistic effect of pramipexole on reward sensitivity using a probabilistic decision-making task. METHODS AND ANALYSIS: PAX-D will assess effectiveness in the short- term (during the first 12 weeks) and in the longer-term (48 weeks) in patients with TRD from the UK. The primary outcome will be change in self-reported depressive symptoms from baseline to week 12 post-randomisation measured using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Performance on the decision-making task will be measured at week 0, week 2 and week 12. Secondary outcomes include anhedonia, anxiety and health economic measures including quality of life, capability, well-being and costs. PAX-D will also assess the adverse effects of pramipexole including impulse control difficulties. DISCUSSION: Pramipexole is a promising augmentation agent for TRD and may be a useful addition to existing treatment regimes. PAX-D will assess its effectiveness and test for a potential mechanism of action in patients with TRD. TRIAL REGISTRATION NUMBER: ISRCTN84666271.
\n \n\n \n \nBackground: Failure to take medicines for diabetes as prescribed contributes to poor outcomes from the condition. Mobile phones are ubiquitous and short message service (SMS) texts have shown promise as a low-cost intervention. We tested the effectiveness of SMS-text messaging in improving outcomes in adults with type 2 diabetes. Methods: StAR2D was a 12-month two-arm randomised trial of SMS-text messaging and usual care in Cape Town, South Africa and Lilongwe, Malawi. Messages used behaviour change theory and were developed with patients and staff. The intervention group received four messages each week. The primary outcome was change in HbA1c. Secondary outcomes were the proportion of patients who collected > 80% medication and changes in systolic blood pressure, lipids, cardiovascular risk, and the proportion of the participants reaching treatment goals. Results: The trial took place between 1 October, 2016 and 1 October 2018, 1186 participants were randomised to intervention (593) and control (593) groups. 91% of participants completed follow-up. There was a reduction in HbA1c (DCCT) in both groups but not in mean change (95% CI) between groups (\u2212 0.08% (\u2212 0.31 to 0.16) (IFCC \u2212 0.82 mmol/mol (\u2212 3.44 to 1.79). There was a small but not significant increase in the proportions of participants likely to have collected 80% or more of medication (Relative risk 1.11 (0.84 to 1.47; P\u00a0= 0.47). There was a significant difference between groups in change in systolic blood pressure from baseline of 3.46 mmHg (1.48 to 5.44, P\u00a0= 0.001) in favour of the intervention group. The between group difference in change in 10-year risk of coronary heart disease was \u2212 0.71% (\u2212 1.46 to 0.04, P\u00a0= 0.064). The proportion of participants meeting treatment goals in the intervention group was 36.0% and in the control group 26.8% (Relative risk 1.36 (1.13 to 1.63, P\u00a0= 0.001). Participants reported many challenges to adherence despite finding messages acceptable and useful. Conclusions: Whilst SMS text messages do not lead to improved glycaemia in these low-resource settings there appeared to be an impact on blood pressure and achievement of treatment goals but the mechanisms for this are unclear. Text messages alone, may be unsuccessful unless accompanied by health system strengthening and other forms of self-management support for type 2 diabetes. Trial registration: Trial registration: ISRCTN, ISRCTN70768808. Registered 1 July 2015, http://www.isrctn.com/I ISRCTN70768808.
\n \n\n \n \nIntroduction There is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications. Methods and analysis The Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50-64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 'hot hubs' and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes. Ethics and dissemination Ethical approval Ref: 20/SC/0158 South Central - Berkshire Research Ethics Committee; IRAS Project ID: 281958; EudraCT Number: 2020-001209-22. Results will be presented to policymakers and at conferences and published in peer-reviewed journals. Trial registration number ISRCTN86534580.
\n \n\n \n \nBACKGROUND: Obtaining accurate estimates of the risk of COVID-19-related death in the general population is challenging in the context of changing levels of circulating infection. METHODS: We propose a modelling approach to predict 28-day COVID-19-related death which explicitly accounts for COVID-19 infection prevalence using a series of sub-studies from new landmark times incorporating time-updating proxy measures of COVID-19 infection prevalence. This was compared with an approach ignoring infection prevalence. The target population was adults registered at a general practice in England in March 2020. The outcome was 28-day COVID-19-related death. Predictors included demographic characteristics and comorbidities. Three proxies of local infection prevalence were used: model-based estimates, rate of COVID-19-related attendances in emergency care, and rate of suspected COVID-19 cases in primary care. We used data within the TPP SystmOne electronic health record system linked to Office for National Statistics mortality data, using the OpenSAFELY platform, working on behalf of NHS England. Prediction models were developed in case-cohort samples with a 100-day follow-up. Validation was undertaken in 28-day cohorts from the target population. We considered predictive performance (discrimination and calibration) in geographical and temporal subsets of data not used in developing the risk prediction models. Simple models were contrasted to models including a full range of predictors. RESULTS: Prediction models were developed on 11,972,947 individuals, of whom 7999 experienced COVID-19-related death. All models discriminated well between individuals who did and did not experience the outcome, including simple models adjusting only for basic demographics and number of comorbidities: C-statistics 0.92-0.94. However, absolute risk estimates were substantially miscalibrated when infection prevalence was not explicitly modelled. CONCLUSIONS: Our proposed models allow absolute risk estimation in the context of changing infection prevalence but predictive performance is sensitive to the proxy for infection prevalence. Simple models can provide excellent discrimination and may simplify implementation of risk prediction tools.
\n \n\n \n \nBackground: Use of telephone, video and e-consultations is increasing. These can make consultations more transactional. This study aimed to develop a complex intervention to address patients\u2019 concerns more comprehensively in general practice and test the feasibility of this in a cluster-randomised framework. The complex intervention used two technologies: a patient-completed pre-consultation form used at consultation opening and a doctor-provided summary report provided at consultation closure. This paper reports on the development and realist evaluation of the summary report. Methods: A person-based approach was used to develop the summary report. An electronic protocol was designed to automatically generate the report after GPs complete a clinical template in the patient record. This was tested with 45 patients in 3 rounds each, with iterative adjustments made based on feedback after each round. Subsequently, an intervention incorporating the pre-consultation form with the summary report was then tested in a cluster-randomised framework with 30 patients per practice in six practices: four randomised to intervention, and two to control. An embedded realist evaluation was carried out. The main feasibility study results are reported elsewhere. Results: Intervention Development: 15 patients were recruited per practice. Eight patients and six GPs were interviewed and 18 changes made. The summary report improved substantially; GPs and patients in the final practice were more satisfied with the report than the first practice. Realist evaluation: The summary was most useful for consultations when safety-netting advice was important or with multiple complex follow-up steps in patients who have difficulty remembering or communicating. It generated greater clarity on the follow-up and greater patient empowerment and reassurance. Conclusions: The person-based approach was successful. The summary report creates clarity, empowerment and reassurance in certain consultations and patients. As it takes a few minutes per patient, GPs prefer to select patients who will benefit most.
\n \n\n \n \nBackground: Use of telephone, video and e-consultations is increasing. These can make consultations more transactional, potentially missing patients\u2019 concerns. This study aimed to develop a complex intervention to address patients\u2019 concerns more comprehensively in general practice and test the feasibility of this in a cluster-randomised framework. The complex intervention used two technologies: a patient-completed pre-consultation form used at consultation opening and a doctor-provided summary report provided at consultation closure. This paper reports on the development and realist evaluation of the pre-consultation questionnaire. Methods: A person-based approach was used to develop the pre-consultation form.\u00a0 An online questionnaire system was designed to allow patient self-completion of a form which could be shared with GPs. This was tested with 45 patients in three rounds, with iterative adjustments made based on feedback after each round. Subsequently, an intervention incorporating the pre-consultation form with the summary report was then tested in a cluster-randomised framework with 30 patients per practice in six practices: four randomised to intervention, and two to control. An embedded realist evaluation was carried out. The main feasibility study results are reported elsewhere. Results: Intervention Development: 15 patients were recruited per practice. Twelve patients, six GPs and three administrators were interviewed and 32 changes were made iteratively in three rounds. Recruitment rates (proportion of patients responding to the text) increased from 15% in round one to 50% in round three. Realist evaluation: The pre-consultation form was most useful for people comfortable with technology and with hidden concerns or anxiety about the consultation. It resulted in more issues being discussed and support provided, more effective use of time and greater patient satisfaction. Conclusions: The person-based approach was successful. The pre-consultation form uncovers more depth and improves satisfaction in certain consultations and patients. Technological improvements are required before this could be rolled out more widely.
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