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We lead multidisciplinary applied research and training to rethink the way health care is delivered in general practice and across the community.
Long-Term outcomes after stress echocardiography in real world practice: five-year follow-up of the UK Evarest study.
AIMS: Stress echocardiography is widely used to assess patients with chest pain. The clinical value of a positive or negative test result to inform on likely longer-term outcomes when applied in real world practice across a healthcare system has not been previously reported. METHODS AND RESULTS: 5503 patients recruited across 32 UK NHS hospitals between 2018 and 2022, participating in the EVAREST/BSE-NSTEP prospective cohort study, with data on medical outcomes up to 2023 available from NHS England were included in analysis. Stress echocardiography results were related to outcomes, including death, procedures, hospital admissions and relevant cardiovascular diagnoses, based on Kaplan-Meier analysis and Cox proportional hazard ratios. Median follow-up was 829 days (IQR 224-1434). A positive stress echocardiogram was associated with a greater risk of myocardial infarction (HR 2.71, 95% CI 1.73-4.24, P<0.001), and a composite endpoint of cardiac-related mortality and myocardial infarction (HR 2.03, 95% CI 1.41-2.93, P<0.001). Hazard ratios increased with ischaemic burden. A negative stress echocardiogram identified an event-free 'warranty period' of at least five years in patients with no prior history of coronary artery disease, and four years for those with disease. CONCLUSIONS: In real-world practice, the degree of myocardial ischaemia recorded by clinicians at stress echocardiography correctly categorises risk of future events over the next five years. Reporting a stress echocardiogram as negative correctly identifies patients with no greater than a background risk of cardiovascular events over a similar time period.
Identifying Key Moments in Type 2 Diabetes Management: A Qualitative Study of the Experiences of People With Type 2 Diabetes and Diabetes Health Coaches.
OBJECTIVE: For people with type 2 diabetes who are overweight, weight loss increases the likelihood of achieving diabetes remission. The aim here was to draw on the experiences of people living with type 2 diabetes and coaches who deliver type 2 diabetes prevention and remission programmes. This was done to develop a service that increases the proportion of people who achieve remission by identifying an effective weight management service. RESEARCH DESIGN AND METHODS: A qualitative researcher and co-researcher with type 2 diabetes conducted 37 narrative interviews with adults with type 2 diabetes (October 2022-June 2023) and 16 semi-structured interviews with health coaches delivering type 2 diabetes programmes in England. Data were analysed using Reflexive Thematic Analysis. Participants were diverse in ethnicity, socioeconomic status, age, gender and years since diabetes diagnosis. RESULTS: Four themes were generated relating to moments in a person's diabetes care: (1) coming to terms with diagnosis, (2) lightbulb moments, (3) sustaining change as normal and (4) becoming expert/building confidence. These four themes were united under a high-level interpretivist theme: 'Same journey, different experience', capturing the mismatch between a linear rigid care pathway described by coaches and the diversity of experience of people living with type 2 diabetes. CONCLUSIONS: Coaches and people with type 2 diabetes are aligned on their reports of key moments in adapting to diabetes. Participants' desire for flexibility in their care contrasted with coach reports of rigid service provision. These insights may enable more people with type 2 diabetes to engage and adhere to weight management services aimed at diabetes remission.
A Narrative Review of Ethical Issues in the Use of Artificial Intelligence Enabled Diagnostics for Diabetic Retinopathy
Introduction: Diabetic retinopathy is one of the leading causes of avoidable blindness among adults globally, and screening programmes can enable early diagnosis and prevention of progression. Artificial intelligence (AI) diagnostic solutions have been developed to diagnose diabetic retinopathy. The aim of this review is to identify ethical concerns related to AI-enabled diabetic retinopathy diagnostics and enable future research to explore these issues further. Methods: This is a narrative review that uses thematic analysis methods to develop key findings. We searched two databases, PubMed and Scopus, for papers focused on the intersection of AI, diagnostics, ethics, and diabetic retinopathy and conducted a citation search. Primary research articles published in English between 1 January 2013 and 14 June 2024 were included. From the 1878 papers that were screened, nine papers met inclusion and exclusion criteria and were selected for analysis. Results: We found that existing literature highlights ensuring patient data has appropriate protection and ownership, that bias in algorithm training data is minimised, informed patient decision-making is encouraged, and negative consequences in the context of clinical practice are mitigated. Conclusions: While the technical developments in AI-enabled diabetic retinopathy diagnostics receive the bulk of the research focus, we found that insufficient attention is paid to how this technology is accessed equitably in different settings and which safeguards are needed against exploitative practices. Such ethical issues merit additional exploration and practical problem-solving through primary research. AI-enabled diabetic retinopathy screening has the potential to enable screening at a scale that was previously not possible and could contribute to reducing preventable blindness. It will only achieve this if ethical issues are emphasised, understood, and addressed throughout the translation of this technology to clinical practice.
Optimization of SARS-CoV-2 culture from clinical samples for clinical trial applications.
UNLABELLED: Clinical trials of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapeutics often include virological secondary endpoints to compare viral clearance and viral load reduction between treatment and placebo arms. This is typically achieved using quantitative reverse-transcriptase PCR (RT-qPCR), which cannot differentiate replicant competent virus from non-viable virus or free RNA, limiting its utility as an endpoint. Culture-based methods for SARS-CoV-2 exist; however, these are often insensitive and poorly standardized for use as clinical trial endpoints. We report optimization of a culture-based approach evaluating three cell lines, three detection methods, and key culture parameters. We show that Vero-angiotensin-converting enzyme 2-transmembrane serine protease 2 cells in combination with RT-qPCR of culture supernatants from the first passage provides the greatest overall detection of Delta viral replication (22 of 32, 68.8%), being able to identify viable virus in 83.3% (20 of 24) of clinical samples with initial Ct values of <30. Likewise, we demonstrate that RT-qPCR using culture supernatants from the first passage of Vero human signaling lymphocytic activation molecule cells provides the highest overall detection of Omicron viral replication (9 of 31, 29%), detecting live virus in 39.1% (9 of 23) of clinical samples with initial Ct values of <25. This assessment demonstrates that combining RT-qPCR with virological endpoint analysis has utility in clinical trials of therapeutics for SARS-CoV-2; however, techniques may require optimization based on dominant circulating strain. IMPORTANCE: RT-qPCR is commonly used for virological endpoints during clinical trials for antiviral therapy to determine the quantity and presence of virus in a sample. However, RT-qPCR identifies viral RNA and cannot determine if viable virus is present. Existing culture-based techniques for SARS-CoV-2 are insensitive and not sufficiently standardized to be employed as clinical study endpoints. The use of a culture system to monitor replicating viruses could mitigate the possibility of molecular techniques identifying viral RNA from inactive or lysed viral particles. The methodology optimized in this study for detecting infectious viruses may have application as a secondary virological endpoint in clinical trials of therapeutics for SARS-CoV-2 in addition to numerous research processes.
A scoping review of unexpected weight loss and cancer: risk, guidelines, and recommendations for follow-up in primary care.
BACKGROUND: Cancer diagnoses often begin with consultations with GPs, but the non-specific nature of symptoms can lead to delayed diagnosis. Unexpected weight loss (UWL) is a common non-specific symptom linked to undiagnosed cancer, yet guidelines for its diagnostic assessment in general practice lack consistency. AIM: To synthesise evidence on the association between UWL and cancer diagnosis, and to review clinical guidelines and recommendations for assessing patients with UWL. DESIGN & SETTING: Systematic search and analysis of studies conducted in primary care. METHOD: Four databases were searched for peer-reviewed literature from 2012 to 2023. Two reviewers conducted all the steps. A narrative review was conducted detailing the evidence for UWL as a risk factor for undiagnosed cancer, existing clinical guidance, and recommended diagnostic approach. RESULTS: We included 25 studies involving 916 092 patients; 92% provided strong evidence of an association between UWL and undiagnosed cancer. The National Institute for Health Care and Excellence (NICE) Cancer Guideline in the UK was frequently cited. General suggestions encompassed regular weight monitoring, family history, risk factor evaluation, additional signs and symptoms, and a comprehensive physical examination. Commonly recommended pathology tests included C-reactive protein (CRP), complete blood count, alkaline phosphatase, and thyroid-stimulating hormone. Immunochemical faecal occult blood test, abdominal ultrasound, and chest X-ray were also prevalent. One large cohort study provided age, sex, and differential diagnosis-specific recommendations. CONCLUSION: This evidence review informs recommendations for investigating patients with UWL and will contribute to a computer decision support tool implementation in primary care, enhance UWL assessment, and potentially facilitate earlier cancer diagnosis.
Predicting COVID-19 related death using the OpenSAFELY platform
Objectives To compare approaches for obtaining relative and absolute estimates of risk of 28-day COVID-19 mortality for adults in the general population of England in the context of changing levels of circulating infection. Design Three designs were compared. (A) case-cohort which does not explicitly account for the time-changing prevalence of COVID-19 infection, (B) 28-day landmarking, a series of sequential overlapping sub-studies incorporating time-updating proxy measures of the prevalence of infection, and (C) daily landmarking. Regression models were fitted to predict 28-day COVID-19 mortality. Setting Working on behalf of NHS England, we used clinical data from adult patients from all regions of England held in the TPP SystmOne electronic health record system, linked to Office for National Statistics (ONS) mortality data, using the OpenSAFELY platform. Participants Eligible participants were adults aged 18 or over, registered at a general practice using TPP software on 1 st March 2020 with recorded sex, postcode and ethnicity. 11,972,947 individuals were included, and 7,999 participants experienced a COVID-19 related death. The study period lasted 100 days, ending 8 th June 2020. Predictors A range of demographic characteristics and comorbidities were used as potential predictors. Local infection prevalence was estimated with three proxies: modelled based on local prevalence and other key factors; rate of A&E COVID-19 related attendances; and rate of suspected COVID-19 cases in primary care. Main outcome measures COVID-19 related death. Results All models discriminated well between patients who did and did not experience COVID-19 related death, with C-statistics ranging from 0.92-0.94. Accurate estimates of absolute risk required data on local infection prevalence, with modelled estimates providing the best performance. Conclusions Reliable estimates of absolute risk need to incorporate changing local prevalence of infection. Simple models can provide very good discrimination and may simplify implementation of risk prediction tools in practice.
Impact of frailty in older people on health care demand: simulation modelling of population dynamics to inform service planning
Background: As populations age, frailty and the associated demand for health care increase. Evidence needed to inform planning and commissioning of services for older people living with frailty is scarce. Accurate information on incidence and prevalence of different levels of frailty and the consequences for health outcomes, service use and costs at population level is needed. Objectives: To explore the incidence, prevalence, progression and impact of frailty within an ageing general practice population and model the dynamics of frailty-related healthcare demand, outcomes and costs, to inform the development of guidelines and tools to facilitate commissioning and service development. Study design and methods: A retrospective observational study with statistical modelling to inform simulation (system dynamics) modelling using routine data from primary and secondary health care in England and Wales. Modelling was informed by stakeholder engagement events conducted in Hampshire, England. Data sources included the Royal College of General Practitioners Research and Surveillance Centre databank, and the Secure Anonymised Information Linkage Databank. Population prevalence, incidence and progression of frailty within an ageing cohort were estimated using the electronic Frailty Index tool, and associated service use and costs were calculated. Association of frailty with outcomes, service use and costs was explored with multistate and generalised linear models. Results informed development of a prototype system dynamics simulation model, exploring population impact of frailty and future scenarios over a 10-year time frame. Simulation model population projections were externally validated against retrospective data from Secure Anonymised Information Linkage. Study population: The Royal College of General Practitioners Research and Surveillance Centre sample comprised an open cohort of the primary care population aged 50 + between 2006 and 2017 (approx. 2.1 million people). Data were linked to Hospital Episode Statistics data and Office for National Statistics death data. A comparable validation data set from Secure Anonymised Information Linkage was generated. Baseline measures: Electronic Frailty Index score calculated annually and stratified into Fit, Mild, Moderate and Severe frailty categories. Other variables included age, sex, Index of Multiple Deprivation score, ethnicity and Urban/rural. Outcomes: Frailty transitions, mortality, hospitalisations, emergency department attendances, general practitioner visits and costs. Findings: Frailty is already present in people aged 50-64. Frailty incidence was 47 cases per 1000 person-years. Frailty prevalence increased from 26.5% (2006) to 38.9% (2017). Older age, higher deprivation, female sex, Asian ethnicity and urban location independently predict frailty onset and progression; 4.8% of 'fit' people aged 50-64 years experienced a transition to a higher frailty state in a year, compared to 21.4% aged 75-84. Individual healthcare use rises with frailty severity, but Mild and Moderate frailty groups have higher overall costs due to larger population numbers. Simulation projections indicate frailty will increase by 7.1%, from 41.5% to 48.7% between 2017 and 2027, and associated costs will rise by £5.8 billion (in England) over an 11-year period. Conclusions: Simulation modelling indicates that frailty prevalence and associated service use and costs will continue to rise in the future. Scenario analysis indicates reduction of incidence and slowing of progression, particularly before the age of 65, has potential to substantially reduce future service use and costs, but reducing unplanned admissions in frail older people has a more modest impact. Study outputs will be collated into a commissioning toolkit, comprising guidance on drivers of frailty-related demand and simulation model outputs. Study registration: This study is registered as NCT04139278 www.clinicaltrials.gov. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 16/116/43) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 44. See the NIHR Funding and Awards website for further award information.
High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed or refractory testicular cancer: a systematic review and meta-analysis.
BACKGROUND: The role of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in the management of patients with relapsed/refractory germ-cell tumors has not been established in prospective studies. Our aim was to estimate the benefits and harm of this treatment in men with relapsed/refractory germ-cell tumors. METHODS: Electronic databases, conference proceedings, and trial registers until April 30, 2023, were searched. Randomized and non-randomized prospective controlled trials were included. Risk of bias assessments were performed using either RoB2 or ROBINS-I tools. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. Time-to-event data were analyzed using the hazard ratio. The primary outcome was overall survival, and a meta-analysis was not conducted to assess it because non-randomized trials were judged to have a critical risk of bias. Categorical data were analyzed using a risk ratio. All results are presented with the corresponding 95% confidence interval. RESULTS: Four out of 3,824 records met the inclusion criteria, and three out of four were used to assess primary and secondary outcomes. Based on the IT94 study (N = 263 participants), single high-dose chemotherapy followed by autologous hematopoietic cell transplantation may have little to no effect on overall survival [hazard ratio (HR) 0.98, 95%CI 0.68 to 1.42; p = 0.916]. Non-randomized trials (N = 43 participants) showed contrasting results, which may be explained by the number of cycles of high-dose chemotherapy administered in each study. Regarding secondary outcomes, information was only provided for event-free survival, response rate, and acute toxicities. CONCLUSIONS: Based on prospective data, there is insufficient evidence to support or refute the proposal that high-dose chemotherapy with autologous hematopoietic cell transplantation improves survival in men with relapsed/refractory germ-cell tumors. If this treatment is considered essential, the choice should be made by experienced clinicians at high-volume cancer centers.