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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.
First metatarsophalangeal joint arthrodesis versus proximal phalanx hemiarthroplasty for hallux rigidus: Feasibility study for a randomised controlled trial
Background: Osteoarthritis of the first metatarsophalangeal joint (hallux rigidus) leads to pain and poor function and mobility. Arthrodesis is the gold standard treatment for end-stage disease. Total joint arthroplasties have been attempted, but early loosening has been attributed to dorsally directed shear forces on the metatarsal component. Metallic proximal phalangeal hemiarthroplasty theoretically avoids this. Whilst early results are promising, no comparative trials exist comparing this to arthrodesis.Methods/Design: The primary objectives are to determine the range of outcome scores between the two treatment arms (to inform a power calculation). Outcome measures will include the MOXFQ, AOFAS-Hallux and EuroQol EQ-5D-5 L. Secondary objectives are to determine the accrual rate, dropout rate and trial acceptability to both patients and surgeons. These data will allow the development of a larger trial with longer follow-up.This is a prospective randomised controlled single-centre study comparing proximal phalanx hemiarthroplasty (AnaToemic, Arthrex Ltd., Sheffield, UK) with arthrodesis (15 patients in each arm). Randomisation will be performed using a 1:1 allocation ratio in blocks of six.Patients meeting the eligibility criteria will be recruited from three foot and ankle consultant surgeon's clinics (East Lancashire Hospitals NHS Trust). If agreeable, informed consent will be obtained before patients are randomised.The outcome measure scores will be completed pre-operatively and repeated at 6 weeks, 3 months and 12 months. A radiological review will be performed at 6 weeks and 12 months to determine rates of loosening (hemiarthroplasty) and union (arthrodesis). Data on length of stay, return to work, complications and re-operation rates will also be collected.The analysis will compare the change in outcome scores between treatment groups at all follow-up time points. Scores will be compared using a Student t-test, adjusting for scores at baseline.This study will be conducted in accordance with the current revision of the Declaration of Helsinki (1996) and the ICH-GCP Guideline (International Conference on Harmonisation, Good Clinical Practice, E6(R1), 1996). This study has been approved by the sponsor, the Trust Research & Development office. Ethical approval has been received from the National Research Ethics Service (North East: 12/NE/0385 for protocol version 5.3 dated 3 June 2013).Trial registration: Current Controlled Trials ISRCTN88273654. © 2014 Divecha et al.; licensee BioMed Central Ltd.
Towards a framework for analysis of eye-tracking studies in the three dimensional environment: A study of visual search by experienced readers of endoluminal CT colonography
Objective: Eye tracking in three dimensions is novel, but established descriptors derived from two-dimensional (2D) studies are not transferable. We aimed to develop metrics suitable for statistical comparison of eye-tracking data obtained from readers of three-dimensional (3D) "virtual" medical imaging, using CT colonography (CTC) as a typical example.
Tracking eye gaze during interpretation of endoluminal three-dimensional CT colonography: Visual perception of experienced and inexperienced readers
Purpose: To identify and compare key stages of the visual process in experienced and inexperienced readers and to examine how these processes are used to search a moving threedimensional (3D) image and their relationship to falsenegative errors.
Giardiasis in North West England: Faecal specimen requesting rates by GP practice
Many cases of giardiasis in the UK are undiagnosed and among other things, diagnosis is dependent upon the readiness of GPs to request a specimen. The aim of this study is to assess the rate of specimens requested per GP practice in Central Lancashire, to examine the differences between GP practices and to estimate the pattern of unexplained spatial variation in the practice rate of specimens after adjustment for deprivation. To achieve this, we fitted a set of binomial and Poisson regression models, with random effects for GP practice. Our analysis suggests that there were differences in the rate of specimens by GP practices (P < 0·001) for a single year, but no difference in the proportion of positive tests per specimen submitted or in the rate of positive specimens per practice population. There was a difference in the cumulative rate of positive specimens per practice population over a 9-year period (P < 0·001). Neither the specimen rate per practice for a single year nor the cumulative rate of positive specimens over multiple years demonstrated significant spatial correlation. Hence, spatial variation in the incidence of giardiasis is unlikely to be confounded by variation in GP rate of specimens.
The effect of computer-aided detection markers on visual search and reader performance during concurrent reading of CT colonography
Objective: We aimed to identify the effect of computer-aided detection (CAD) on visual search and performance in CT Colonography (CTC) of inexperienced and experienced readers. Methods: Fifteen endoluminal CTC examinations were recorded, each with one polyp, and two videos were generated, one with and one without a CAD mark. Forty-two readers (17 experienced, 25 inexperienced) interpreted the videos during infrared visual search recording. CAD markers and polyps were treated as regions of interest in data processing. This multi-reader, multi-case study was analysed using multilevel modelling. Results: CAD drew readers’ attention to polyps faster, accelerating identification times: median ‘time to first pursuit’ was 0.48 s (IQR 0.27 to 0.87 s) with CAD, versus 0.58 s (IQR 0.35 to 1.06 s) without. For inexperienced readers, CAD also held visual attention for longer. All visual search metrics used to assess visual gaze behaviour demonstrated statistically significant differences when “with” and “without” CAD were compared. A significant increase in the number of correct polyp identifications across all readers was seen with CAD (74 % without CAD, 87 % with CAD; p < 0.001). Conclusions: CAD significantly alters visual search and polyp identification in readers viewing three-dimensional endoluminal CTC. For polyp and CAD marker pursuit times, CAD generally exerted a larger effect on inexperienced readers. Key Points: • Visual gaze is attracted by computer-assisted detection (CAD) marks on polyps • Inexperienced readers’ gaze is affected more by CAD than experienced readers. • CAD marks could mean that the unannotated endoluminal surface is relatively neglected. • Correct polyp identification is increased significantly by CAD.
Giardiasis in North West England: Faecal specimen requesting rates by GP practice
Many cases of giardiasis in the UK are undiagnosed and among other things, diagnosis is dependent upon the readiness of GPs to request a specimen. The aim of this study is to assess the rate of specimens requested per GP practice in Central Lancashire, to examine the differences between GP practices and to estimate the pattern of unexplained spatial variation in the practice rate of specimens after adjustment for deprivation. To achieve this, we fitted a set of binomial and Poisson regression models, with random effects for GP practice. Our analysis suggests that there were differences in the rate of specimens by GP practices (P < 0·001) for a single year, but no difference in the proportion of positive tests per specimen submitted or in the rate of positive specimens per practice population. There was a difference in the cumulative rate of positive specimens per practice population over a 9-year period (P < 0·001). Neither the specimen rate per practice for a single year nor the cumulative rate of positive specimens over multiple years demonstrated significant spatial correlation. Hence, spatial variation in the incidence of giardiasis is unlikely to be confounded by variation in GP rate of specimens.
An empirical investigation into the role of subjective prior probability in searching for potentially missing items
There are many examples from the scientific literature of visual search tasks in which the length, scope and success rate of the search have been shown to vary according to the searcher's expectations of whether the search target is likely to be present. This phenomenon has major practical implications, for instance in cancer screening, when the prevalence of the condition is low and the consequences of a missed disease diagnosis are severe. We consider this problem from an empirical Bayesian perspective to explain how the effect of a low prior probability, subjectively assessed by the searcher, might impact on the extent of the search. We show how the searcher’s posterior probability that the target is present depends on the prior probability and the proportion of possible target locations already searched, and also consider the implications of imperfect search, when the probability of false-positive and false-negative decisions is non-zero. The theoretical results are applied to two studies of radiologists’ visual assessment of pulmonary lesions on chest radiographs. Further application areas in diagnostic medicine and airport security are also discussed.
Small polyps at endoluminal CT colonography are often seen but ignored by radiologists
OBJECTIVE. The objective of our study was to describe the characteristics of polyps viewed but then dismissed incorrectly by radiologists at endoluminal CT colonography (CTC), eye movements during these errors, and features provoking false-positive diagnoses. MATERIALS AND METHODS. Forty-two radiologists viewed 30 endoluminal CTC videos, each depicting a polyp, while their eye movements were tracked. Half of the videos had computer-assisted detection (CAD), and half did not. Classification errors were defined when proven polyps were seen but dismissed. Eye movements during these errors and during correct polyp identifications were compared with multilevel modeling. Polyps were divided subsequently into "difficult to classify" and "easy to classify" using a classification error threshold of more than 15%. Polyp diameter, height, and subjective conspicuity and the proportion of time viewed were compared between groups. RESULTS. Eye tracking revealed that 97% of false-negative polyp diagnoses were nonetheless preceded by the reader observing the polyp. The difficult polyps were significantly smaller than the easy polyps (mean diameter, 5.4 vs 8.2 mm, respectively p = 0.014) and were subjectively less conspicuous (median score, 4 vs 2; p = 0.0032). Readers spent proportionally less time viewing difficult polyps than viewing easy polyps (29.0% of the time they were on-screen vs 42.6%, respectively; p = 0.01) regardless of the presence of CAD. CONCLUSION. Even small and subjectively inconspicuous polyps attract reader gaze, but they are nonetheless ignored. These errors are made rapidly even with CAD. Efforts to improve reader performance at CTC should focus on decision making rather than detection alone.
Optimal strategies for monitoring lipid levels in patients at risk or with cardiovascular disease: A systematic review with statistical and cost-effectiveness modelling
Background Various lipid measurements in monitoring/screening programmes can be used, alone or in cardiovascular risk scores, to guide treatment for prevention of cardiovascular disease (CVD). Because some changes in lipids are due to variability rather than true change, the value of lipid-monitoring strategies needs evaluation. Objective To determine clinical value and cost-effectiveness of different monitoring intervals and different lipid measures for primary and secondary prevention of CVD. Data sources We searched databases and clinical trials registers from 2007 (including the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the Clinical Trials Register, the Current Controlled Trials register, and the Cumulative Index to Nursing and Allied Health Literature) to update and extend previous systematic reviews. Patient-level data from the Clinical Practice Research Datalink and St Luke’s Hospital, Japan, were used in statistical modelling. Utilities and health-care costs were drawn from the literature. Methods In two meta-analyses, we used prospective studies to examine associations of lipids with CVD and mortality, and randomised controlled trials to estimate lipid-lowering effects of atorvastatin doses. Patient-level data were used to estimate progression and variability of lipid measurements over time, and hence to model lipid-monitoring strategies. Results are expressed as rates of true-/false-positive and true-/false-negative tests for high lipid or high CVD risk. We estimated incremental costs per quality-adjusted life-year. Results A total of 115 publications reported strength of association between different lipid measures and CVD events in 138 data sets. The summary adjusted hazard ratio per standard deviation of total cholesterol (TC) to high-density lipoprotein (HDL) cholesterol ratio was 1.25 (95% confidence interval 1.15 to 1.35) for CVD in a primary prevention population but heterogeneity was high (I2 = 98%); similar results were observed for non-HDL cholesterol, apolipoprotein B and other ratio measures. Associations were smaller for other single lipid measures. Across 10 trials, low-dose atorvastatin (10 and 20 mg) effects ranged from a TC reduction of 0.92 mmol/l to 2.07 mmol/l, and low-density lipoprotein reduction of between 0.88 mmol/l and 1.86 mmol/l. Effects of 40 mg and 80 mg were reported by one trial each. For primary prevention, over a 3-year period, we estimate annual monitoring would unnecessarily treat 9 per 1000 more men (28 vs. 19 per 1000) and 5 per 1000 more women (17 vs. 12 per 1000) than monitoring every 3 years. However, annual monitoring would also undertreat 9 per 1000 fewer men (7 vs. 16 per 1000) and 4 per 1000 fewer women (7 vs. 11 per 1000) than monitoring at 3-year intervals. For secondary prevention, over a 3-year period, annual monitoring would increase unnecessary treatment changes by 66 per 1000 men and 31 per 1000 women, and decrease undertreatment by 29 per 1000 men and 28 per 1000 men, compared with monitoring every 3 years. In cost-effectiveness, strategies with increased screening/monitoring dominate. Exploratory analyses found that any unknown harms of statins would need utility decrements as large as 0.08 (men) to 0.11 (women) per statin user to reverse this finding in primary prevention. Limitation Heterogeneity in meta-analyses. Conclusions While acknowledging known and potential unknown harms of statins, we find that more frequent monitoring strategies are cost-effective compared with others. Regular lipid monitoring in those with and without CVD is likely to be beneficial to patients and to the health service. Future research should include trials of the benefits and harms of atorvastatin 40 and 80 mg, large-scale surveillance of statin safety, and investigation of the effect of monitoring on medication adherence. Study registration This study is registered as PROSPERO CRD42013003727. Funding The National Institute for Health Research Health Technology Assessment programme.
Lymphangiogenesis and carcinoma in the uterine cervix: Joint and hierarchical models for random cluster sizes and continuous outcomes
Although the lymphatic system is clearly linked to the metastasis of most human carcinomas, the mechanisms by which lymphangiogenesis occurs in response to the presence of carcinoma remain unclear. Hierarchical models are presented to investigate the properties of lymphatic vessel production in 2997 fields taken from 20 individuals with invasive carcinoma, 21 individuals with cervical intraepithelial neoplasia and 21 controls. Such data demonstrate a high degree of correlation within tumour samples from the same individual. Joint hierarchical models utilising shared random effects are discussed and fitted in a Bayesian framework to allow for the correlation between two key outcome measures: a random cluster size (the number of lymphatic vessels in a tissue sample) and a continuous outcome (vessel size). Results show that invasive carcinoma samples are associated with increased production of smaller and more irregularly-shaped lymphatic vessels and suggest a mechanistic link between carcinoma of the cervix and lymphangiogenesis.
Adaptive Sampling Design for Spatio-Temporal Prediction
Environmental monitoring provides a typical setting that gives rise to spatio-temporal design problems. This chapter considers the model-based design, in which the optimal design problem requires two key features to be specified: (i) a statistical or mathematical model for the process under consideration; and, (ii) a criterion with respect to which the design is required to be optimized. After reviewing spatial and spatio-temporal adaptive designs it considers the performance of adaptive design-finding algorithms with respect to these for two different models for stochastic process S: the stationary Gaussian model; and a dynamic process convolution model. The chapter uses the second of these models to consider adaptive designs for the Upper Austria rainfall data. It concludes that adaptive designs should be constructed by a criterion that directly measures the extent to which the primary scientific goal of the analysis is being met, and should therefore be strongly context-dependent.
Behavioural interventions for smoking cessation: an overview and network meta-analysis
Background: Smoking is a leading cause of disease and death worldwide. In people who smoke, quitting smoking can reverse much of the damage. Many people use behavioural interventions to help them quit smoking; these interventions can vary substantially in their content and effectiveness. Objectives: To summarise the evidence from Cochrane Reviews that assessed the effect of behavioural interventions designed to support smoking cessation attempts and to conduct a network meta-analysis to determine how modes of delivery; person delivering the intervention; and the nature, focus, and intensity of behavioural interventions for smoking cessation influence the likelihood of achieving abstinence six months after attempting to stop smoking; and whether the effects of behavioural interventions depend upon other characteristics, including population, setting, and the provision of pharmacotherapy. To summarise the availability and principal findings of economic evaluations of behavioural interventions for smoking cessation, in terms of comparative costs and cost-effectiveness, in the form of a brief economic commentary. Methods: This work comprises two main elements. 1. We conducted a Cochrane Overview of reviews following standard Cochrane methods. We identified Cochrane Reviews of behavioural interventions (including all non-pharmacological interventions, e.g. counselling, exercise, hypnotherapy, self-help materials) for smoking cessation by searching the Cochrane Library in July 2020. We evaluated the methodological quality of reviews using AMSTAR 2 and synthesised data from the reviews narratively. 2. We used the included reviews to identify randomised controlled trials of behavioural interventions for smoking cessation compared with other behavioural interventions or no intervention for smoking cessation. To be included, studies had to include adult smokers and measure smoking abstinence at six months or longer. Screening, data extraction, and risk of bias assessment followed standard Cochrane methods. We synthesised data using Bayesian component network meta-analysis (CNMA), examining the effects of 38 different components compared to minimal intervention. Components included behavioural and motivational elements, intervention providers, delivery modes, nature, focus, and intensity of the behavioural intervention. We used component network meta-regression (CNMR) to evaluate the influence of population characteristics, provision of pharmacotherapy, and intervention intensity on the component effects. We evaluated certainty of the evidence using GRADE domains. We assumed an additive effect for individual components. Main results: We included 33 Cochrane Reviews, from which 312 randomised controlled trials, representing 250,563 participants and 845 distinct study arms, met the criteria for inclusion in our component network meta-analysis. This represented 437 different combinations of components. Of the 33 reviews, confidence in review findings was high in four reviews and moderate in nine reviews, as measured by the AMSTAR 2 critical appraisal tool. The remaining 20 reviews were low or critically low due to one or more critical weaknesses, most commonly inadequate investigation or discussion (or both) of the impact of publication bias. Of note, the critical weaknesses identified did not affect the searching, screening, or data extraction elements of the review process, which have direct bearing on our CNMA. Of the included studies, 125/312 were at low risk of bias overall, 50 were at high risk of bias, and the remainder were at unclear risk. Analyses from the contributing reviews and from our CNMA showed behavioural interventions for smoking cessation can increase quit rates, but effectiveness varies on characteristics of the support provided. There was high-certainty evidence of benefit for the provision of counselling (odds ratio (OR) 1.44, 95% credibility interval (CrI) 1.22 to 1.70, 194 studies, n = 72,273) and guaranteed financial incentives (OR 1.46, 95% CrI 1.15 to 1.85, 19 studies, n = 8877). Evidence of benefit remained when removing studies at high risk of bias. These findings were consistent with pair-wise meta-analyses from contributing reviews. There was moderate-certainty evidence of benefit for interventions delivered via text message (downgraded due to unexplained statistical heterogeneity in pair-wise comparison), and for the following components where point estimates suggested benefit but CrIs incorporated no clinically significant difference: individual tailoring; intervention content including motivational components; intervention content focused on how to quit. The remaining intervention components had low-to very low-certainty evidence, with the main issues being imprecision and risk of bias. There was no evidence to suggest an increase in harms in groups receiving behavioural support for smoking cessation. Intervention effects were not changed by adjusting for population characteristics, but data were limited. Increasing intensity of behavioural support, as measured through the number of contacts, duration of each contact, and programme length, had point estimates associated with modestly increased chances of quitting, but CrIs included no difference. The effect of behavioural support for smoking cessation appeared slightly less pronounced when people were already receiving smoking cessation pharmacotherapies. Authors' conclusions: Behavioural support for smoking cessation can increase quit rates at six months or longer, with no evidence that support increases harms. This is the case whether or not smoking cessation pharmacotherapy is also provided, but the effect is slightly more pronounced in the absence of pharmacotherapy. Evidence of benefit is strongest for the provision of any form of counselling, and guaranteed financial incentives. Evidence suggested possible benefit but the need of further studies to evaluate: individual tailoring; delivery via text message, email, and audio recording; delivery by lay health advisor; and intervention content with motivational components and a focus on how to quit. We identified 23 economic evaluations; evidence did not consistently suggest one type of behavioural intervention for smoking cessation was more cost-effective than another. Future reviews should fully consider publication bias. Tools to investigate publication bias and to evaluate certainty in CNMA are needed.
Towards a More Evidence-Based Risk Assessment for People in the Criminal Justice System: the Case of OxRec in the Netherlands
Risk assessment tools are widely used throughout the criminal justice system to assist in making decisions about sentencing, supervision, and treatment. In this article, we discuss several methodological and practical limitations associated with risk assessment tools currently in use. These include variable predictive performance due to the exclusion of important background predictors; high costs, including the need for regular staff training, in order to use many tools; development of tools using suboptimal methods and poor transparency in how they create risk scores; included risk factors being based on dated evidence; and ethical concerns highlighted by legal scholars and criminologists, such as embedding systemic biases and uncertainty about how these tools influence judicial decisions. We discuss the potential that specific predictors, such as living in a deprived neighbourhood, may indirectly select for individuals in racial or ethnic minority groups. To demonstrate how these limitations and ethical concerns can be addressed, we present the example of OxRec, a risk assessment tool used to predict recidivism for individuals in the criminal justice system. OxRec was developed in Sweden and has been externally validated in Sweden and the Netherlands. The advantages of OxRec include its predictive accuracy based on rigorous multivariable testing of predictors, transparent reporting of results and the final model (including how the probability score is derived), scoring simplicity (i.e. without the need for additional interview), and the reporting of a wide range of performance measures, including those of discrimination and calibration, the latter of which is rarely reported but a key metric. OxRec is intended to be used alongside professional judgement, as a support for decision-making, and its performance measures need to be interpreted in this light. The reported calibration of the tool in external samples clearly suggests no systematic overestimation of risk, including in large subgroups.
Prediction of reoffending risk in men convicted of sexual offences: development and validation of novel and scalable risk assessment tools (OxRIS)
Background: Current risk assessment tools have a limited evidence base with few validations, poor reporting of outcomes, and rarely include modifiable factors. Methods: We examined a national cohort of men convicted of sexual crimes in Sweden. We developed prediction models for three outcomes: violent (including sexual), any, and sexual reoffending. We used Cox proportional hazard regression to develop multivariable prediction models and validated these in an external sample. We reported discrimination and calibration statistics at prespecified cut-offs. Findings: We identified 16,231 men convicted of sexual offences, of whom 14.8% violently reoffended during a mean follow up of 38 months, 31.4% for any crime (34 months), and 3.6% for sexual crimes (42 months). Models for violent and any reoffending showed good discrimination and calibration. At 1, 3, and 5 years, the area under the curve (AUC) was 0.75–0.76 for violent reoffending and 0.74–0.75 for any reoffending. The prediction model for sexual reoffending showed modest discrimination (AUC = 0.67) and good calibration. We have generated three simple and web-based risk calculators, which are freely available. Interpretation: Scalable evidence-based risk assessment tools for sexual offenders in the criminal justice system and forensic mental health could assist decision-making and treatment allocation by identifying those at higher risk, and screening out low risk persons.
The ‘double whammy’ of low prevalence in clinical risk prediction
Background Worldwide, around 800 000 people die each year from suicide,1 which is the leading cause of death in the UK in young adults.2 Prediction modelling studies have attempted to incorporate demographic, clinical and other factors to identify high-risk individuals so that appropriate interventions can be offered.3 4 This approach has a large literature but has not always been judged successful. In one review, all 35 suicide risk prediction studies assessed were classified as having high risk of bias or insufficient diagnostic accuracy, based on targets of 80% sensitivity and 50% specificity.5 Others have written of a performance ‘glass ceiling’ in suicide prediction, and even that ‘risk categorization of individual patients has no role to play in preventing the suicide of psychiatric inpatients’.6 In spite of the mortality data quoted previously, in most populations, risk of death from suicide is low, usually below 1%. This has led to claims about performance of prediction models that appear counterintuitive, such as ‘suicide prediction models produce accurate overall classification models, but their accuracy of predicting a future event is near 0’, while noting that even in high-risk populations, the positive predictive value (PPV) of many prediction rules may be less than 1%.3 We describe two principal reasons why the nature of developing clinical prediction rules in low prevalence scenarios will almost invariably result in concerns about performance, on standards by which this is usually judged. Although we focus primarily on suicide prediction, these points apply more generally to other low prevalence clinical areas, some examples of which are also discussed.
Prediction of violent reoffending in people released from prison in England: External validation study of a risk assessment tool (OxRec)
We aimed to externally validate the Oxford Risk of Recidivism (OxRec) tool to estimate 1- and 2-year risk of violent reoffending in people released from prison in England. We identified individuals using administrative data shared between official prison and police services. We extracted information on criminal history, clinical and sociodemographic risk predictors, and outcomes. Predictive ability was examined using measures of calibration and discrimination for predetermined risk thresholds. In total, 1770 individuals (median age = 33 [IQR 27–40]; 92% were male) were identified. 31% and 43% reoffended within 1 and 2 years, respectively. Discrimination was good, with AUCs of 0.71 (95% CI: 0.69-0.74) for 1 year and 0.71 (0.68-0.74) for 2-year follow up. At a pre-specified threshold of 40% for 2-year risk, sensitivity was 77% (74%–80%), specificity 54% (51%–58%), PPV 56% (53%–59%) and NPV 76% (73%–79%). Simple model validation found a systematic underestimation of the probability of reoffending. However, after updating the model, calibration was good. External validations of risk assessment tools can be conducted using linked data between prison and police, and may require recalibration before implementation. In this validation, OxRec had good performance on discrimination and calibration measures. It can be considered to be used to improve decision-making about risk of serious offending and the allocation of resources.
Patient-centred care, health behaviours and cardiovascular risk factor levels in people with recently diagnosed type 2 diabetes: 5-year follow-up of the ADDITION-Plus trial cohort
Objective: To examine the association between the experience of patient-centred care (PCC), health behaviours and cardiovascular disease (CVD) risk factor levels among people with type 2 diabetes. Design: Population-based prospective cohort study. Setting: 34 general practices in East Anglia, UK, delivering organised diabetes care. Participants: 478 patients recently diagnosed with type 2 diabetes aged between 40 and 69 years enrolled in the ADDITION-Plus trial. Main outcome measures: Self-reported and objectively measured health behaviours (diet, physical activity, smoking status), CVD risk factor levels (blood pressure, lipid levels, glycated haemoglobin, body mass index, waist circumference) and modelled 10- year CVD risk. Results: Better experiences of PCC early in the course of living with diabetes were not associated with meaningful differences in self-reported physical activity levels including total activity energy expenditure (β-coefficient: 0.080 MET h/day (95% CI 0.017 to 0.143; p=0.01)), moderate-to-vigorous physical activity (β-coefficient: 5.328 min/day (95% CI 0.796 to 9.859; p=0.01)) and reduced sedentary time (β-coefficient: -1.633 min/day (95% CI -2.897 to -0.368; p=0.01)). PCC was not associated with clinically meaningful differences in levels of high-density lipoprotein cholesterol (β-coefficient: 0.002 mmol/L (95% CI 0.001 to 0.004; p=0.03)), systolic blood pressure (β-coefficient: -0.561 mm Hg (95% CI -0.653 to -0.468; p=0.01)) or diastolic blood pressure (β-coefficient: -0.565 mm Hg (95% CI -0.654 to -0.476; p=0.01)). Over an extended follow-up of 5 years, we observed no clear evidence that PCC was associated with self-reported, clinical or biochemical outcomes, except for waist circumference (β- coefficient: 0.085 cm (95% CI 0.015 to 0.155; p=0.02)). Conclusions: We found little evidence that experience of PCC early in the course of diabetes was associated with clinically important changes in health-related behaviours or CVD risk factors. Trial registration number: ISRCTN99175498; Postresults.
The comparative interrupted time series design for assessment of diagnostic impact: methodological considerations and an example using point-of-care C-reactive protein testing.
BACKGROUND: In diagnostic evaluation, it is necessary to assess the clinical impact of a new diagnostic as well as its diagnostic accuracy. The comparative interrupted time series design has been proposed as a quasi-experimental approach to evaluating interventions. We show how it can be used in the design of a study to evaluate a point-of-care diagnostic test for C-reactive protein in out-of-hours primary care services, to guide antibiotic prescribing among patients presenting with possible respiratory tract infection. This study consisted of a retrospective phase that used routinely collected monthly antibiotic prescribing data from different study sites, and a prospective phase in which antibiotic prescribing rates were monitored after the C-reactive protein diagnostic was introduced at some of the sites. METHODS: Of 8 study sites, 3 were assigned to receive the diagnostic and 5 were assigned as controls. We obtained retrospective monthly time series of respiratory tract targeted antibiotic prescriptions at each site. Separate ARIMA models at each site were used these to forecast monthly prescription counts that would be expected in the prospective phase, using simulation to obtain a set of 1-year predictions alongside their standard errors. We show how these forecasts can be combined to test for a change in prescription rates after introduction of the diagnostic and estimate power to detect this change. RESULTS: Fitted time series models at each site were stationary and showed second-order annual seasonality, with a clear December peak in prescriptions, although the timing and extent of the peak varied between sites and between years. Mean one-year predictions of antibiotic prescribing rates based on the retrospective time series analysis differed between sites assigned to receive the diagnostic and those assigned to control. Adjusting for the trend in the retrospective time series at each site removed these differences. CONCLUSIONS: Quasi-experimental designs such as comparative interrupted time series can be used in diagnostic evaluation to estimate effect sizes before conducting a full randomised controlled trial or if a randomised trial is infeasible. In multi-site studies, existing retrospective data should be used to adjust for underlying differences between sites to make outcome data from different sites comparable, when possible.
Risk of death by suicide following self-harm presentations to healthcare: development and validation of a multivariable clinical prediction rule (OxSATS)
BACKGROUND: Assessment of suicide risk in individuals who have self-harmed is common in emergency departments, but is often based on tools developed for other purposes. OBJECTIVE: We developed and validated a predictive model for suicide following self-harm. METHODS: We used data from Swedish population-based registers. A cohort of 53 172 individuals aged 10+ years, with healthcare episodes of self-harm, was split into development (37 523 individuals, of whom 391 died from suicide within 12 months) and validation (15 649 individuals, 178 suicides within 12 months) samples. We fitted a multivariable accelerated failure time model for the association between risk factors and time to suicide. The final model contains 11 factors: age, sex, and variables related to substance misuse, mental health and treatment, and history of self-harm. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis guidelines were followed for the design and reporting of this work. FINDINGS: An 11-item risk model to predict suicide was developed using sociodemographic and clinical risk factors, and showed good discrimination (c-index 0.77, 95% CI 0.75 to 0.78) and calibration in external validation. For risk of suicide within 12 months, using a 1% cut-off, sensitivity was 82% (75% to 87%) and specificity was 54% (53% to 55%). A web-based risk calculator is available (Oxford Suicide Assessment Tool for Self-harm or OxSATS). CONCLUSIONS: OxSATS accurately predicts 12-month risk of suicide. Further validations and linkage to effective interventions are required to examine clinical utility. CLINICAL IMPLICATIONS: Using a clinical prediction score may assist clinical decision-making and resource allocation.
Electronic cigarettes for smoking cessation.
BACKGROUND: Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, but some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This is an update conducted as part of a living systematic review. OBJECTIVES: To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long-term smoking abstinence. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 May 2021, and reference-checked and contacted study authors. We screened abstracts from the Society for Research on Nicotine and Tobacco (SRNT) 2021 Annual Meeting. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and randomized cross-over trials, in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. Studies had to report abstinence from cigarettes at six months or longer or data on safety markers at one week or longer, or both. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included the proportion of people still using study product (EC or pharmacotherapy) at six or more months after randomization or starting EC use, changes in carbon monoxide (CO), blood pressure (BP), heart rate, arterial oxygen saturation, lung function, and levels of carcinogens or toxicants or both. We used a fixed-effect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in meta-analyses. MAIN RESULTS: We included 61 completed studies, representing 16,759 participants, of which 34 were RCTs. Five of the 61 included studies were new to this review update. Of the included studies, we rated seven (all contributing to our main comparisons) at low risk of bias overall, 42 at high risk overall (including all non-randomized studies), and the remainder at unclear risk. There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.53, 95% confidence interval (CI) 1.21 to 1.93; I2 = 0%; 4 studies, 1924 participants). In absolute terms, this might translate to an additional three quitters per 100 (95% CI 1 to 6). There was low-certainty evidence (limited by very serious imprecision) that the rate of occurrence of AEs was similar (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs were rare, but there was insufficient evidence to determine whether rates differed between groups due to very serious imprecision (RR 1.30, 95% CI 0.89 to 1.90: I2 = 0; 4 studies, 1424 participants). There was moderate-certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.94, 95% CI 1.21 to 3.13; I2 = 0%; 5 studies, 1447 participants). In absolute terms, this might lead to an additional seven quitters per 100 (95% CI 2 to 16). There was moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 3 studies, 601 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 1.06, 95% CI 0.47 to 2.38; I2 = 0; 5 studies, 792 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.61, 95% CI 1.44 to 4.74; I2 = 0%; 6 studies, 2886 participants). In absolute terms this represents an additional six quitters per 100 (95% CI 2 to 15). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was some evidence that non-serious AEs were more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants), and again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 1.51, 95% CI 0.70 to 3.24; I2 = 0%; 7 studies, 1303 participants). Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued use. Very few studies reported data on other outcomes or comparisons, hence evidence for these is limited, with CIs often encompassing clinically significant harm and benefit. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to NRT and compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the effect size. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no difference in AEs between nicotine and non-nicotine ECs. Overall incidence of SAEs was low across all study arms. We did not detect evidence of harm from nicotine EC, but longest follow-up was two years and the number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates, but further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, this review is now a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.