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• QTc prolongation was associated with atrial fibrillation. • QTc prolongation was associated with stroke and sudden cardiac death. • No association was found for myocardial infarction. Conflicting findings have described the association between prolonged heart rate-corrected QT interval (QTc) and cardiovascular disease. To identify articles investigating the association between QTc and cardiovascular disease morbidity and mortality, and to summarize the available evidence for the general and type 2 diabetes populations. A systematic search was performed in PubMed and Embase in May 2022 to identify studies that investigated the association between QTc prolongation and cardiovascular disease in both the general and type 2 diabetes populations. Screening, full-text assessment, data extraction and risk of bias assessment were performed independently by two reviewers. Effect estimates were pooled across studies using random-effect models. Of the 59 studies included, 36 qualified for meta-analysis. Meta-analysis of the general population studies showed a significant association for: overall cardiovascular disease (fatal and non-fatal) (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.33–2.12; I 2 = 69%); coronary heart disease (fatal and non-fatal) in women (HR 1.27, 95% CI 1.08–1.50; I 2 = 38%; coronary heart disease (fatal and non-fatal) in men (HR 2.07, 95% CI 1.26–3.39; I 2 = 78%); stroke (HR 1.59, 95% CI 1.29–1.96; I 2 = 45%); sudden cardiac death (HR 1.60, 95% CI 1.14–2.25; I 2 = 68%); and atrial fibrillation (HR 1.55, 95% CI 1.31–1.83; I 2 = 0.0%). No significant association was found for cardiovascular disease in the type 2 diabetes population. QTc prolongation was associated with risk of cardiovascular disease in the general population, but not in the type 2 diabetes population. [ABSTRACT FROM AUTHOR]

BackgroundDentists prescribe approximately 10% of antibiotics dispensed in UK community pharmacies. Despite clear clinical guidance, dentists often prescribe antibiotics inappropriately. This cluster-randomised controlled trial used routinely collected National Health Service (NHS) dental prescribing and treatment claim data to compare the impact of individualised audit and feedback (A&F) interventions on dentists' antibiotic prescribing rates.Methods and findingsAll 795 antibiotic prescribing NHS general dental practices in Scotland were included. Practices were randomised to the control (practices = 163; dentists = 567) or A&F intervention group (practices = 632; dentists = 1,999). A&F intervention practices were allocated to one of two A&F groups: (1) individualised graphical A&F comprising a line graph plotting an individual dentist's monthly antibiotic prescribing rate (practices = 316; dentists = 1,001); or (2) individualised graphical A&F plus a written behaviour change message synthesising and reiterating national guidance recommendations for dental antibiotic prescribing (practices = 316; dentists = 998). Intervention practices were also simultaneously randomised to receive A&F: (i) with or without a health board comparator comprising the addition of a line to the graphical A&F plotting the monthly antibiotic prescribing rate of all dentists in the health board; and (ii) delivered at 0 and 6 mo or at 0, 6, and 9 mo, giving a total of eight intervention groups. The primary outcome, measured by the trial statistician who was blinded to allocation, was the total number of antibiotic items dispensed per 100 NHS treatment claims over the 12 mo post-delivery of the baseline A&F. Primary outcome data was available for 152 control practices (dentists = 438) and 609 intervention practices (dentists = 1,550). At baseline, the number of antibiotic items prescribed per 100 NHS treatment claims was 8.3 in the control group and 8.5 in the intervention group. At follow-up, antibiotic prescribing had decreased by 0.4 antibiotic items per 100 NHS treatment claims in control practices and by 1.0 in intervention practices. This represents a significant reduction (-5.7%; 95% CI -10.2% to -1.1%; p = 0.01) in dentists' prescribing rate in the intervention group relative to the control group. Intervention subgroup analyses found a 6.1% reduction in the antibiotic prescribing rate of dentists who had received the written behaviour change message relative to dentists who had not (95% CI -10.4% to -1.9%; p = 0.01). There was no significant between-group difference in the prescribing rate of dentists who received a health board comparator relative to those who did not (-4.3%; 95% CI -8.6% to 0.1%; p = 0.06), nor between dentists who received A&F at 0 and 6 mo relative to those who received A&F at 0, 6, and 9 mo (0.02%; 95% CI -4.2% to 4.2%; p = 0.99). The key limitations relate to the use of routinely collected datasets which did not allow evaluation of any effects on inappropriate prescribing.ConclusionsA&F derived from routinely collected datasets led to a significant reduction in the antibiotic prescribing rate of dentists.Trial registrationCurrent Controlled Trials ISRCTN49204710.

Physical function is a crucial factor in the prevention and treatment of health conditions in older adults and is usually measured objectively with physical performance tests and/or physical activity monitoring.To examine whether 1) physical performance (PP) and physical activity (PA) constitute separate domains of physical function; 2) differentiation of PA classes is more informative than overall PA.Cross-sectional study to explore the relationships within and among PP and PA measures.In 49 older participants (83 ± 7 years; M ± SD), performance-based tests were conducted and PA was measured for one week. Activity monitor data were reduced in terms of duration, periods, and mean duration of periods of lying, sitting, standing and locomotion. The relation between and within PP scores and PA outcomes were analysed using rank order correlation and factor analysis.Factor structure after varimax rotation revealed two orthogonal factors explaining 78% of the variance in the data: one comprising all PA variables and one comprising all PP variables. PP scores correlated moderately with PA in daily life. Differentiation of activity types and quantification of their duration, intensity and frequency of occurrence provided stronger associations with PP, as compared to a single measure of acceleration expressing overall PA.For independent validation, the conclusions about the validity of the presented conceptual framework and its clinical implications need to be confirmed in other studies.PP and PA represent associated but separate domains of physical function, suggesting that an improvement of PP does not automatically imply an increase of PA, i.e. a change to a more active lifestyle. Differentiation of activity classes in the analysis of PA provides more insights into PA and its association with PP than using a single overall measure of acceleration.

Incidence rates of non-hip major osteoporotic fractures (MOF) remain poorly characterized in the Netherlands. The Dutch FRAX® algorithm, which predicts 10-year probabilities of hip fracture and MOF (first of hip, humerus, forearm, clinical vertebral), therefore incorporates imputed MOF rates. Swedish incidence rate ratios for hip fracture to MOF (Malmo 1987-1996) were used to perform this imputation. However, equality of these ratios between countries is uncertain and recent evidence is scarce. Aims were to estimate incidence rates of hip fracture and MOF and to compare observed MOF rates to those predicted by the imputation method for the Netherlands.Using hospitalisation and general practitioner records from the Dutch PHARMO Database Network (2002-2011) we calculated age-and-sex-specific and age-standardized incidence rates (IRs) of hip and other MOFs (humerus, forearm, clinical vertebral) and as used in FRAX®. Observed MOF rates were compared to those predicted among community-dwelling individuals ≥50 years by the standardized incidence ratio (SIR; 95% CI).Age-standardized IRs (per 10,000 person-years) of MOF among men and women ≥50 years were 25.9 and 77.0, respectively. These numbers were 9.3 and 24.0 for hip fracture. Among women 55-84 years, observed MOF rates were significantly higher than predicted (SIR ranged between 1.12-1.50, depending on age). In men, the imputation method performed reasonable.Observed MOF incidence was higher than predicted for community-dwelling women over a wide age-range, while it agreed reasonable for men. As miscalibration may influence treatment decisions, there is a need for confirmation of results in another data source. Until then, the Dutch FRAX® output should be interpreted with caution.

Background: Denosumab offers an alternative, or additional, treatment for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumours. Objectives: The aim of this review was to assess the clinical effectiveness and cost-effectiveness of denosumab, within its licensed indication, for the prevention of SREs in patients with bone metastases from solid tumours. Data sources: Databases searched were MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), The Cochrane Library (all sections; Issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011). Review methods: Only randomised controlled trials (RCTs) assessing denosumab, bisphosphonates (BPs) or best supportive care (BSC) in patients with bone metastases were included. Systematic reviews and observational studies were used for safety and quality-of-life assessments. Study quality was assessed using the Cochrane risk of bias tool. Studies suitable for meta-analysis were synthesised using network meta-analysis (NMA). A systematic review was conducted for cost, quality-of-life and cost-effectiveness studies. The results of this informed the cost–utility modelling. This principally estimated the cost-effectiveness of denosumab relative to zoledronic acid for when BPs are currently recommended and relative to BSC when BPs are not recommended or are contraindicated. Results: A literature search identified 39 studies (eight suitable for NMA). Denosumab was effective in delaying time to first SRE and reducing the risk of multiple SREs compared with zoledronic acid. Generally speaking, denosumab was similar to zoledronic acid for quality of life, pain, overall survival and safety. The NMA demonstrated that denosumab was more effective in delaying SREs than placebo, but was limited by numerous uncertainties. Cost–utility modelling results for denosumab relative to zoledronic acid were driven by the availability of the patient access scheme (PAS) for denosumab. Without this, denosumab was not estimated to be cost-effective compared with zoledronic acid. With it, the cost-effectiveness ranged between dominance for breast and prostate cancer, to between £5400 and £15,300 per quality-adjusted life-year (QALY) for other solid tumours (OSTs) including non-small cell lung cancer (NSCLC) and £12,700 per QALY for NSCLC. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. Denosumab was not estimated to be cost-effective compared with BSC. Limitations: Only subgroup data were available for denosumab for NSCLC, and OSTs excluding NSCLC. The NMA was subject to numerous uncertainties. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. Conclusions: Denosumab, compared with zoledronic acid and placebo, is effective in delaying SREs, but is similar with regard to quality of life and pain. Cost-effectiveness showed that without the PAS denosumab was not estimated to be cost-effective relative to either zoledronic acid or BSC. With the PAS, denosumab was estimated to be cost-effective relative to zoledronic acid but not BSC. Study registration: PROSPERO number CRD42011001418. Funding: The National Institute for Health Research Health Technology Assessment programme.

Objectives: To determine effective and efficient monitoring criteria for ocular hypertension [raised intraocular pressure (IOP)] through (i) identification and validation of glaucoma risk prediction models; and (ii) development of models to determine optimal surveillance pathways. Design: A discrete event simulation economic modelling evaluation. Data from systematic reviews of risk prediction models and agreement between tonometers, secondary analyses of existing datasets (to validate identified risk models and determine optimal monitoring criteria) and public preferences were used to structure and populate the economic model. Setting: Primary and secondary care. Participants: Adults with ocular hypertension (IOP > 21mmHg) and the public (surveillance preferences). Interventions: We compared five pathways: two based on National Institute for Health and Clinical Excellence (NICE) guidelines with monitoring interval and treatment depending on initial risk stratification, ‘NICE intensive’ (4-monthly to annual monitoring) and ‘NICE conservative’ (6-monthly to biennial monitoring); two pathways, differing in location (hospital and community), with monitoring biennially and treatment initiated for a ≥ 6% 5-year glaucoma risk; and a ‘treat all’ pathway involving treatment with a prostaglandin analogue if IOP > 21 mmHg and IOP measured annually in the community. Main outcome measures: Glaucoma cases detected; tonometer agreement; public preferences; costs; willingness to pay and quality-adjusted life-years (QALYs). Results: The best available glaucoma risk prediction model estimated the 5-year risk based on age and ocular predictors (IOP, central corneal thickness, optic nerve damage and index of visual field status). Taking the average of two IOP readings, by tonometry, true change was detected at two years. Sizeable measurement variability was noted between tonometers. There was a general public preference for monitoring; good communication and understanding of the process predicted service value. ‘Treat all’ was the least costly and ‘NICE intensive’ the most costly pathway. Biennial monitoring reduced the number of cases of glaucoma conversion compared with a ‘treat all’ pathway and provided more QALYs, but the incremental cost-effectiveness ratio (ICER) was considerably more than £30,000. The ‘NICE intensive’ pathway also avoided glaucoma conversion, but NICE-based pathways were either dominated (more costly and less effective) by biennial hospital monitoring or had a ICERs > £30,000. Results were not sensitive to the risk threshold for initiating surveillance but were sensitive to the risk threshold for initiating treatment, NHS costs and treatment adherence. Limitations: Optimal monitoring intervals were based on IOP data. There were insufficient data to determine the optimal frequency of measurement of the visual field or optic nerve head for identification of glaucoma. The economic modelling took a 20-year time horizon which may be insufficient to capture long-term benefits. Sensitivity analyses may not fully capture the uncertainty surrounding parameter estimates. Conclusions: For confirmed ocular hypertension, findings suggest that there is no clear benefit from intensive monitoring. Consideration of the patient experience is important. A cohort study is recommended to provide data to refine the glaucoma risk prediction model, determine the optimum type and frequency of serial glaucoma tests and estimate costs and patient preferences for monitoring and treatment. Funding: The National Institute for Health Research Health Technology Assessment Programme