There are major concerns about the decline in translational research capacity in the UK with potential knock-on implications for advances in clinical care and the growth of the life sciences sector. As co-leads and student representative for a UK-wide Postgraduate Training and Capacity building programme for the Asthma UK Centre for Applied Research (AUKCAR), we have learnt much from our 10 years of developing and delivering a UK-wide academic training initiative involving 17 partner universities. We discuss learnings from a broader research capacity building perspective, with a focus on maintaining a pipeline of respiratory-interested researchers, including clinical academics. In this article, we reflect on what we hoped to achieve, the lessons learnt along the way, and implications for others seeking to improve the research pipeline.

Abstract Seasonal respiratory viral infections are the major cause of increased pressure on national health systems such as the UK’s national health service (NHS) during winter months. Emergency departments and hospitals are full as increasing numbers of patients require hospitalisation for lower respiratory tract infections and exacerbations of COPD, asthma, and other respiratory conditions. These winter pressures are largely predictable. Forecasting models give healthcare managers the chance to mitigate winter pressures by allocating resources more effectively. Despite this predictability and the production of NHS resilience plans, the UK is particularly susceptible to winter pressures. Communities facing social and environmental disadvantage are at increased risk of hospitalisation. Despite the focus on real-life research and guideline dissemination and implementation over the last 20–30 years, care of patients with respiratory conditions in the UK remains sub-optimal. To tackle winter pressures, a different approach is needed. The UK Centre for Applied Respiratory Research Innovation and Impact (CARRii) is a new UK-wide network which aims to drive policy change and use innovative ways of implementing research to achieve maximum impact on patient care. Its missions are to reduce NHS winter pressures and respiratory health inequalities, and its focus is on three areas: prevention; self-management and connected care; and optimisation of clinical care. CARRii unites leading experts across respiratory research, clinical medicine, data science, public health, industry innovation, and patient advocacy. CARRii’s first Annual Scientific Meeting was held recently. Implementation of research is more likely to succeed if it is based on real-world data, there is multi-agency involvement in its design and implementation, it is patient-focussed, and policy makers are convinced of its benefits. By positioning implementation and impact as a central scientific goal, CARRii aims to show how healthcare systems can deliver respiratory solutions at scale. This requires investment and cross-sector collaboration. If successful, this approach will reduce winter pressures, improve health equity and strengthen system resilience.

Pharmacovigilance is vital for post-market drug safety monitoring. Traditional trials inadequately capture adverse reactions. Patient-generated opinions offer valuable insights but pose challenges due to limited availability, inefficient annotation scheme, and volume of drug reviews, indicating the need of automation. To address the challenge posed by the limited availability of annotated drug reviews, we introduce a novel mechanism of annotating drug reviews dataset through human intervention, specifically tailored for Aspect Term Extraction (ATE) and Polarity Detection (PD) in three medical conditions: Depression, Arthritis and Birth control, thereby making it publicly available to facilitate future research. We first designed, ATEdrug, an automated annotation scheme with minimal human intervention by employing an expert-driven rule-based approach. We further deploy ATEdrug for sequence labelling and classification tasks in drug reviews. The automatically labeled data is further used for training and testing of deep learning models: BERT, BioBERT, and ClinicalBERT, for clinical use. We manually evaluate the results through annotator agreement to validate the effectiveness of ATEdrug. The labeled dataset is further used to construct transformer-based models. Our proposed model is reliable, safe and trustworthy for healthcare domain, thereby eliminating the compromises with hallucination and data security through generative AI models. All experimental codes and data are available on GitHub (https://github.com/CMOONCS/ateDrug.git).

BACKGROUND:Inequalities in chronic respiratory diseases persist, yet up-to-date evidence on outcomes remains limited. We described national mortality and exacerbation rates in people with asthma and chronic obstructive pulmonary disease (COPD) since the beginning of the COVID-19 pandemic and assessed variation by inequalities. METHODS:England primary care records from the General Practice Extraction Service data for Pandemic Planning and Research were linked to Hospital Episode Statistics and Office for National Statistics mortality data. Cohorts of primary care diagnosed asthma and COPD were defined prior to 1 November 2019. Monthly age-sex-standardised exacerbation rates (Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) and Internationl Classification of Diseases (ICD) 10 codes) and mortality rates (ICD-10 codes) were calculated from 1 November 2019 to 31 March 2025, stratified by sex, Index of Multiple Deprivation (IMD), ethnicity and region. RESULTS:The study included 7644 510 people with asthma and 1 211 975 with COPD. Mean monthly exacerbation rates were higher in females than males (33% and 30% higher for asthma and COPD, respectively), while mean monthly all-cause mortality rates were 13% and 15% higher in males than females. Mean monthly exacerbation and all-cause mortality rates were higher in IMD-1 compared with IMD-10 across all conditions (asthma: 123% and 100% higher, COPD: 68% and 41% higher, respectively). Mean monthly all-cause mortality and exacerbation rates were higher in the northeast than the southwest (asthma: 22% and 69% COPD: 15% and 42% higher, respectively). Outcome rates varied by ethnicity across conditions. CONCLUSIONS:Inequalities in chronic respiratory disease outcomes persist across England despite sustained policy focus on reducing health inequalities.

Immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis, psoriasis, inflammatory bowel disease, and severe asthma, affect millions of people worldwide and often require long-term treatment with targeted immune-modifying therapies such as biologics and Janus kinase (JAK) inhibitors. While these therapies have significantly improved disease outcomes, they are associated with potential safety risks, including serious infections, cardiovascular events, thromboembolism, and malignancies. Traditional pharmacovigilance approaches and clinical trials may not fully capture these rare but clinically important outcomes due to limited follow-up and selective study populations. Linked real-world health data offer opportunities to strengthen post-marketing medicines safety surveillance; however, exposure data for specialist medicines supplied through homecare services are often poorly integrated with national outcome datasets. This study aims to evaluate the feasibility of using the Medicines in Acute and Chronic Care in Scotland (MACCS) linked data infrastructure to support real-world safety surveillance of targeted immune-modifying therapies across immune-mediated inflammatory diseases. A national retrospective cohort study will be conducted using linked routinely collected healthcare datasets within the MACCS environment in Scotland. Adults aged ≥18 years initiating targeted immune-modifying therapies supplied through NHS Homecare Medicines Services between July 2019 and March 2025 will be included using a new-user design with a 6-month washout period. Exposure data will be derived from national homecare medicines supply records and deterministically linked to hospital admissions, cancer registry, critical care, prescribing, and mortality datasets. Primary safety outcomes include serious infections, major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and malignancies. Secondary outcomes include all-cause hospitalisations, critical care admissions, and mortality. Analyses will primarily be descriptive, with incidence rates calculated per 1,000 person-years. Where event counts permit, exploratory Cox proportional hazards models will assess associations between therapy classes and safety outcomes. As of March 2025, the MACCS environment includes nationally aggregated Homecare Medicines Services data from six providers representing approximately 98% of the Scottish homecare medicines market. Data linkage with national hospital, cancer, and mortality datasets has been successfully implemented with linkage rates exceeding 99%. Cohort construction using the new-user design has been completed, and preliminary analyses confirm that therapy exposure can be reliably linked to downstream clinical outcomes. Final analyses are ongoing and are expected to be completed by June 2026. This study will provide the first evaluation of whether nationally linked homecare medicines supply data can support systematic safety surveillance of targeted immune-modifying therapies across multiple immune-mediated diseases. Demonstrating the feasibility of this approach could inform the development of scalable real-world pharmacovigilance systems capable of generating timely regulatory safety evidence and supporting next-generation medicines safety monitoring in the UK.

BACKGROUND:Preexisting multiple (two or more) long-term conditions (MLTCs) may negatively affect recovery after COVID-19. We investigated how preexisting MLTCs, including different categorization and patterns of MLTCs, affect 1-year health outcomes after severe COVID-19. METHODS:Adults post-hospitalization after COVID-19 were recruited during 2020-2021. We compared recovery at 1 year after discharge using adjusted multivariable logistic regression in 1:1 propensity-matched adults (for age, sex, ethnicity, social deprivation, obesity, and smoking history) with and without preexisting MLTCs. In adults with MLTCs, different categorization such as number of conditions, number and types of body systems involved (e.g. respiratory, cardiovascular), and latent class analysis-derived patterns of condition co-occurrence were assessed for their association with recovery at 1 year. RESULTS:A total of 647 adults with MLTCs were matched with 647 adults without MLTCs (n = 1294; 61.9% male, 79.6% of White ethnicity, median age 59 [interquartile range 52-67] years). The presence of MLTCs was associated with lower odds of feeling fully recovered (odds ratio 0.66 [95% confidence interval 0.51-0.85], P = 0.001). In those with MLTCs, recovery was negatively affected by number and type of body systems involved (e.g. respiratory [odds ratio 0.49 (95% confidence interval 0.34-0.69), P <0.001]) but not by the number of conditions (P >0.1). Four latent classes of MLTC co-occurrence were estimated with different risks of recovery (P <0.01). CONCLUSION:Adults with preexisting MLTCs were 34% less likely to feel fully recovered at 1 year after COVID-19 hospitalization than adults without MLTCs. We describe prognostic classifications of MLTCs, with future work needed to understand whether they have prognostication in broader post-acute infection sequalae.

Hypertension is a leading contributor to cardiovascular disease in South Asia, affecting over 40% of adults, of whom most remain undiagnosed or poorly managed. Despite urgent healthcare needs, the already overstretched public primary care systems in low-and middle-income countries, particularly in rapidly growing urban areas, are falling short. Community pharmacies, often the first point of contact for low-income urban residents, represent an opportunity for delivering frontline chronic disease care. The Community-Pharmacies managing hypertension: intervention development and Evaluation in Bangladesh and Pakistan (COPE-BP) programme aims to investigate whether these widely accessed yet under-evaluated community pharmacists are effective and cost-effective, and assess whether the COPE-BP intervention can be successfully integrated into hypertension care pathways in Bangladesh and Pakistan. Beyond evaluating clinical and economic outcomes, COPE-BP seeks to reframe the role of semi-formal providers, including community pharmacies, which are key actors in primary care delivery. Through a stepwise programme encompassing intervention development, a multicentre clinical trial, implementation research, and policy engagement, COPE-BP aims to provide a scalable model for integrating non-traditional providers into national health strategies. In doing so, COPE-BP will help strengthen inclusive, people-centred health systems in LMICs.

INTRODUCTION:Pakistan implemented the Track and Trace System (TTS) to administer cigarette tax in July 2022. We assessed its implementation by examining the presence and validity of tax stamps (evidence of tax collection) on cigarette packs and how these varied by manufacturer and over time. METHODS:We collected cigarette packs from points-of-sale (POS) in two waves: August 2023 (POS=648) and October 2024 (POS=718). POS were located within a stratified random sample of 72 enumeration blocks (EBs) within purposively selected nine districts of Pakistan. Within each EB, we collected one cigarette pack per brand variant. These were examined for the presence and validity of digital tax stamps using the TransAct mobile app. RESULTS:We collected 1617 and 2278 cigarette packs in waves I and II, respectively. The presence of tax stamps was higher on the cigarette packs manufactured by the local subsidiary of British American Tobacco, Pakistan Tobacco Company (PTC) (2023: 89.9% (295/328) and 2024: 97.7% (428/438)) and Philip Morris International (PMI) (2023: 79.0% (207/262) and 2024: 83.7% (302/361)) than those manufactured by local companies (2023: 1.9% (17/893) and 2024: 3.9% (56/1440)). Between 2023 and 2024, the proportion of packs bearing valid tax stamps increased from 53.2% (157/295) to 77.6% (332/428) (p<0.001) for PTC and from 56.0% (116/207) to 79.1% (239/302) (p<0.001) for PMI; for local manufacturers, the increase from 52.9% (9/17) to 80.4% (45/56) was non-significant (p=0.10). CONCLUSION:Within 2 years of TTS implementation, cigarette tax administration improved significantly for the two leading multinational manufacturers, but not for local manufacturers.

BACKGROUND:A regional trial indicated that implementing at-risk asthma registers in primary care could reduce hospital admissions. This national study assessed whether the intervention lowered asthma crisis events. METHODS:This cluster randomised trial involved 275 UK primary care practices. The intervention included identifying at-risk patients, staff training, a clinical decision support system alerting practice staff to patients' at-risk status to facilitate prompt and opportunistic care, and ongoing support. Control practices continued with standard care. Patients (n=10 945) were included if identified as at-risk, unless they declined data sharing. Routine data linked across care settings captured asthma-related crisis events (hospitalisations, accident and emergency visits or death), asthma care indicators and healthcare costs over 12 months. RESULTS:Complete data were available from 185 practices (6207 patients), with exclusions mainly due to record linkage issues. Crisis events occurred in 7.2% of control versus 6.3% of intervention patients (OR 0.82, 95% CI 0.66 to 1.03, p=0.09). Individual components of the composite outcome showed similar, non-significant reductions. The use of systemic corticosteroids for asthma attacks had an OR of 1.18 (95% CI 0.99 to 1.41, p=0.07); personalised asthma action plans, OR 1.05 (95% CI 0.78 to 1.42, p=0.74); inhaler technique assessments, OR 1.13 (95% CI 0.93 to 1.38, p=0.23). Economic analysis estimated the intervention was cost-effective, with average annual National Health Service costs £306 lower in the intervention group. CONCLUSION:This trial did not provide sufficient evidence to show that the establishment and integration of at-risk registers for asthma in primary care reduces asthma-related crisis events for people with at-risk asthma, but there was some indication of benefit. TRIAL REGISTRATION NUMBER:ISRCTN95472706.

Background Hazardous prescribing is an important and expensive preventable cause of patient harm, which can be identified using electronic healthcare records. In our Programme Grant we investigated the large-scale roll-out of a type of clinical decision support called OptimiseRx® (First Databank, Hearst Health, Exeter, United Kingdom) (which had not been independently evaluated previously) and two large-scale roll-outs of pharmacist-led IT-based intervention (an intervention that had been shown to reduce hazardous prescribing in a cluster randomised trial). Objectives To estimate harm and economic impact of specific hazardous prescribing events. To investigate whether a clinical decision support intervention (OptimiseRx) was associated with reduction in hazardous prescribing. To investigate whether a pharmacist-led IT-based intervention was associated with reduction in hazardous prescribing. To undertake economic and process evaluations of both interventions. Design and methods The harm and economic impact of hazardous prescribing events were investigated using data from published sources to generate estimates of patient outcomes and cost associated with 11 prescribing safety indicators. An incomplete (not randomised) stepped-wedge design study with control groups was used to investigate the effectiveness of OptimiseRx (409 general practices). Incremental cost-effectiveness ratios were generated for OptimiseRx compared with standard care (cost per hazardous prescribing event prevented), subgroup analysis: cost per quality-adjusted life-year. Incomplete stepped-wedge design studies [East Midlands study (343 and 115 general practices); whole of England study (725 and 179 general practices)] investigated the effectiveness of pharmacist-led IT-based intervention. Incremental cost-effectiveness ratios were generated for pharmacist-led IT-based intervention compared with standard care (cost per hazardous prescribing event prevented, cost per quality-adjusted life-year). Data from interviews, focus groups, a survey and stakeholder events were analysed qualitatively to identify factors influencing the sustained implementation and operation of OptimiseRx or pharmacist-led IT-based intervention. Setting and participants The interventions took place in general practices in England. The process evaluation involved clinicians, patients and other stakeholders in England. Interventions Clinical decision support intervention (OptimiseRx). Pharmacist-led IT-based intervention. Main outcome measures Changes in hazardous prescribing rates. Cost per quality-adjusted life-year. Data sources Clinical Practice Research Datalink. ResearchOne. General practice clinical records. Process evaluation with clinicians, patients and other stakeholders. Results All the hazardous prescribing events studied were associated with loss of quality-adjusted life-years. The costliest for the National Health Service were prescriptions of antipsychotics to patients with dementia (£1168 per patient) and anticoagulants in combination with nonsteroidal anti-inflammatory drugs (£1020 per patient). Of 409 practices included in the clinical decision support study, 227 (56%) were intervention practices. Deployment of OptimiseRx was associated with a 10% reduction in exposure to hazardous prescribing after 2 years (odds ratio 0.90, 95% confidence interval 0.88 to 0.92). OptimiseRx costs £14–48 per hazardous prescribing event prevented, depending on time point and patient volume. Based on two indicators only, OptimiseRx costs £236 per quality-adjusted life-year gained at 6 months and becomes dominant (quality-adjusted life-year increasing; cost saving) at 24 months. Of 343 general practices included in the East Midlands pharmacist-led IT-based intervention evaluation, we completed further data extraction for 115 (33.5%) of these. Pharmacist-led IT-based intervention was associated with a decrease in hazardous prescribing of 18% (adjusted odds ratio 0.82, 95% confidence interval 0.78 to 0.86) at 6 months, and 22% (adjusted odds ratio 0.78, 95% confidence interval 0.73 to 0.84) at 24 months post intervention. Pharmacist-led IT-based intervention generates approximately 0.15 quality-adjusted life-years per practice extra compared with no intervention. Expected savings do not fully offset delivery costs, so pharmacist-led IT-based intervention costs just over £1000 per practice. Pharmacist-led IT-based intervention was estimated to be £7449. With 12- and 24-month intervention effects, health gains rise to over 0.2 quality-adjusted life-years and net expenditure falls to < £800 per practice; around £3500 per quality-adjusted life-year gained. Of 725 practices that implemented pharmacist-led IT-based intervention nationally, we had usable data for only 179 because of the COVID-19 pandemic. For these practices, pharmacist-led IT-based intervention was associated with a reduction in hazardous prescribing of 11% (adjusted odds ratio 0.89, 95% confidence interval 0.86 to 0.92) at 6 months post intervention. The process evaluation studies demonstrated the importance of collaboration and system-level support for the clinical decision support and pharmacist-led IT-based interventions. Limitations The main limitation was that we could not robustly evaluate the impact of OptimiseRx on serious harm outcomes and the analysis was limited for pharmacist-led IT-based intervention because of the COVID-19 pandemic. Future work Further research is needed to determine whether interventions that reduce hazardous prescribing, also reduce serious harm to patients. Conclusions Large-scale implementation of OptimiseRx was associated with reduced hazardous prescribing, at less than £50 per hazardous prescribing event avoided. Large-scale implementation of pharmacist-led IT-based intervention was also associated with reduced hazardous prescribing with a cost per quality-adjusted life-year of £7449. It should be noted, however, that these were quasi-experimental studies using observational data and so the findings may have been affected by unknown confounding. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20012) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 15. See the NIHR Funding and Awards website for further award information. Plain language summary There is usually some risk of harm from prescribed medicines, but there are ways of reducing this risk. The purpose of this research was to test two new ways of doing this in general practices. We did some background research to estimate the harm (and costs) associated with certain types of hazardous prescribing. We then looked at computer software called OptimiseRx® which provides ‘alerts’ on the computer screen to warn general practitioners if they are about to prescribe a medicine that may be harmful to the patient. The software has been used in many parts of England since 2014 but had not previously been studied independently. We looked at changes in potentially harmful prescribing from 2011 to 2019 in 409 general practices, including 227 using OptimiseRx. After 2 years, there was a 10% reduction in hazardous prescribing in practices using the software. In another two studies, we looked at the roll-out of an approach called pharmacist-led IT-based intervention, which involves searching general practitioner computer records to find patients who have received medicines which might harm them, and a pharmacist working with the general practice to correct the problems found. In a previous study (a randomised trial) we showed that pharmacist-led IT-based intervention reduced potentially harmful prescribing. The first study looked at changes in potentially harmful prescribing from 2013 to 2019 in relation to the roll-out of pharmacist-led IT-based intervention to 115 general practices in the East Midlands; we found that potentially harmful prescribing went down by 18% after 6 months and 22% after 2 years. The second study looked at changes in potentially harmful prescribing from 2018 to 2020 in relation to the roll-out of pharmacist-led IT-based intervention nationally; for 179 general practices included in the study there was an 11% reduction in hazardous prescribing after 6 months. We talked to patients, health professionals and healthcare leaders about these ways to improve prescribing safety, finding it was important for long-term success, that people worked together and senior leaders gave support. Our studies appear to show that OptimiseRx and pharmacist-led IT-based intervention can reduce potentially harmful prescribing in general practices, but we cannot be sure because these were ‘observational’ studies, and the results may have been influenced by things we were not able to control for. Scientific summary This section contains material reproduced from Penner LS, Gavan SP, Ashcroft DM, Peek N, Elliott RA. Does coprescribing nonsteroidal anti-inflammatory drugs and oral anticoagulants increase the risk of major bleeding, stroke and systemic embolism? Br J Clin Pharmacol 2022;88:4789–811. https://doi.org/10.1111/bcp.15371. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. Background Hazardous prescribing is an important preventable cause of harm to patients. Prescribing safety indicators (PSIs) describe potentially hazardous prescribing events (HPEs) and many of these can be identified using electronic healthcare records. There are two ways in which PSIs have been used in primary care to reduce potentially hazardous prescribing. The first is to incorporate them into computerised clinical decision support (CDS) alerts used at the point of prescribing decision-making; systematic reviews have shown benefits but there have been few studies in primary care. The second is to run computer searches to identify patients with hazardous prescribing and to intervene to reduce risk; we have previously shown the benefits of such an approach in a cluster randomised trial using pharmacists [the pharmacist-led IT-based intervention (PINCER) intervention]. In our Programme Grant we investigated the large-scale roll-out of a type of CDS called OptimiseRx® (First Databank, Hearst Health, Exeter, UK) (which had not been independently evaluated previously) and two large-scale roll-outs of PINCER. Work package 1: Estimating harm and economic impact of hazardous prescribing; validating codes and algorithms Objectives To estimate harm associated with specific HPEs and economic impact of the HPEs in the PINCER intervention. To validate code lists and algorithms for identifying serious harm outcomes (SHOs) associated with the HPEs. Methods Project 1 We conducted two population-based cohort studies using linked primary care [Clinical Practice Research Datalink (CPRD)] and Hospital Episode Statistics (HES) records to examine the risk of serious harm associated with (a) coprescribing nonsteroidal anti-inflammatory drugs (NSAIDs) and oral anticoagulants (OAC) and (b) antipsychotic prescribing in people with dementia. Project 2 Cohort-level state transition (Markov) models were developed to generate estimates of patient outcomes [quality-adjusted life-years (QALYs)] and cost to the NHS in England associated with each of 11 HPEs. Project 3 We validated computer code lists and algorithms used to define five SHOs associated with the HPEs. Four general practices ran computer searches for these SHOs. Clinicians reviewed patient records to identify confirmatory evidence. From this we calculated the positive predictive value (PPV) for each SHO. We compared the number of SHOs identified within primary and secondary care data to estimate percentage of SHOs missed when using either data-source alone. Results Project 1 Compared with OAC therapy alone, concomitant prescription of NSAIDs with OACs was associated with increased risk of gastrointestinal (GI) bleeding [hazard ratio (HR) 3.01, 95% confidence interval (CI) 1.63 to 5.55], stroke (HR 2.71, 95% CI 1.48 to 4.96) and major bleeding (HR 2.77, 95% CI 1.84 to 4.19). Compared with non-exposure, antipsychotic exposure among people with dementia was associated with elevated risks for all outcomes investigated except ventricular arrhythmia. Project 2 All HPEs were associated with QALY loss. The costliest HPEs were prescribing antipsychotics to patients with dementia (£1168) and anticoagulants with NSAIDs (£1020). Project 3 The PPV for the code lists and algorithms for identifying SHOs was at least 70% when the clinical reviewer had ‘moderate certainty’ and between 79% and 95% when they had ‘high certainty’. There were considerable differences between primary care records (CPRD) and secondary care records (HES) in the proportion of SHO cases ‘missed’ when using each type of record alone. Limitations Project 1 Residual confounding cannot be excluded from our studies using observational data. Project 2 A key uncertainty in the economic analysis is how long people subjected to HPEs are exposed to the risk. Project 3 We used a relatively small number of general practices to undertake validation of the SHO codes. Conclusions Coprescription of NSAIDs with OACs was associated with increased risk of GI bleeding. Antipsychotic prescribing in people with dementia was associated with a range of serious adverse outcomes. Hazardous prescribing events are associated with loss of QALYs. The algorithm and codes used to identify the SHOs associated with the PINCER indicators are reasonably specific. The comparison of SHO codes from primary care (CPRD) and secondary care (HES) showed that many serious harms were not identified by either data set alone. Work package 2: Evaluating OptimiseRx clinical decision support Objectives To describe the nature and incidence of prescribing safety alerts generated by OptimiseRx CDS and frequency of alert overrides. To evaluate whether OptimiseRx was associated with reduced hazardous prescribing rates. To assess the cost-effectiveness of OptimiseRx compared with standard practice, and cost per extra QALY in a subgroup analysis of prescribing indicators. Methods Project 1 We conducted a retrospective observational study. We analysed data from general practices contributing to The Phoenix Partnership ResearchOne database (1 January 2014–31 December 2019), some of which deployed OptimiseRx during that period. We estimated the trends in numbers of alerts per practice per month (pppm) over time, and trends in overriding of alerts. Project 2 We analysed 48 PSIs in OptimiseRx. We used patient-level, de-identified primary care data from ResearchOne database from all practices that contributed data between 2011 and 2019. Study design was an incomplete (not randomised) stepped-wedge design with control groups. Intervention practices implemented OptimiseRx between 2014 and 2018 and contributed at least 12 months of post-intervention data; some practices were censored (see synopsis for details) and all others were counted as controls. We derived composite outcomes for all prescribing HPEs, all monitoring HPEs, and three types of prescribing HPE at quarterly intervals. Outcomes were analysed using binomial mixed regression analysis with a random intercept for each practice, adjusting for secular trends and seasonal effects. Assessment points were 6, 12 and 24 months after intervention start. Project 3 We used similar study design, data, indicators and outcomes as work package 2 (WP 2), Project 2. The unit of analysis for Project 3 was the HPE. We estimated the cost of the prescribing safety component of OptimiseRx by apportioning the annual licence-fee according to the proportion of active indicators that relate to safety. We estimated cost per HPE prevented, compared with standard care, by dividing costs for an average practice by expected HPE reduction. We derived a partial estimate of cost-per-QALY-gained for OptimiseRx, compared with standard care, for the two indicators overlapping with PINCER. Results Project 1 In 258 general practices that deployed OptimiseRx, 146,993 interruptive alerts were generated during the study period, of which 109,687 alerts (74.6%) were overridden. On average, 11.1 interruptive alerts were generated by OptimiseRx pppm. In the first 24 months of deployment, the average number of alerts pppm decreased from 12.21 to 10.07, while the average override rate did not change. Project 2 From a total of 409 practices, 31 of the 258 that deployed OptimiseRx were censored, leaving 227 (56%) intervention practices. The percentage of people exposed to at least one prescribing HPE decreased over time, and this trend was accelerated after deployment of OptimiseRx. Two years after the intervention began, OptimiseRx was associated with an additional 10% reduction in exposure to prescribing HPEs [odds ratio (OR) 0.90, 95% CI 0.88 to 0.92] and a 6% reduction in exposure to monitoring HPEs (OR 0.94, 95% CI 0.93 to 0.95). Project 3 We estimate that OptimiseRx costs £44–48, £14–16 and £22–24 per HPE prevented, at 6, 12 and 24 months, respectively. In a subgroup analysis assessing the only two indicators for which we could estimate long-term cost and QALY impacts, OptimiseRx has an incremental cost-effectiveness ratio (ICER) of £236 per QALY gained at 6 months and becomes dominant (QALY-increasing; cost saving) at 24 months. Limitations While our evaluation of OptimiseRx used a quasi-experimental design, it was an observational study and so the reductions in hazardous prescribing could have been due to unknown confounding factors. We did not achieve linkage of primary care data to HES and deaths data and so were not able to evaluate the impact of OptimiseRx on SHOs. Conclusions The majority of OptimiseRx alerts were overridden, in common with most other studies of CDS implementations. OptimiseRx was associated with a reduction in hazardous prescribing. Based solely on the two indicators for which we could estimate long-term impacts, OptimiseRx has an ICER of £236 per QALY gained at 6 months and was QALY-increasing and cost saving at 24 months. Work package 3: Evaluating pharmacist-led IT-based intervention Objectives To evaluate the effectiveness of a PINCER when widely implemented in general practices to: Reduce the prevalence of patient exposure to hazardous prescribing. Reduce the incidence of serious harm in patients at risk of hazardous prescribing. To assess the cost-effectiveness of PINCER compared with standard care, and cost per extra QALY. Methods Project 1 This was an incomplete (not randomised) stepped-wedge design without controls. For consenting practices from our previous East Midlands PINCER roll-out, we collected quarterly data for 11 HPEs between 2013 and 2019, and composite indicators were calculated. To model the time series, we represented the time post intervention as a categorical variable coding each post-intervention quarter; all pre-intervention quarters were assigned a single reference level for the treatment effect. Calendar time (to account for secular trends) was included as a covariate; random intercept terms for general practice allowed for within-practice correlations, seasonality included. We used a mixed effects logistical regression; effect sizes are presented as (adjusted) OR (aOR) compared with the pre-intervention period. We determined the cost-effectiveness of the PINCER intervention compared with standard care by combining the effectiveness in HPE reduction and intervention costs with the effect of the individual HPEs on patient outcomes and healthcare costs, to estimate the overall effect on costs and QALYs. The economic analysis generated ICERs; cost per HPE avoided and QALYs generated using PINCER compared with standard practice, at practice level, from the perspective of the NHS. Project 2 We obtained data from CPRD for general practices implementing PINCER as part of the national roll-out between 2018 and 2021, along with implementation date. We used a similar design and approach to analysis as WP 3, Project 1, but also examined changes in SHOs associated with the HPEs. Results Project 1 We extracted data from 115 (33.5%) of the 343 general practices included in our East Midlands PINCER roll-out. For the composite indicator, PINCER was associated with a decrease in the rate of hazardous prescribing of 18% [aOR 0.82, 95% CI 0.78 to 0.86] at 6 months, 23% (aOR 0.77, 95% CI 0.73 to 0.81) at 12 months and 22% (aOR 0.78, 95% CI 0.73 to 0.84) at 24 months post intervention. The base-case analysis, using 6-month observed effects, shows that PINCER generates approximately 0.15 QALYs per practice extra compared with no intervention, with a net cost of just over £1000 per practice, giving an ICER of approximately £7500 per QALY gained compared with no intervention. The probability that PINCER represents good value for money when QALYs are valued at £20,000 each is 0.947. Project 2 Of the 2817 practices that implemented PINCER as part of the national roll-out, 725 were included in the CPRD data with HES linkage. To minimise the effects of the COVID-19 pandemic on the analysis, we used pre-lockdown data only, up until March 2020, and only 179 practices had at least 6 months’ follow-up data. These 179 practices had an 11% reduction in hazardous prescribing overall (aOR 0.89, 95% CI 0.86 to 0.92) and an 18% reduction in hazardous prescribing associated with risk of GI bleeding (aOR 0.82, 95% CI 0.78 to 0.86). There was no change in SHOs when using primary and secondary care data combined, but when using secondary care data (HES) alone there was a 5% reduction (aOR 0.95, 95% CI 0.91 to 0.99). There was no impact on hospitalisations or deaths. Limitations While our evaluations of PINCER used quasi-experimental designs, these were observational studies and so the reductions in hazardous prescribing and SHOs could have been due to unknown confounding factors. Only a third of eligible general practices provided data for our more detailed evaluation of the roll-out of PINCER across the East Midlands. As a result of the COVID-19 pandemic, only a quarter of potentially eligible practices in the CPRD database had sufficient usable follow-up data for our analysis. Conclusions The implementation of PINCER across the East Midlands, and subsequently across England was associated with a reduction in hazardous prescribing. The implementation of PINCER across the East Midlands had an estimated ICER of approximately £7500 per QALY gained compared with no intervention. The implementation of PINCER across England was associated with a small reduction in SHOs, but only when examining secondary care data alone. Work package 4: Process evaluation Objectives To develop learning about the key technical, organisational, contextual and policy factors that influence the sustained implementation and operation of CDS and PINCER (or similar approaches) in primary care. To generate overarching recommendations for optimal reach, implementation and sustainable use. Methods Project 1 (clinical decision support) We conducted 39 semistructured interviews with stakeholders involved in the implementation and use of CDS across 2 English regions, with 11 follow-up interviews. We used all the interviews for a thematic analysis using Normalisation Process Theory (NPT) and 23 interviews for interpretive data analysis using socio-technical theory. Project 2 (pharmacist-led IT-based intervention) A longitudinal process evaluation incorporated 50 semistructured interviews across 27 organisations, and 18 follow-up interviews. A national electronic survey accompanied the interviews, involving 81 general practices and 3 Clinical Commissioning Groups, across 11 NIHR Clinical Research Networks. Data analysis used an inductive approach. Findings were mapped to the four NPT constructs. Project 3 We undertook a consolidated learning exercise including: A documentary review of findings from other WPs within the Avoiding patient harm through the application of prescribing safety indicators in English general practices (PRoTeCT) study alongside relevant policies and studies. Semistructured interviews with 27 key stakeholders, with key themes mapped to the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Two sequential online consensus-building workshops involving 20 stakeholders. Results Project 1 (clinical decision support) Participants understood the CDS as having value and a role in both medication safety and cost saving. Most of the ‘work’ required to embed and sustain the impact of CDS was required at system level in supporting general practices to use the tool. General practitioners (GPs) reported ignoring CDS alerts where they were perceived as inaccurate, overwhelming or irrelevant for decision-making. Project 2 (pharmacist-led IT-based intervention) Participants reported that ‘top-down’ approaches were used to raise awareness of PINCER. Facilitators for uptake included collaboration across health organisations using recent impact and uptake data. Inclusion of PINCER indicators in national policy helped to raise awareness and influenced uptake and receiving appropriate training and support also influenced ongoing engagement. Overall, public perceptions of PINCER were positive with participants seeing potential benefits for medication safety and recognising the value of utilising pharmacists to deliver PINCER. Project 3 The RE-AIM framework was used to synthesise findings into five main themes: fitting into current context; engaging hearts and minds; building resilience; achieving engagement with secondary care to align prescribing safety guidelines and emphasising complementary use of PSI-based interventions. A clear strategy emerged to align services and work in teams across the healthcare system for a consistent focus on prescribing safety, emphasising the role of organisational support at multiple levels. Limitations There were recruitment challenges that affected our sampling, and while we observed a wide spectrum of responses, some viewpoints may have been missed. Conclusions Successful implementation requires appropriate engagement with, and support for, general practices. Overall conclusions In keeping with systematic review evidence for the effectiveness of CDS, large-scale implementation of OptimiseRx CDS was associated with reduced hazardous prescribing, at less than £50 per HPE avoided. Having previously demonstrated the effectiveness of PINCER in a cluster randomised trial, large-scale implementation of PINCER was also associated with reduced hazardous prescribing with a cost per QALY of £7449. It should be noted, however, that these were quasi-experimental studies using observational data and so the findings may have been due to unknown confounding. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20012) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 15. See the NIHR Funding and Awards website for further award information.

Aims To develop, assess the feasibility and test the effectiveness and cost-effectiveness of a multifaceted ePrescribing-based Antimicrobial Stewardship intervention to safely reduce inappropriate antibiotic use in adult medical inpatient settings. Methods We undertook a mixed-methods programme of work organised into four interlinked work packages: Work package 1: (a) planning, developing and optimising all elements of ePrescribing-based Antimicrobial Stewardship; and (b) carrying out qualitative, feasibility and process studies of ePrescribing-based Antimicrobial Stewardship implementation. Work package 2: agreeing secondary outcome measures through an expert consensus building workshop, developing the methods to collect outcome data and establishing the feasibility of evaluating ePrescribing-based Antimicrobial Stewardship through a hybrid cluster-randomised stepped-wedge trial. Work package 3: evaluating the effectiveness of ePrescribing-based Antimicrobial Stewardship in achieving our coprimary outcomes of reducing antibiotic consumption without any adverse impact on 30-day mortality through piloting and undertaking a formal evaluation. Work package 4: estimating the cost-effectiveness of ePrescribing-based Antimicrobial Stewardship, including cost-minimisation and sensitivity analyses through evidence synthesis and expert engagement. Our research (which started on 1 January 2019) was majorly disrupted by the COVID-19 pandemic, with members of the team being redeployed to clinical and government advisory roles, and limited opportunities to undertake hospital fieldwork compounded by strikes. These delays resulted in our trial plans being pushed back by ≈ 3 years, by which time it was no longer possible to recruit sufficient numbers of hospitals into the planned definitive trial. Following discussion with the funders, we aborted plans to run the pilot and definitive trials, replacing this with qualitative scoping work to understand the ways in which trusts had innovated in the intervening period to promote antimicrobial stewardship (work package 5). Results We developed the ePrescribing-based Antimicrobial Stewardship intervention, comprising technical, educational and behavioural components and were able to agree secondary outcome measures and the cost-effectiveness model. The feasibility trial was undertaken in two hospitals in one trust, studying 24,884 antibiotic orders on 1958 admissions. This demonstrated that several aspects of the intervention were deliverable and that we were able to extract data on 20/43 outcome measures. Modelling of the coprimary outcomes, total antibiotic defined daily dose per admission, was feasible and enabled its variability to be estimated to support further research planning. There was, however, limited engagement of clinical staff with the training element of the intervention, which was initially only voluntary. Given the severe delays, many trusts had begun implementing their own approaches to deal with growing challenge of antimicrobial stewardship. As such, we were unable to find sufficient naive sites to progress the trial. Our additional qualitative scoping work identified the myriad ways in which trusts were attempting to respond to antimicrobial stewardship. These included order sets and order protocols, default durations, alerts for review, incorporation of guidelines, and audit and feedback functionality. Limitations We identify five key limitations: (1) the COVID-19 pandemic caused major delays, and non-COVID research activities had a lower priority than front-line clinical work and COVID-related research. The timescale for the development work is, therefore, unlikely to be representative of the time it should take to develop an intervention of this scope outside of pandemic contexts. (2) Although there was considerable stakeholder input into the development of ePrescribing-based Antimicrobial Stewardship, this did not include the entire potential user population. Nurses were under-represented. Although not directly involved in prescribing, more engagement with nurses would have been useful because they were involved in medication management workflows. (3) Undertaking the work in one trust limits generalisability, although inclusion of several ward types should help ensure that our findings related to a breadth of clinical contexts. (4) Implementation of ePrescribing-based Antimicrobial Stewardship within Cerner Millennium (North Kansas City, Missouri, USA) means feasibility in other systems still needs to be established. (5) The add-on study of antimicrobial stewardship practices included views of antimicrobial stewardship pharmacists and consultant microbiologists but did not include all hospitals nor ward prescribers. Nonetheless, this study provided many valuable insights into approaches, including the need for development of evidence for different practices. Conclusions We developed ePrescribing-based Antimicrobial Stewardship and conducted a feasibility trial of this in inpatient settings. This development and feasibility work was, however, undertaken during challenging circumstances resulting from a combination of the COVID-19 pandemic and National Health Service pressures, making it difficult for clinicians to fully engage. Delays with our work resulted in provisionally recruited trusts innovating in relation to antimicrobial stewardship such that it was no longer possible to deliver the planned follow-on pilot and definitive trials. In summary, ePrescribing-based Antimicrobial Stewardship is, in its present format, not suitable for use in National Health Service hospitals. Future work Hospitals are currently pursuing a range of approaches in an attempt to promote antimicrobial stewardship. There is a need to develop a typology of these approaches and establish the strength of the underpinning evidence using naturalistic designs. Trial registration This trial is registered as ISRCTN13429325. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0617-20009) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 12. See the NIHR Funding and Awards website for further award information. Plain language summary Increasingly, bacteria (germs) no longer respond to antibiotics. This can result in patients experiencing more severe or longer infections and may lead to an increased risk of dying from infections. This is due to too much – inappropriate – use of antibiotics. The reasons for overuse of antibiotics include doctors not having relevant information when prescribing, concerns about missing possibly serious infections, and limited opportunities to review diagnoses and stop antibiotics if no longer needed. From our previous research, we found that hospital electronic prescribing (ePrescribing) systems can support new ways of working to safely reduce unnecessary antibiotic prescribing. We built on our previous work to see if ePrescribing systems can safely reduce antibiotic prescribing. We conducted interviews with clinicians and undertook observations in hospitals, and used these insights to develop new tools to support prescribers, training of prescribers and organisational changes. The development and go-live date of this complex intervention, which we called ePrescribing-based Antimicrobial Stewardship, were delayed due to COVID-19. Once pandemic restrictions were lifted, we were able to progress a trial of ePrescribing-based Antimicrobial Stewardship across two hospitals, showing it was possible to implement ePrescribing-based Antimicrobial Stewardship and to extract the information we needed to see if it was reducing inappropriate antibiotic usage. We found little appetite from clinicians to engage with the training and use ePrescribing-based Antimicrobial Stewardship as hospitals were under pressure from pandemic backlogs and National Health Service strikes. The delays to our main trial resulted in other already recruited hospitals having to innovate locally to address antibiotic over-usage. These innovations overlapped with ePrescribing-based Antimicrobial Stewardship such that it was no longer possible to progress the main trial as planned. We decided not to progress the trial, as we would have struggled to recruit enough hospitals to generate a clear answer. Finally, we interviewed National Health Service staff to understand new ways hospitals were attempting to reduce inappropriate antibiotic use. Scientific summary Background Antibiotic-resistant infections are responsible for considerable morbidity and mortality globally. In response to the growing problem of antimicrobial resistance (AMR), there are global efforts afoot to minimise the inappropriate, excessive use of antibiotics, particularly in healthcare settings. Aims We sought to develop, assess the feasibility of and test the effectiveness and cost-effectiveness of a multifaceted ePrescribing-based Antimicrobial Stewardship (ePAMS+) intervention to safely reduce inappropriate antibiotic use in adult medical inpatient settings. Research questions We sought to answer the following research questions that were pursued through five interlinked work packages (WPs): What were the main challenges to and facilitators for reducing inappropriate antibiotic use? (WP1 phase 1 and phase 2a) In what ways could ePAMS+ promote antimicrobial stewardship (AMS)? (WP1 phase 1 and phase 2b) How should ePAMS+ best conceptualised/delivered? [WP1 (phase 1 and phases 2a and b) and WP2] What are suitable secondary outcomes and process measures? [WPs1 (phase 1 and phase 2a and b) and WP2] Was ePAMS+ acceptable/feasible to implement? (WP2) Were our trial procedures acceptable/feasible? (WP2) How much patient-level variability was there in the coprimary outcomes? (WP2) Was ePAMS+ effective in safely reducing inappropriate antibiotic use? (WP3) What were the mechanisms of action/unintended consequences of ePAMS+? [WP1 (phase 2b), WP2 and WP3] Was ePAMS+ cost-effective? (WP4) What approaches were being pursued by hospitals in the pandemic era to promote AMS? (WP5) Methods We undertook a mixed-methods programme of work that comprised of in-depth qualitative work, consensus building approaches, a feasibility trial and evidence synthesis. This work was originally organised into four interlinked WPs, but not all WPs were able to proceed as planned because of the emergence of the COVID-19 pandemic, with associated major impacts on the NHS. A fifth WP was added towards the end of the work to help contextualise our work within the changed AMS landscape in the aftermath of the pandemic. The methods employed in our WPs are summarised below: Work packages 1–5 Work package 1 phase 1 Some text in this section has been reproduced with permission from Mureyi D, Cresswell K, Sivyer K, Heed A, Weir CJ, Adamestam I, et al. The development of a complex digital and behavioural Antimicrobial Stewardship intervention for hospitals in England. BMC Med Inform Decis Mak 2024. https://doi.org/10.21203/rs.3.rs-3715230/v1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. ePrescribing-based Antimicrobial Stewardship’s development was informed by a qualitative person-based approach. This involved literature reviews, structured stakeholder workshops and interviews with policy-makers, practitioner and patient representatives, vendors and international experts. Engagements and interviews focused on identifying key barriers to and facilitators of appropriate prescribing and post-prescription reviewing of antimicrobial therapy by users of ePrescribing systems in hospitals. Qualitative data were thematically analysed and, where feasible, used to inform the design ePAMS+ features. Work package 1 phase 2a We conducted 18 semistructured interviews with medical prescribers and pharmacists with varying levels of seniority exploring current AMS practices and investigating potential areas for improvement before ePAMS+ was implemented. Participants were recruited with the help of local gatekeepers. Topic guides sought to explore both formal and informal practices surrounding AMS, and challenges and opportunities for ePrescribing-based intervention. Work package1 phase 2b Some text in this section has been reproduced from Cresswell K, Hinder S, Sheikh A, Pontefract S, Watson NW, Price D, et al. ePrescribing-based antimicrobial stewardship practices in an English National Health Service Hospital: qualitative interview study among medical prescribers and pharmacists. JMIR Form Res 2023;7:e37863. https://doi.org/10.2196/37863 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. Two and 7 weeks after intervention initiation, we interviewed 25 users of the intervention, including senior and junior prescribers, a senior nurse, a pharmacist and a microbiologist. Topics discussed included perceived impacts of different elements of the intervention, and facilitators and barriers to effective use. Interviews were supplemented by two observations of ward rounds to gain insights into AMS practices. Work package 2a A scoping review of the literature was conducted to identify AMS interventions and outcomes measures for the hospital setting. The review was published in the Journal of Antimicrobial Chemotherapy – AMR (AMS using electronic prescribing systems in hospital settings: scoping review of interventions and outcome measures). This identified 33 indicators that have been used to measure AMS in hospitals, which, together with an additional 3 indicators from other scoping work, was used to inform an eDelphi to gain consensus on 36 potential study outcome measures: 20 quality indicators (relating to the appropriateness of antibiotic use) 11 quantity indicators (relating to the cost or volume of antibiotic use) 5 indicators relating to clinical decision support. Additional measures from expert review at eDelphi identified an additional 43 outcome measures to a total of 79 outcome measures that were taken forward to assess for appropriateness, reliability and feasibility. Work package 2b We undertook a before-and-after feasibility trial (non-randomised), introducing ePAMS+ in two English hospitals which were established users of the Cerner Millennium ePrescribing and Medicines Administration (EPMA) system. Several specialties were studied among the wards participating in the trial. Patient participants, but not prescribers, were blinded to whether ePAMS+ was in use. By applying a mixed-methods evaluation, we aimed to establish: the usability and acceptability of ePAMS+ and trial procedures; the feasibility of implementing ePAMS+ and recording quantitative outcomes; and, to measure the degree to which ePAMS+ was delivered as planned, a Fidelity Index. We performed a series of qualitative semistructured interviews of doctors, nurses and pharmacists, as well as non-participant observations; we derived quantitative summaries of prescribing data from the EPMA system. Through normal linear modelling of the defined daily dose (DDD) of antibiotic per admission, we informed the sample size calculation for a future large-scale evaluation of ePAMS+. Work package 3 We intended to evaluate ePAMS+ using a hybrid stepped-wedge cluster-randomised trial (with internal pilot study) to determine its impact on the coprimary outcomes of antibiotic usage (total DDD per admission) and mortality 30 days following admission, alongside a series of secondary outcomes and prescribing process measures. Work package 4 A scoping review of the literature on cost-effectiveness studies of Antimicrobial Stewardship Programmes (ASPs) was undertaken. In line with the original intention of the programme, we considered ASPs that affect the duration, route and type of antibiotic administered during follow-up after the initial antibiotic prescription. We selected studies that measured both cost (intervention cost, antibiotic cost or hospital costs) and clinical effectiveness. Only studies that included a valued (i.e. clinical) outcome [death, length of stay (LOS), Clostridioides difficile infection (CDI)] were included. We did not include studies that only mentioned process outcomes such as DDD and total antibiotic use. We also excluded antifungal stewardship programmes and studies using diagnostic tests to improve antibiotic utilisation (e.g. procalcitonin tests and rapid diagnosis tests). Following extensive consultation with experts, we identified three causal routes through which an ASP might affect patient health and health service costs: Reduction in opportunistic infection by a micro-organism agent that is normally held in control by other micro-organisms that are inactivated by antibiotic agents. We focused on Clostridioides difficile as it is, by a considerable margin, the most important of these opportunistic infections. Changing from intravenous (i.v.) to oral therapy, which has numerous advantages in terms of cost (including staff time) and patient comfort/mobility. Switching to a more appropriate antibiotic in the case of bug-antibiotic mismatch (BAM). In populating the model, we utilised 22 parameter estimates. Some of these estimates were taken from the literature. For many parameters, there was no estimate available from the literature (e.g. how often is a BAM mis-diagnosed), and for others, the link to the literature was tenuous (e.g. effect of DDD of antibiotic on risk of CDI). Some data (e.g. the proportion of patients on antibiotics where a sample was submitted for microbiological analysis) were estimated from hospital summary records. The model was subjected to deterministic and probabilistic sensitivity analysis. Work package 5 We carried out semistructured qualitative interviews with 38 AMS leads, pharmacists and microbiologists in 23 hospitals. We explored the participant experiences with AMS electronic prescribing systems and other activities relating to AMS. We sought to provide insights into the AMS functionality of EPMA systems and other related AMS activities, and make recommendations with regard to the interventions most valued by participants. We also sought to understand future strategic priorities and challenges and possible ways to tackle these. We analysed the data thematically using technology, people, organisations and macroenvironmental as a coding framework. Qualitative analysis was iterative, allowing emerging themes to be explored further and disconfirming evidence to be sought. Thematic analysis allowed exploration of various perspectives and contexts. Results We summarise our findings below by WP. Work package 1 phase 2a Antimicrobial prescribing and review processes were characterised by competing priorities and uncertainty of prescribers and reviewers around prescribing decisions. For example, medical prescribers often had to face trade-offs between individual patient benefit and more diffuse population health benefits, and the rationale for prescribing decisions was not always clear. Prescribing involved a complex set of activities carried out by various healthcare practitioners who each only had a partial and temporary view of the whole process, and whose relationships were characterised by deeply engrained hierarchies that shaped interactions and varied across specialties. For example, newly qualified doctors and pharmacists were hesitant to change a consultant’s prescribing decision when reviewing prescriptions. Multidisciplinary communication, collaboration and co-ordination promoted good AMS practices by reducing uncertainty. Work package 1 phase 2b Tracing the adoption and impact of the various components of the intervention was difficult as it had been introduced into a setting with competing pressures. These particularly affected behavioural/educational components (e.g. training, awareness building activities) which were often delivered ad hoc. We found that the participatory intervention design had addressed typical use cases but had not catered for edge cases that only became visible when the intervention was delivered in real-world settings (e.g. variations in prescribing workflows across different specialties and conditions). Work package 2a An online learning tool was developed to develop knowledge relating to AMS and to communicate information about the EPAMS. Online AMS and ePAMS+ training (approximately 30 minutes of learning): Hosted online using an NHS-approved URL: https://epams.helmlms.com/login. The online module had the following learning outcomes: List the factors to consider when initiating antibiotics, switching the route of administration, and stopping treatment. Discuss the risks of staying on antibiotics for longer than is clinically needed. List the tools provided by the ePAMS+ intervention in this hospital. Explain how order plans work and how these have been set up to aid your decision-making. Explain the components of the antibiotic reduction and conservation decision aid and how these can encourage good stewardship within ePAMS+. A pre/post-test was developed so learners can assess baseline knowledge and knowledge acquisition. The module comprised videos of the ePAMS+ tool to explain to learners how the tool is accessed and utilised in practice. Work package 2b It was feasible to gather 20 of the 43 planned outcome and process measures using data extracted from the Cerner EPMA system. Overall, where data extraction was possible, data completeness was high. We successfully derived total antibiotic DDD per admission, a key outcome measure for future research on ePAMS+, and analysed its variability to inform the sample size calculation for future studies. The small number of antibiotic review records available confirmed the limited use of ePAMS+ within wards during the feasibility trial. Future data extraction efforts should focus on obtaining antibiotic indication data, to allow indication-based outcomes to be measured (e.g. the number of antibiotic courses for the same indication). In developing the Fidelity Index, we identified the critical decision-making points for prescribers that are linked to adherence to the ePAMS+ intervention, enabling proxy measures for these to be developed using the electronic patient record data. The limited use of ePAMS+ order sets during the feasibility trial meant that we could not, as originally planned, develop a scoring system to quantify each decision point and specify automation of the scoring within the Cerner EPMA system. Work package 3 Due to the challenges in recruiting sufficient study sites because of the changing landscape of AMS across NHS Cerner sites, as well as the further ePAMS+ development requirements identified during the feasibility trial, the planned pilot and hybrid stepped-wedge cluster-randomised trial was not undertaken. Work package 4 Our literature review on economic evaluations of ASPs found that the intervention types evaluated research methods, outcomes assessed and contexts all varied widely across studies. Given this heterogeneity, any attempt to estimate a ‘typical’ cost-effectiveness parameter would be a quixotic undertaking. It was this analysis that led us to a completely different approach – namely, the generation of a causal model to help derive the essential effectiveness and cost parameters that might drive the decision-analytic (cost–utility) model. The base-case results from our model suggests that, even at the low absolute health gains estimated and despite uncertainty as to intervention costs, the intervention is highly likely to dominate by yielding a net saving of money and a health benefit – albeit a small one. The sensitivity analyses found that the cost savings predominately turn on the impact of i.v. to oral switch on LOS, so this should be a parameter that is closely monitored. Work package 5 We found there was considerable variety across the 23 English hospitals studied in terms of their adoptions of functionality and other interventions to support AMS and a lack of evidence base to support these approaches. Secondary uses of data allowing AMS pharmacists and microbiologists to view prescribing data remotely (e.g. which patients are on antibiotics) were viewed as important in improving AMS. An indication of the source of infection was viewed as an important part of prescribing antibiotics to help other clinicians in the patient’s journey. The views of interviewees varied on the usefulness of order protocols (prescribing on the basis of infection, e.g. community acquired pneumonia). For those with ePrescribing systems without in-built protocols, designing them took some time. Conclusions We developed the ePAMS+ intervention and conducted a feasibility trial of this in hospital medical inpatient settings. This feasibility work was, however, undertaken during challenging circumstances resulting from a combination of the COVID-19 pandemic and NHS strikes, making it difficult for clinicians to find time to engage with the intervention. Challenges with the feasibility trial and delays to the research associated with the pandemic resulted in the wider AMS landscape having changed such that it would not have been prudent to proceed with the planned follow-on pilot and definitive trials. Our qualitative work mapping the NHS landscape has identified a number of promising areas for further development and evaluation to support AMS in NHS hospitals. In summary, the ePAMS+ intervention has been pre-empted by the adoption of similar measures, often resulting from local innovation which in consequence may lack an evidence base. The landscape into which complex interventions supporting AMS may be implemented is extremely heterogeneous in terms of both technological functionality and organisational practices. Interventions need to be overlaid onto this installed base. More systematic research is needed to better understand the context for further improvement. Trial registration This trial is registered as ISRCTN13429325. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0617-20009) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 12. See the NIHR Funding and Awards website for further award information.

For the last 40 years, the first line of asthma treatment has been short-acting beta2 agonists (SABA) used as symptom relief alongside daily inhaled corticosteroids (ICS) as preventers. New guidelines recommend replacing SABA relievers with ICS-based relievers (ICS-formoterol) because of clear risks from excess and sole use of SABA. This study aimed to explore patient perceptions of SABA, ICS and ICS-formoterol, with a focus on identifying barriers to adherence to new recommended treatments. A qualitative study was carried out investigating UK asthma online community forum posts using keyword searches between July 2021 and March 2025. Inductive thematic analysis was used to analyze the data, informed by the Necessity Concerns Framework. 326 posts were identified across 206 adults with asthma. Thematic analysis highlighted that many people remained attached to their SABA and viewed it as a key element of their treatment. They appeared unconvinced by warnings around SABA over-use and were dissatisfied with the quality of advice from health care professionals (HCPs). In contrast, they raised a range of concerns about ICS and ICS-formoterol, and had reservations about replacing SABA with these treatments. A common objection to replacing SABA was that ICS-formoterol does not provide the same symptom relief. Results highlight a perceived lack of individualized care from HCPs and insufficient explanation and justification of treatment changes. This analysis highlights several potential barriers to adherence to recommended asthma treatment. Strategies to support the implementation of asthma treatment guidelines should include addressing patients' treatment beliefs and educating clinicians to better communicate treatment changes.

BackgroundPeople with symptomatic COPD and comorbidities often experience suboptimal prescribing and may be housebound. A tailored, home-based intervention by independent prescriber pharmacists collaborating with consultant physicians (TICC-PCP) may improve outcomes and optimise healthcare resource use. This economic evaluation alongside the TICC-PCP multicentre pilot RCT, assessed the feasibility of collecting healthcare resource use and health-related quality of life (HRQoL) data and characterised these outcomes in this patient population.MethodsThe pilot RCT recruited 110 adults with moderate to severe COPD and comorbidities across two sites in Scotland. Participants were randomised to receive TICC-PCP plus usual care or usual care alone. Healthcare resource use and HRQoL (EQ-5D-5L) data were collected at baseline and at three-month follow-ups over 21 months. Costs were estimated from the NHS perspective (2021 GBP), applying a micro-costing approach.ResultsParticipants were 59% female with a mean age of 67.4 (SD: 8.2) and a mean of 11.5 (SD 6.9) comorbidities. EQ-5D questionnaire completion rates exceeded 90% at follow-ups with baseline mean utility being 0.324 (SD 0.369) and 25.5% of participants reporting utilities less than 0 (considered “worse than death”). Mean annual direct medical cost at baseline was £7,717.86 (SD: £9,163.52), largely driven by inpatient care. The intervention cost averaged £401.25 (SD: £159.87) per participant. Compared with usual care, the intervention showed indicative HRQoL improvement along with increased healthcare costs.ConclusionFindings demonstrate feasibility of health economic data collection and characterise the high disease burden in this population. A definitive RCT is required to determine cost effectiveness.

Introduction A chronic disease management programme anchored on a digital platform was scaled in Ghana, Kenya, Sierra Leone and Tanzania following successful pilot studies. We investigated blood pressure (BP) changes and their associated factors among patients with hypertension.Methods In this retrospective cohort study, the primary outcome was the relative reduction in BP and an absolute reduction in systolic BP (SBP) of >5 mm Hg at 6 (±2) months post-enrolment. We used the paired t-test, McNemar’s test and multivariable logistic regression to compare changes in mean SBP, compare changes in proportions and examine the association between patient characteristics and achieving >5 mm Hg SBP reduction, respectively.Results As of May 2024, 131 912 patients with hypertension had completed at least 6 months of the programme. The study cohort included 63 003 (48%) patients with documented enrolment and 6-month BP measurements. The mean age was 60.8 years (SD: 13.1) and 74.7% were female. Mean SBP and diastolic BP decreased by 8.3 mm Hg (95% CI −8.5 to −8.1; p<0.001) and 4.5 mm Hg (95% CI −4.7 to −4.4; p<0.001), respectively. Patients with uncontrolled SBP (≥140 mm Hg) at enrolment (n=38 079) experienced a mean SBP reduction of 18.1 mm Hg (95% CI −18.3 to −17.8; p<0.001). The proportion of patients with controlled BP increased from 35% at enrolment to 53% at 6 months. Factors associated with higher odds of >5 mm Hg SBP reduction included follow-up by community health workers (adjusted OR (AOR)=1.06; p=0.041), ≥3 medical reviews (AOR=1.16; p<0.001) and ≥8 BP assessments (AOR=1.35; p<0.001).Conclusion Significant BP improvements were observed under routine programme conditions among patients with 6-month documented measurements. Despite limitations in causal inference owing to the lack of a control arm and the high proportion of patients without a documented follow-up BP, the findings highlight the potential real-world value of digital-enabled community-based and decentralised care in hypertension management.

Introduction Within the UK there are 33 deaths every day from prostate cancer, second only to lung cancer as the most common cause of cancer death in males in the UK. Of the 55 000 new cases each year, up to 50% of these patients will receive radiotherapy either alone or after prostatectomy. Although there have been significant improvements in the accuracy of radiotherapy delivery leading to better tumour targeting and a reduction in dose to normal tissues, significant permanent genito-urinary or gastrointestinal-related side effects are all too common. With nearly 80% of patients with prostate cancer surviving for 10 years or more, minimising life-limiting radiation damage to normal tissues is vitally important. However, at present, it is not possible to identify which patients will suffer a poorer outcome after radiotherapy. The aim of this study, improving radiotherapy in PROState cancer using EleCtronic population-based healthCAre data (PROSECCA), is to do this by using the existing information in a patient’s digital healthcare record. By linking primary, secondary and tertiary clinical data, including digital image information, with radiotherapy treatment plans and outcome data, the PROSECCA study will identify de novo predictive biomarkers of radiation response and provide clinicians with a tool to individualise a radiotherapy dose and plan to maximise cure and minimise toxicity.Methods and analysis The PROSECCA study is a large multidisciplinary project, the purpose of which is to analyse healthcare records from up to 15 000 patients with prostate cancer who underwent radiotherapy in the treatment of their cancer in Scotland between 2010 and 2022. Through the linkage of data obtained specifically for radiotherapy and data held within each patient’s unique electronic health record (EHR), the factors that indicate why some patients have a poor response to treatment, or an increased risk of side effects from radiation, will be identified. This will be made possible by the use of artificial intelligence and machine learning (AL/ML), which will help to identify at-risk patients earlier and allow adaptation of their treatment accordingly.Ethics and dissemination The study is being conducted in accordance with the ethical principles set out in the Declaration of Helsinki and Good Clinical Practice that respects and protects the rights, and maintains confidentiality, of all trial participants. The study protocol (V.1.0) was reviewed by the South Central Oxford A Research Ethics Committee (REC) on 13 December 2021 and received a favourable opinion subject to each National Health Service (NHS) organisation confirming permission for patients treated within their area. Approval for the use of unconsented healthcare record data for patients included in the study and treated at one of the five Scottish Cancer Centres required an application to the NHS Scotland Public Benefit and Privacy Panel for Health and Social Care (HSC-PBPP). Full approval from the HSC-PBPP panel was received on 1 July 2024, which covered the use of pseudoanonymised EHR data for all patients participating in the study. The study is publicly listed on the NHS Health Research Authority site, with IRAS ID 306245 and REC reference 21/SC/0402. Dissemination of the study findings will take place through field-leading cancer, radiation oncology and medical physics journals. All manuscripts will be approved by the main study team and authorship determined by mutual agreement.Trial registration number NCT06714630.

Abstarct Background Blood cancers are among the most common and deadliest in the UK, affecting over 40,000 people annually. Survival varies by subtype, but this is not routinely reported for the UK. This study estimated survival for haematological malignancies in the UK stratified by time period, age, sex, ethnicity, deprivation, and rurality. Methods Four retrospective cohorts of patients aged 15–99 diagnosed with haematological malignancies (2009–2019) across UK cancer registries were used to estimate 1-, 5-, and 10-year net survival by subtype. Results We identified 413,286 blood cancer cases. Survival in all blood cancer combined significantly improved in England (3.8%), Northern Ireland (5.1%), and Wales (3%), but not Scotland. Men had ≥3% lower survival than women in many subtypes. Older age and higher deprivation were significantly linked to lower survival. In England, white ethnic groups had ≥3% lower survival than non-white groups for myelodysplastic syndrome, myeloid malignancies, plasma cell neoplasms, myeloproliferative neoplasms. In Wales, rural areas showed ≥3% higher survival than urban and mixed regions for lymphoid malignancies, myeloid malignancies, plasma cell neoplasms, Hodgkin lymphoma, mature B-cell neoplasms, acute myeloid leukaemia. Conclusion Net survival varied markedly by subtype and demographic factors across the UK. Given possible differences in case ascertainment, findings are descriptive and hypothesis‑generating.

BACKGROUND:Traffic-related air pollution is a risk factor for lung disease and early mortality. Clean air zones are public health policy interventions used to reduce traffic-related air pollution in urban areas, but evidence of their health benefits is limited. We describe a natural experiment study evaluating the impact of the Ultra Low Emission Zone (ULEZ) in London, UK. The primary aim was to assess the impact of the ULEZ on children's lung function growth trajectories, by comparing forced expiratory volume in 1 s (FEV1) measurements over 5 years between children in London and Luton, UK. METHODS:The Children's Health in London and Luton (CHILL) study is a prospective, two-arm, parallel cohort study. We recruited children aged 6-9 years from primary schools in central London (the original area of the ULEZ implementation) and Luton (a comparator site with no clean air zone). Children were excluded if they had symptoms of lung disease (excluding asthma) or learning or physical disabilities preventing them from giving informed assent. Lung function was measured by spirometry at annual school visits at baseline (before ULEZ implementation) and over the following 4 years. Annual residential exposures to nitrogen dioxide (NO2) and particulate matter with aerodynamic diameters of less than 10 μm (PM10) and less than 2·5 μm (PM2·5) were estimated at each child's home address at 20 m2 resolution using a validated dispersion modelling system. The primary outcome was the annual rate of lung function growth, measured as post-bronchodilator FEV1 over the 5-year study period. We assessed growth trajectories against individualised residential exposure to NO2, PM10, and PM2·5. We used mixed-effects linear regression to compare lung function growth between London and Luton and to examine associations between air pollution exposures and lung growth. FINDINGS:Of 122 schools approached, 84 (69%) agreed to participate (44 schools in London; 40 schools in Luton). Of 9419 children invited, we recruited 3414 children (1664 in London and 1750 in Luton) between June 5, 2018, and April 4, 2019, before ULEZ implementation. 3209 (94·0%) of 3414 children were included in the FEV1 analysis (1557 children in London, 1652 children in Luton). Children were similar across the two sites in terms of age, height, and weight, with a higher proportion of girls in London (867 [56%] of 1557) than in Luton (809 [49%] of 1652). Baseline adjusted FEV1 was lower in London than Luton (difference -38 mL, 95% CI -58 to -18; p=0·0002). At baseline, children's modelled annual exposures to NO2, the pollutant most reflective of exhaust emissions, were 18·95 μg/m3 (95% CI 18·51 to 19·38; p<0·0001) higher in London than in Luton. Over the follow-up period, children's FEV1 growth increased by 10 mL/year (95% CI 5 to 15; p=0·0002) more in London than in Luton (233 mL/year vs 223 mL/year), with modelled residential exposures to NO2 decreasing faster in London than in Luton (decreases of -3·77 μg/m3 per year in London vs -1·77 μg/m3 per year in Luton; p<0·0001). After 4 years, mean FEV1 reached parity across sites: 2283 mL (2207 to 2354) in London; 2282 mL (2185 to 2376) in Luton. The proportion of children with clinically impaired lung function fell from 184 (14%) of 1280 children to 51 (9%) of 585 children in London, and from 126 (9%) of 1339 children to 41 (7%) of 606 children in Luton. INTERPRETATION:Introduction of the London ULEZ was associated with improved lung function growth trajectories in children in London compared with children in Luton, suggesting that previous deficits in lung development were restored. This evidence supports wider implementation of clean air zones as a public health intervention. FUNDING:National Institute for Health and Care Research and Natural Environment Research Council UK Research and Innovation.

We quantified the extent to which socio-economic position (SEP) contributed to ethnic inequalities in severe COVID-19 outcomes (hospitalization or death) in Scotland. We used linked 2011 Scottish Census and health records to assess whether ethnic inequalities were mediated by different SEP measures: area deprivation, educational status, household composition, and multigenerational household. We considered disaggregated ethnicities ‘White Scottish’, ‘White British or Irish’, ‘Other White’, ‘South Asian’, ‘African, Caribbean, or Black’, and ‘Other’. We applied marginal structural models to estimate causal pathways. Of the 3 297 205 individuals analysed, 38 213 (1.2%) had severe COVID-19 outcomes. South Asians had elevated risk of severe COVID-19 compared to White Scottish (hazard ratio: 1.7; 95% confidence interval: 1.5–1.9), while White British or Irish (hazard ratio: 0.7; confidence interval: 0.6–08) and other White (hazard ratio: 0.8; confidence interval: 0.7–0.9) had reduced risk. When holding area deprivation constant, the risk of severe COVID-19 declined by 16.5% for South Asians and 49.2% for White British or Irish; but increased for other White (75.4%). When holding education constant, the risk of severe COVID-19 reduced by 24.8% for White British or Irish and 20.6% for other White; but increased by 74.6% for South Asians. Only a slight change in risk was observed for the South Asians after holding household size and multigenerational household constant. Risk estimates for African, Caribbean or Black, and other groups were underpowered. SEP measures differed substantially in the extent to which they mediated ethnic inequalities in severe COVID-19. This highlights the necessity of addressing multiple dimensions of SEP that drive ethnic inequalities.

Abstract Background The Ultra-Low Emission Zone (ULEZ), introduced in Central London in April 2019, aims to enhance air quality and improve public health. The Children's Health in London and Luton (CHILL) study evaluates the impact of the ULEZ on children's health. This analysis focuses on the one-year impacts on the shift towards active travel to school. Methods CHILL is a prospective parallel cohort study of ethnically diverse children, aged 6–9 years attending 84 primary schools within or with catchment areas encompassing London’s ULEZ (intervention) and Luton (non-intervention area). Baseline (2018/19) and one-year follow-up (2019/20) data were collected at school visits from 1992 (58%) children who reported their mode of travel to school ‘today’ (day of assessment). Multilevel logistic regressions were performed to analyse associations between the introduction of the ULEZ and the likelihood of switching from inactive to active travel modes, and vice-versa. Interactions between intervention group status and pre-specified effect modifiers were also explored. Results Among children who took inactive modes at baseline, 42% of children in London and 20% of children in Luton switched to active modes. For children taking active modes at baseline, 5% of children in London and 21% of children in Luton switched to inactive modes. Relative to the children in Luton, children in London were more likely to have switched from inactive to active modes (OR 3.64, 95% CI 1.21–10.92). Children in the intervention group were also less likely to switch from active to inactive modes (OR 0.11, 0.05–0.24). Moderator analyses showed that children living further from school were more likely to switch from inactive to active modes (OR 6.06,1.87–19.68) compared to those living closer (OR 1.43, 0.27–7.54). Conclusions Implementation of clean air zones can increase uptake of active travel to school and was particularly associated with more sustainable and active travel in children living further from school.