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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.
Preexisting Neuropsychiatric Conditions and Associated Risk of Severe COVID-19 Infection and Other Acute Respiratory Infections
Importance: Evidence indicates that preexisting neuropsychiatric conditions confer increased risks of severe outcomes from COVID-19 infection. It is unclear how this increased risk compares with risks associated with other severe acute respiratory infections (SARIs). Objective: To determine whether preexisting diagnosis of and/or treatment for a neuropsychiatric condition is associated with severe outcomes from COVID-19 infection and other SARIs and whether any observed association is similar between the 2 outcomes. Design, Setting, and Participants: Prepandemic (2015-2020) and contemporary (2020-2021) longitudinal cohorts were derived from the QResearch database of English primary care records. Adjusted hazard ratios (HRs) with 99% CIs were estimated in April 2022 using flexible parametric survival models clustered by primary care clinic. This study included a population-based sample, including all adults in the database who had been registered with a primary care clinic for at least 1 year. Analysis of routinely collected primary care electronic medical records was performed. Exposures: Diagnosis of and/or medication for anxiety, mood, or psychotic disorders and diagnosis of dementia, depression, schizophrenia, or bipolar disorder. Main Outcomes and Measures: COVID-19-related mortality, or hospital or intensive care unit admission; SARI-related mortality, or hospital or intensive care unit admission. Results: The prepandemic cohort comprised 11134789 adults (223569 SARI cases [2.0%]) with a median (IQR) age of 42 (29-58) years, of which 5644525 (50.7%) were female. The contemporary cohort comprised 8388956 adults (58203 severe COVID-19 cases [0.7%]) with a median (IQR) age of 48 (34-63) years, of which 4207192 were male (50.2%). Diagnosis and/or treatment for neuropsychiatric conditions other than dementia was associated with an increased likelihood of a severe outcome from SARI (anxiety diagnosis: HR, 1.16; 99% CI, 1.13-1.18; psychotic disorder diagnosis and treatment: HR, 2.56; 99% CI, 2.40-2.72) and COVID-19 (anxiety diagnosis: HR, 1.16; 99% CI, 1.12-1.20; psychotic disorder treatment: HR, 2.37; 99% CI, 2.20-2.55). The effect estimate for severe outcome with dementia was higher for those with COVID-19 than SARI (HR, 2.85; 99% CI, 2.71-3.00 vs HR, 2.13; 99% CI, 2.07-2.19). Conclusions and Relevance: In this longitudinal cohort study, UK patients with preexisting neuropsychiatric conditions and treatments were associated with similarly increased risks of severe outcome from COVID-19 infection and SARIs, except for dementia.
Association between mirtazapine use and serious self-harm in people with depression: an active comparator cohort study using UK electronic health records
Background Studies report an increased risk of self-harm or suicide in people prescribed mirtazapine compared with other antidepressants. Objectives To compare the risk of serious self-harm in people prescribed mirtazapine versus other antidepressants as second-line treatments. Design and setting Cohort study using anonymised English primary care electronic health records, hospital admission data and mortality data with study window 1 January 2005 to 30 November 2018. Participants 24 516 people diagnosed with depression, aged 18-99 years, initially prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine, a different SSRI, amitriptyline or venlafaxine. Main outcome measures Hospitalisation or death due to deliberate self-harm. Age-sex standardised rates were calculated and survival analyses were performed using inverse probability of treatment weighting to account for baseline covariates. Results Standardised rates of serious self-harm ranged from 3.8/1000 person-years (amitriptyline) to 14.1/1000 person-years (mirtazapine). After weighting, the risk of serious self-harm did not differ significantly between the mirtazapine group and the SSRI or venlafaxine groups (HRs (95% CI) 1.18 (0.84 to 1.65) and 0.85 (0.51 to 1.41) respectively). The risk was significantly higher in the mirtazapine than the amitriptyline group (3.04 (1.36 to 6.79)) but was attenuated after adjusting for dose. Conclusions There was no evidence for a difference in risk between mirtazapine and SSRIs or venlafaxine after accounting for baseline characteristics. The higher risk in the mirtazapine versus the amitriptyline group might reflect residual confounding if amitriptyline is avoided in people considered at risk of self-harm. Clinical implications Addressing baseline risk factors and careful monitoring might improve outcomes for people at risk of serious self-harm.
An evidence-based approach to the use of telehealth in long-term health conditions: development of an intervention and evaluation through pragmatic randomised controlled trials in patients with depression or raised cardiovascular risk
BackgroundHealth services internationally are exploring the potential of telehealth to support the management of the growing number of people with long-term conditions (LTCs).AimTo develop, implement and evaluate new care programmes for patients with LTCs, focusing on two common LTCs as exemplars: depression or high cardiovascular disease (CVD) risk.MethodsDevelopmentWe synthesised quantitative and qualitative evidence on the effectiveness of telehealth for LTCs, conducted a qualitative study based on interviews with patients and staff and undertook a postal survey to explore which patients are interested in different forms of telehealth. Based on these studies we developed a conceptual model [TElehealth in CHronic disease (TECH) model] as a framework for the development and evaluation of the Healthlines Service for patients with LTCs.ImplementationThe Healthlines Service consisted of regular telephone calls to participants from health information advisors, supporting them to make behaviour change and to use tailored online resources. Advisors sought to optimise participants’ medication and to improve adherence.EvaluationThe Healthlines Service was evaluated with linked pragmatic randomised controlled trials comparing the Healthlines Service plus usual care with usual care alone, with nested process and economic evaluations. Participants were adults with depression or raised CVD risk recruited from 43 general practices in three areas of England. The primary outcome was response to treatment and the secondary outcomes included anxiety (depression trial), individual risk factors (CVD risk trial), self-management skills, medication adherence, perceptions of support, access to health care and satisfaction with treatment.Trial resultsDepression trialIn total, 609 participants were randomised and the retention rate was 86%. Response to treatment [Patient Health Questionnaire 9-items (PHQ-9) reduction of ≥ 5 points and score of < 10 after 4 months] was higher in the intervention group (27%, 68/255) than in the control group (19%, 50/270) [odds ratio 1.7, 95% confidence interval (CI) 1.1 to 2.5;p = 0.02]. Anxiety also improved. Intervention participants reported better access to health support, greater satisfaction with treatment and small improvements in self-management, but not improved medication adherence.CVD risk trialIn total, 641 participants were randomised and the retention rate was 91%. Response to treatment (maintenance of/reduction in QRISK®2 score after 12 months) was higher in the intervention group (50%, 148/295) than in the control group (43%, 124/291), which does not exclude a null effect (odds ratio 1.3, 95% CI 1.0 to 1.9;p = 0.08). The intervention was associated with small improvements in blood pressure and weight, but not smoking or cholesterol. Intervention participants were more likely to adhere to medication, reported better access to health support and greater satisfaction with treatment, but few improvements in self-management.The Healthlines Service was likely to be cost-effective for CVD risk, particularly if the benefits are sustained, but not for depression. The intervention was implemented largely as planned, although initial delays and later disruption to delivery because of the closure of NHS Direct may have adversely affected participant engagement.ConclusionThe Healthlines Service, designed using an evidence-based conceptual model, provided modest health benefits and participants valued the better access to care and extra support provided. This service was cost-effective for CVD risk but not depression. These findings of small benefits at extra cost are consistent with previous pragmatic research on the implementation of comprehensive telehealth programmes for LTCs.Trial registrationCurrent Controlled Trials ISRCTN14172341 (depression trial) and ISRCTN27508731 (CVD risk trial).FundingThe National Institute for Health Research Programme Grants for Applied Research programme.
Trends in general practitioner consultations for hand foot and mouth disease in England between 2017 and 2022
Hand foot and mouth disease (HFMD) is a contagious communicable disease, with a high incidence in children aged under 10 years. It is a mainly self-limiting disease but can also cause serious neurological or cardiopulmonary complications in some cases, which can lead to death. Little is known about the burden of HMFD on primary care health care services in the UK. The aim of this work was to describe trends in general practitioner (GP) consultations for HFMD in England from January 2017 to December 2022 using a syndromic surveillance network of GPs. Daily GP consultations for HFMD in England were extracted from 1 January 2017 to 31 December 2022. Mean weekly consultation rates per 100,000 population and 95% confidence intervals (CI) were calculated. Consultation rates and rate ratios (RR) were calculated by age group and sex. During the study period, the mean weekly consultation rate for HFMD (per 100,000 registered GP patients) was 1.53 (range of 0.27 to 2.47). In England, children aged 1-4 years old accounted for the largest affected population followed by children < 1 years old. We observed a seasonal pattern of HFMD incidence during the non-COVID years, with a seasonal peak of mean weekly rates between months of September and December. HFMD is typically diagnosed clinically rather than through laboratory sampling. Therefore, ability to look at the daily HFMD consultation rates provides excellent epidemiological overview on disease trends. The use of a novel GP-in hours surveillance system allowed a unique epidemiological insight into the recent trends of general practitioner consultations for HFMD. We demonstrate a male predominance of cases, the impact of the non-pharmaceutical interventions during the COVID-19 pandemic, and a change in the week in which the peak number of cases happens post pandemic.
Doing 'detective work' to find a cancer: how are non-specific symptom pathways for cancer investigation organised, and what are the implications for safety and quality of care? A multisite qualitative approach.
BACKGROUND: Over the past two decades, the UK has actively developed policies to enhance early cancer diagnosis, particularly for individuals with non-specific cancer symptoms. Non-specific symptom (NSS) pathways were piloted and then implemented in 2015 to address delays in referral and diagnosis. The aim of this study was to outline the functions that enable NSS teams to investigate cancer and other diagnoses for patients with NSSs. METHODS: The analysis was derived from a multisite ethnographic study conducted between 2020 and 2023 across four major National Health Service (NHS) trusts. Data collection encompassed observations, patient shadowing, interviews with clinicians and patients (n=54) and gathered documents. We used principles of the functional resonance analysis method to identify the functions of the NSS pathway and analyse their relevance to patient safety. RESULTS: Our analysis produced 29 distinct functions within NSS pathways, organised into two clusters: pretesting assessment and information gathering, and post-testing interpretation and management. Safety-critical functions encompassed assessing the reason for referral, deciding on a plan of investigation and estimating the remaining cancer risk. We also identified ways that teams build and maintain safety across all functions, for example, by cultivating generalist-specialist expertise within the team and creating continuity through patient navigation. Variation in practice across sites revealed targets for an NSS pathway blueprint that would foster local development and quality improvement. CONCLUSIONS: Our findings suggest that national and local improvement plans could differentiate specific policies to reduce unwarranted variation and support adaptive variation that facilitates the delivery of safe care within the local context. Enhancing multidisciplinary teams with additional consultants and deploying patient navigators with clinical backgrounds could improve safety within NSS pathways. Future research should investigate different models of generalist-specialist team composition.
Multimodal cell-free DNA whole-genome TAPS is sensitive and reveals specific cancer signals
The analysis of circulating tumour DNA (ctDNA) through minimally invasive liquid biopsies is promising for early multi-cancer detection and monitoring minimal residual disease. Most existing methods focus on targeted deep sequencing, but few integrate multiple data modalities. Here, we develop a methodology for ctDNA detection using deep (80x) whole-genome TET-Assisted Pyridine Borane Sequencing (TAPS), a less destructive approach than bisulphite sequencing, which permits the simultaneous analysis of genomic and methylomic data. We conduct a diagnostic accuracy study across multiple cancer types in symptomatic patients, achieving 94.9% sensitivity and 88.8% specificity. Matched tumour biopsies are used for validation, not for guiding the analysis, imitating an early detection scenario. Furthermore, in silico validation demonstrates strong discrimination (86% AUC) at ctDNA fractions as low as 0.7%. Additionally, we successfully track tumour burden and ctDNA shedding from precancerous lesions post-treatment without requiring matched tumour biopsies. This pipeline is ready for further clinical evaluation to extend cancer screening and improve patient triage and monitoring.
COLOFIT: Development and Internal-External Validation of Models Using Age, Sex, Faecal Immunochemical and Blood Tests to Optimise Diagnosis of Colorectal Cancer in Symptomatic Patients
Background: Colorectal cancer (CRC) is the third most common cancer in the United Kingdom and the second largest cause of cancer death. Aim: To develop and validate a model using available information at the time of faecal immunochemical testing (FIT) in primary care to improve selection of symptomatic patients for CRC investigations. Methods: We included all adults (≥ 18 years) referred to Nottingham University Hospitals NHS Trust between 2018 and 2022 with symptoms of suspected CRC who had a FIT. Predicted 1-year CRC diagnosis were calculated, and externally validated, using Cox proportional hazards modelling with selected multiple fractional polynomial transformations for age, faecal haemoglobin concentration (f-Hb) value, mean corpuscular volume (MCV), platelet count and sex. Results: At a CRC risk threshold of 0.6% (equivalent to f-Hb = 10 μg Hb/g (μg/g)) overall performance of the validated model across age strata using Harrell's C index was ≥ 0.91% (overall C-statistic 93%, 95% CI 92%–95%) with acceptable calibration. Using this model yields similar numbers of detected and missed cancers, but requires ~20% fewer investigations than a f-Hb ≥ 10 μg/g strategy. For approximately 100,000 people per year with symptoms of suspected CRC, we predict it might save > 4500 colonoscopies with no evidence that more cancers would be missed if we used our model compared to using FIT f-Hb ≥ 10 μg/g. Conclusions: Including age, sex, MCV, platelets and f-Hb in a survival analysis model to predict the risk of CRC yields greater diagnostic utility than a simple binary cut off f-Hb ≥ 10 μg/g.
Exploring the policy implementation of a holistic approach to cancer investigation in non-specific symptom pathways in England: An ethnographic study
Objectives: This study aimed to explore the policy implementation of non-specific symptom pathways within the English National Health Service. Methods: A multi-site ethnographic project was conducted in four hospitals that contained non-specific symptom pathways between November 2021 and February 2023. The research involved observation (44 h), interviews (n = 54), patient shadowing, and document review. Results: The study examined how the policy concept of ‘holistic’ care was understood and put into practice within four non-specific symptom pathways. Several challenges associated with providing holistic care were identified. One key challenge was the conflict between delivering holistic care and meeting timed targets, such as the Faster Diagnosis Standard, due to limited availability of imaging and diagnostic tools. The interpretation of a holistic approach varied among participants, with some acknowledging that the current model did not recognise holistic care beyond cancer exclusion. The findings also revealed a lack of clarity and differing opinions on the boundaries of holistic care, resulting in wide variation in NSS pathway implementation across health care providers. Additionally, holistic investigation of non-specific symptoms in younger patients were seen to pose difficulties due to younger patients’ history of health anxiety or depression, as well as concerns over radiological risk exposure. Conclusions: The study highlights the complexity of implementing non-specific symptom pathways in light of standardised timed cancer targets and local cancer policies. There is a need for appropriately funded organisational models of care that prioritise holistic care in a timely manner over solely meeting cancer targets. Decision-makers should also consider the role of non-specific symptom pathways within the broader context of chronic disease management, with a particular emphasis on expanding diagnostic capacity.
Changing power narratives: an exemplar case study on the professionalisation of community health workers in Liberia
Despite their central role in achieving health equity and Universal Health Coverage, only a minority of community health workers (CHWs) is formally recognised as health workforce and receives a salary. Community health policies are formed within the power dynamics of global health practice. We argue that critical investigations of the power dynamics that influence the design of CHW programmes can contribute system-level insights to strengthen their roles. We present a national-level case study of the Liberian Community Health Assistant programme as an exemplar case of successfully introducing a nationwide CHW policy that professionalises CHWs. Using a theory of how power is exercised (Steven Lukes) for our analysis, we argue that Liberia's success in overcoming external funder push-back on the payment of CHWs was enabled by strong political commitment and (re-)claiming government authority in and outside of decision-making processes. Consensus-building across government departments strengthened the government's decision-making power. The availability and strategic use of suitable and contextualised evidence focused on the rights of CHWs allowed for proactive engagement with external funders' concerns. To draw on learnings from the experience of Liberia, we recommend looking beyond the common effectiveness-oriented narratives in academic literature that focus on CHW's functional role. By focussing on how power is exerted through policy negotiations around professionalisation, it could be possible to reframe conventional approaches to the role of CHW in other contexts as well.
Cost-effectiveness of ten commonly used antipsychotics in first-episode schizophrenia in the UK: economic evaluation based on a de novo discrete event simulation model
Background Previous economic evidence about interventions for schizophrenia is outdated, non-transparent and/or limited to a specific clinical context. Aims We developed a de novo discrete event simulation (DES) model for estimating the cost-effectiveness of interventions in schizophrenia in the UK. Method The DES model was developed based on the structure of previous models, populated with demographic, clinical and cost data from the UK, and antipsychotics’ effects from recent network meta-analyses. We simulated treatment pathways for patients with first-episode schizophrenia including events such as relapse, remission, treatment discontinuation, cardiovascular disease and death and estimated costs (2020£) taking the National Health Service perspective and quality-adjusted life years (QALYs) over ten years. Using the model, we ranked ten first-line antipsychotics based on their QALYs and cost-effectiveness. Results Amisulpride was associated with the highest QALYs, followed by risperidone long-acting injection (LAI), aripiprazole-LAI (6.121, 6.084, 6.070, respectively) and others (5.947–6.058). The most cost-effective antipsychotics were amisulpride, olanzapine and risperidone-LAI, with total probability of rankings of 1, ≤2, ≤3, that is, 95%, 89%, 80%, respectively; meanwhile, the least cost-effective were cariprazine, lurasidone and quetiapine, with total probability of rankings of 10, ≥9, ≥8, that is, 96%, 92%, 81%, respectively. Results were robust across sensitivity analyses and influenced primarily by relapse relevant parameters. Conclusions Our findings suggest amisulpride (or risperidone-LAI where oral treatment is inappropriate) as the best overall first-line option based on QALYs and cost-effectiveness. Our ranking may be used to guide decision-making between antipsychotics. Our model is open source and could be applied to the other settings.
A pilot protocol for surveillance of infection and antibiotic prescribing in primary healthcare across the globe: Antibiotic Prescribing in Primary Healthcare Point Prevalence Survey (APC-PPS)
Little data is available from the primary healthcare setting in low- and middle-income countries to describe the burden of clinical infections and antibiotic prescribing proportions for those infections. The AWaRe Antibiotic Book provides a framework for assessing antibiotic prescribing in primary healthcare but requires understanding both frequency of clinical infections and their antibiotic prescribing proportions. The Antibiotic Prescribing in Primary Healthcare Point Prevalence Survey (APC-PPS) project is a series of point prevalence surveys conducted at primary healthcare facilities in LMICs to capture the frequency of consultation for different clinical infections and diagnoses and the frequency and type of antibiotic prescribing associated with these infections in primary healthcare facilities. This study aims to assess the feasibility of using a PPS methodology to collect data on clinical presentation and antibiotic prescribing in primary healthcare settings. The data collected are necessary to be able to summarise relative rates of presentation of different clinical infections and antibiotic prescribing practices to inform global estimates of antibiotic use and inform the development of surveillance methods and representative sampling frames. Each site will conduct 6-8 point prevalence surveys over the course of 12 months. Completely anonymous data on age, sex, relevant comorbidities, infection symptoms and diagnoses and antibiotic prescription are collected for patients of all ages with acute infection symptoms (up to 14 days of symptoms) who present to the facility on the day of the survey. No identifiable data will be collected from individuals. Data is collected via ODK Collect and stored in a secure ODK Cloud server hosted by City St. George’s, University of London. Sites will be active between early 2023- end 2024, with regular interim data analysis scheduled and final data analysis planned by mid 2025. All required local and national ethical and regulatory approvals will be obtained prior to sites starting.
Umbrella review of economic evaluations of interventions for the prevention and management of healthcare-associated infections in adult hospital patients.
INTRODUCTION: Healthcare-associated infections result in worse outcomes for patients and greater financial burden. An estimated 4.8 million HCAIs occurred in hospitals across Europe in 2022-23. Sixty-four percent of antibiotic-resistant infections in Europe are associated with healthcare. It is therefore vital to identify cost-effective interventions. Our objective was to summarise the cost-effectiveness evidence of interventions addressing HCAIs in hospitals. METHODS: An umbrella review was conducted to identify evidence on the cost-effectiveness of antimicrobial stewardship, infection prevention and control, and microbiology and diagnostic stewardship interventions for the prevention and clinical management of HCAIs in adult hospital patients. Medline, Embase and EconLit databases were searched. A qualitative synthesis was undertaken. RESULTS: Twenty-four systematic reviews met the inclusion criteria, with 101 separate analyses extracted and grouped into 10 intervention and 14 infection/organism categories, across various countries and settings. Most evidence focussed on screening followed by contact precautions, isolation and/or decolonisation, with selective screening most cost-effective. Most IPC bundles were cost-effective, although interventions were heterogeneous. The evidence base was sparse for the remaining intervention categories, with more research required. The limited evidence suggests standalone environmental cleaning, hand hygiene, diagnostics, surveillance, ABS, and decolonisation interventions were mostly cost-effective. The cost-effectiveness of standalone personal protective equipment, and education and training interventions was mixed. Most interventions focussed on methicillin-resistant Staphylococcus aureus and other Gram-positive infections, with more research needed on Gram-negative infections. The comparator was unclear in many extracted analyses. CONCLUSIONS: Cost-effective interventions to address HCAIs in hospitals exist, although more evidence is needed for most interventions.
Local excision for T1 rectal cancer: A population-based study of practice patterns and oncological outcomes
Aim: Local excision (LE) for T1 rectal cancer may be recommended in those with low-risk disease, while resection is typically recommended in those with a high risk of luminal recurrence or lymph node metastasis. The aim of this work was to compare survival between resection and LE. Method: This was a population-based retrospective cohort study set in the Canadian province of Ontario. Patients were individuals with T1Nx rectal cancer between 2010 and 2014 and demographics, disease characteristics, treatments and outcomes were determined using linked administrative databases. This study does not include clinical information regarding individual patient treatment decisions. The main outcome measure was overall survival (OS). Results: A total of 719 patients were identified, including 359 with upfront resection, 113 with LE and immediate resection (<90 days) and 247 with LE with definitive intent. The majority of LEs were performed via colonoscopy. Piecemeal excision (42% vs. 49%, p = 0.28) and positive margin (50% vs. 77%, p < 0.01) rates were high in both LE groups, with the highest rate in those with immediate resection. The prevalence of poor differentiation (<5%, p = 0.70) and lymphovascular invasion (LVI) (14%, p = 0.80) was similar across groups. In those with LE with definitive intent, 21% ultimately underwent resection (median 150 days, interquartile range 114–181 days) and 4% received radiation. There was no difference in 5-year OS between groups (resection 83.2% vs. LE and immediate resection 82.3% vs. definitive LE 83.3%; p = 0.33). Adjusted analyses demonstrated no association between approach and survival [definitive intent LE hazard ratio (HR) 0.97 (95% CI 0.70–1.35), LE and immediate resection HR 0.97 (95% CI 0.60–1.45), upfront resection HR 1 (Ref); p = 0.98]. Differentiation, piecemeal excisions and LVI were not associated with OS in the LE groups. Conclusion: There were no observed differences in survival between those who underwent resection, LE and immediate resection and definitive intent LE. Although, these are observational data, they call into question the reflexive decision to offer radical resection for those with suspected T1 rectal cancer.