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Introduction: Recurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether a multi-component (complex) self-management intervention to support adherence would reduce exacerbation rates over 12 months.Methods: Between October 2017 and May 2018, adults with CF (aged ≥16 years; 19 UK centres) were randomised to the intervention (data-logging nebulisers, a digital platform and behavioural change sessions with trained clinical interventionists) or usual care (data-logging nebulisers). Outcomes included pulmonary exacerbations (primary outcome), objectively measured adherence, body mass index (BMI), lung function (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Analyses were by intent to treat over 12 months.Results: Among intervention (n=304) and usual care (n=303) participants (51% female, median age 31 years), 88% completed 12-month follow-up. Mean exacerbation rate was 1.63/year with intervention and 1.77/year with usual care (adjusted ratio 0.96; 95% CI 0.83 to 1.12; p=0.64). Adjusted mean differences (95% CI) were in favour of the intervention versus usual care for objectively measured adherence (9.5% (8.6% to 10.4%)) and BMI (0.3 (0.1 to 0.6) kg/m2), with no difference for %FEV1 (1.4 (-0.2 to 3.0)). Seven CFQ-R subscales showed no between-group difference, but treatment burden reduced for the intervention (3.9 (1.2 to 6.7) points). No intervention-related serious adverse events occurred.Conclusions: While pulmonary exacerbations and FEV1 did not show statistically significant differences, the intervention achieved higher objectively measured adherence versus usual care. The adherence difference might be inadequate to influence exacerbations, though higher BMI and lower perceived CF treatment burden were observed. [ABSTRACT FROM AUTHOR]

Objectives Latent class trajectory modelling (LCTM) is a relatively new methodology in epidemiology to describe life-course exposures, which simplifies heterogeneous populations into homogeneous patterns or classes. However, for a given dataset, it is possible to derive scores of different models based on number of classes, model structure and trajectory property. Here, we rationalise a systematic framework to derive a 'core' favoured model. Methods We developed an eight-step framework: step 1: a scoping model; step 2: refining the number of classes; step 3: refining model structure (from fixed-effects through to a flexible random-effect specification); step 4: model adequacy assessment; step 5: graphical presentations; step 6: use of additional discrimination tools ('degree of separation'; Elsensohn's envelope of residual plots); step 7: clinical characterisation and plausibility; and step 8: sensitivity analysis. We illustrated these steps using data from the NIH-AARP cohort of repeated determinations of body mass index (BMI) at baseline (mean age: 62.5 years), and BMI derived by weight recall at ages 18, 35 and 50 years. Results From 288 993 participants, we derived a fiveclass model for each gender (men: 177 455; women: 111 538). From seven model structures, the favoured model was a proportional random quadratic structure (model F). Favourable properties were also noted for the unrestricted random quadratic structure (model G). However, class proportions varied considerably by model structure- concordance between models F and G were moderate (Cohen κ: men, 0.57; women, 0.65) but poor with other models. Model adequacy assessments, evaluations using discrimination tools, clinical plausibility and sensitivity analyses supported our model selection. Conclusion We propose a framework to construct and select a 'core' LCTM, which will facilitate generalisability of results in future studies. [ABSTRACT FROM AUTHOR]

Objective: Existing clinical prediction models (CPM) for short-term mortality after transcatheter aortic valve implantation (TAVI) have limited applicability in the UK due to moderate predictive performance and inconsistent recording practices across registries. The aim of this study was to derive a UK-TAVI CPM to predict 30-day mortality risk for benchmarking purposes.Methods: A two-step modelling strategy was undertaken: first, data from the UK-TAVI Registry between 2009 and 2014 were used to develop a multivariable logistic regression CPM using backwards stepwise regression. Second, model-updating techniques were applied using the 2013-2014 data, thereby leveraging new approaches to include frailty and to ensure the model was reflective of contemporary practice. Internal validation was performed by bootstrapping to estimate in-sample optimism-corrected performance.Results: Between 2009 and 2014, up to 6339 patients were included across 34 centres in the UK-TAVI Registry (mean age, 81.3; 2927 female (46.2%)). The observed 30-day mortality rate was 5.14%. The final UK-TAVI CPM included 15 risk factors, which included two variables associated with frailty. After correction for in-sample optimism, the model was well calibrated, with a calibration intercept of 0.02 (95% CI -0.17 to 0.20) and calibration slope of 0.79 (95% CI 0.55 to 1.03). The area under the receiver operating characteristic curve, after adjustment for in-sample optimism, was 0.66.Conclusion: The UK-TAVI CPM demonstrated strong calibration and moderate discrimination in UK-TAVI patients. This model shows potential for benchmarking, but even the inclusion of frailty did not overcome the need for more wide-ranging data and other outcomes might usefully be explored. [ABSTRACT FROM AUTHOR]

Objectives Previous studies indicate frailty to be associated with poor outcomes following transcatheter aortic valve implantation (TAVI), but there is limited evidence from multicentre registries. The aim was to investigate the independent association of frailty with TAVI outcomes, and the prognostic utility of adding frailty into existing clinical prediction models (CPMs). Design The UK TAVI registry incorporated three frailty measures since 2013: Canadian Study of Health and Ageing, KATZ and poor mobility. We investigated the associations between these frailty measures with short-term and long-term outcomes, using logistic regression to estimate multivariable adjusted ORs, and Cox proportional hazards models to explore long-term survival. We compared the predictive performance of existing TAVI CPMs before and after updating them to include each frailty measure. Setting All patients who underwent a TAVI procedure in England or Wales between 2013 and 2014. Participants 2624 TAVI procedures were analysed in this study. Primary and secondary outcomes The primary endpoints in this study were 30-day mortality and long-term survival. The Valve Academic Research Consortium (VARC)-2 composite early safety endpoint was considered as a secondary outcome. Results KATZ <6 (OR 2.10, 95% CI 1.39 to 3.15) and poor mobility (OR 2.15, 95% CI 1.41 to 3.28) predicted 30-day mortality after multivariable adjustment. All frailty measures were associated with increased odds of the VARC-2 composite early safety endpoint. We observed a significant increase in the area under the receiver operating characteristic curves by approximately 5% after adding KATZ <6 or poor mobility into the TAVI CPMs. Risk stratification agreement was significantly improved by the addition of each frailty measure, with an increase in intraclass correlation coefficient of between 0.15 and 0.31. Conclusion Frailty was associated with worse outcomes following TAVI, and incorporating frailty metrics significantly improved the predictive performance of existing CPMs. Physician-estimated frailty measures could aid TAVI risk stratification, until more objective scales are routinely collected. [ABSTRACT FROM AUTHOR]

The paper by Body et al is concerned with the evaluation of decision aids, which can be used to identify potential acute coronary syndromes (ACS) in the ED. The authors previously developed the Manchester Acute Coronary Syndromes model (MACS) decision aid, which uses several clinical variables and two biomarkers to 'rule in' and 'rule out' ACS. However, one of the two biomarkers (heart-type fatty acid bindingprotein, H-FABP) is not widely used so a revised decision aid has been developed (Troponin-only Manchester Acute Coronary Syndromes, T-MACS), which include a single biomarker hs-cTnT. In this issue, the authors show how they derive a revised decision aid and describe its performance in a number of independent diagnostic cohort studies. Decision aids (as well as other types of 'diagnostic tests') are often evaluated in terms of diagnostic testing parameters such as the area under the receiver operating characteristic (ROC) curve, sensitivity and specificity. In this article, we explain how the ROC analysis is conducted and why it is an essential step towards developing a test with the desirable levels of sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Objective: To estimate the impact and equity of existing and potential UK salt reduction policies on primary prevention of cardiovascular disease (CVD) and gastric cancer (GCa) in England. Design: A microsimulation study of a close-to-reality synthetic population. In the first period, 2003-2015, we compared the impact of current policy against a counterfactual 'no intervention' scenario, which assumed salt consumption persisted at 2003 levels. For 2016-2030, we assumed additional legislative policies could achieve a steeper salt decline and we compared this against the counterfactual scenario that the downward trend in salt consumption observed between 2001 and 2011 would continue up to 2030. Setting: Synthetic population with similar characteristics to the non-institutionalised population of England. Participants: Synthetic individuals with traits informed by the Health Survey for England. Main measure: CVD and GCa cases and deaths prevented or postponed, stratified by fifths of socioeconomic status using the Index of Multiple Deprivation. Results: Since 2003, current salt policies have prevented or postponed ~52 000 CVD cases (IQR: 34 000-76 000) and 10 000 CVD deaths (IQR: 3000-17 000). In addition, the current policies have prevented ~5000 new cases of GCa (IQR: 2000-7000) resulting in about 2000 fewer deaths (IQR: 0-4000). This policy did not reduce socioeconomic inequalities in CVD, and likely increased inequalities in GCa. Additional legislative policies from 2016 could further prevent or postpone ~19 000 CVD cases (IQR: 8000-30 000) and 3600 deaths by 2030 (IQR: -400-8100) and may reduce inequalities. Similarly for GCa, 1200 cases (IQR: -200-3000) and 700 deaths (IQR: -900-2300) could be prevented or postponed with a neutral impact on inequalities. Conclusions: Current salt reduction policies are powerfully effective in reducing the CVD and GCa burdens overall but fail to reduce the inequalities involved. Additional structural policies could achieve further, more equitable health benefits. [ABSTRACT FROM AUTHOR]

OBJECTIVES To estimate the potential impact of universal screening for primary prevention of cardiovascular disease (National Health Service Health Checks) on disease burden and socioeconomic inequalities in health in England, and to compare universal screening with alternative feasible strategies. DESIGN Microsimulation study of a close-to-reality synthetic population. Five scenarios were considered: baseline scenario, assuming that current trends in risk factors will continue in the future; universal screening; screening concentrated only in the most deprived areas; structural population-wide intervention; and combination of population-wide intervention and concentrated screening. SETTING Synthetic population with similar characteristics to the community dwelling population of England. PARTICIPANTS Synthetic people with traits informed by the health survey for England. MAIN OUTCOME MEASURE Cardiovascular disease cases and deaths prevented or postponed by 2030, stratified by fifths of socioeconomic status using the index of multiple deprivation. RESULTS Compared with the baseline scenario, universal screening may prevent or postpone approximately 19 000 cases (interquartile range 11 000-28 000) and 3000 deaths (-1000-6000); concentrated screening 17 000 cases (9000-26 000) and 2000 deaths (-1000-5000); population-wide intervention 67 000 cases (57 000-77 000) and 8000 deaths (4000-11 000); and the combination of the population-wide intervention and concentrated screening 82 000 cases (73 000-93 000) and 9000 deaths (6000-13 000). The most equitable strategy would be the combination of the population-wide intervention and concentrated screening, followed by concentrated screening alone and the population-wide intervention. Universal screening had the least apparent impact on socioeconomic inequalities in health. CONCLUSIONS When primary prevention strategies for reducing cardiovascular disease burden and inequalities are compared, universal screening seems less effective than alternative strategies, which incorporate population-wide approaches. Further research is needed to identify the best mix of population-wide and risk targeted CVD strategies to maximise cost effectiveness and minimise inequalities. [ABSTRACT FROM AUTHOR]

Objective: First-degree atrioventricular block is frequently encountered in clinical practice and is generally considered a benign process. However, there is emerging evidence that prolonged PR interval may be associated with adverse outcomes. This study aims to determine if prolonged PR interval is associated with adverse cardiovascular outcomes and mortality.Methods: We searched MEDLINE and EMBASE for studies that evaluated clinical outcomes associated with prolonged and normal PR intervals. Relevant studies were pooled using random effects meta-analysis for risk of mortality, cardiovascular mortality, heart failure, coronary heart disease, atrial fibrillation and stroke or transient ischaemic attack (TIA). Sensitivity analyses were performed considering the population type and the use of adjustments.Results: Our search yielded 14 studies that were undertaken between 1972 and 2011 with 400,750 participants. Among the studies that adjusted for potential confounders, the pooled results suggest an increased risk of mortality with prolonged PR interval risk ratio (RR) 1.24 95% CI 1.02 to 1.51, five studies. Prolonged PR interval was associated with significant risk of heart failure or left ventricular dysfunction (RR 1.39 95% CI 1.18 to 1.65, three studies) and atrial fibrillation (RR 1.45 95% CI 1.23 to 1.71, eight studies) but not cardiovascular mortality, coronary heart disease or myocardial infarction or stroke or TIA. Similar observations were recorded when limited to studies of first-degree heart block.Conclusions: Data from observational studies suggests a possible association between prolonged PR interval and significant increases in atrial fibrillation, heart failure and mortality. Future prospective studies are needed to confirm the relationships reported, consider possible mechanisms and define the optimal monitoring strategy for such patients. [ABSTRACT FROM AUTHOR]

Background: The original Manchester Acute Coronary Syndromes model (MACS) 'rules in' and 'rules out' acute coronary syndromes (ACS) using high sensitivity cardiac troponin T (hs-cTnT) and heart-type fatty acid binding protein (H-FABP) measured at admission. The latter is not always available. We aimed to refine and validate MACS as Troponin-only Manchester Acute Coronary Syndromes (T-MACS), cutting down the biomarkers to just hs-cTnT.Methods: We present secondary analyses from four prospective diagnostic cohort studies including patients presenting to the ED with suspected ACS. Data were collected and hs-cTnT measured on arrival. The primary outcome was ACS, defined as prevalent acute myocardial infarction (AMI) or incident death, AMI or coronary revascularisation within 30 days. T-MACS was built in one cohort (derivation set) and validated in three external cohorts (validation set).Results: At the 'rule out' threshold, in the derivation set (n=703), T-MACS had 99.3% (95% CI 97.3% to 99.9%) negative predictive value (NPV) and 98.7% (95.3%-99.8%) sensitivity for ACS, 'ruling out' 37.7% patients (specificity 47.6%, positive predictive value (PPV) 34.0%). In the validation set (n=1459), T-MACS had 99.3% (98.3%-99.8%) NPV and 98.1% (95.2%-99.5%) sensitivity, 'ruling out' 40.4% (n=590) patients (specificity 47.0%, PPV 23.9%). T-MACS would 'rule in' 10.1% and 4.7% patients in the respective sets, of which 100.0% and 91.3% had ACS. C-statistics for the original and refined rules were similar (T-MACS 0.91 vs MACS 0.90 on validation).Conclusions: T-MACS could 'rule out' ACS in 40% of patients, while 'ruling in' 5% at highest risk using a single hs-cTnT measurement on arrival. As a clinical decision aid, T-MACS could therefore help to conserve healthcare resources. [ABSTRACT FROM AUTHOR]

Objective: To describe, for the first time, distribution (by geography, age, sex) and time trends in burn injury in England and Wales over the period that the international Burn Injury Database (iBID) has been in place. Setting: Data from the iBID for the years 2003-2011 were used for a retrospective descriptive observational study of specialised services workload and admissions in England and Wales. Participants: All patients who have been visited or admitted to the burn injury specialised health service of England and Wales during the time period 2003-2011. Data cleaning was performed omitting patients with incomplete records (missingness never exceeded 5%). Outcome measures: Workload, admissions, mortality, length of stay (LOS), geographical distribution, sex differences, age differences, total burn surface area, mechanism of Injury. Results: During 2003-2011, 81 181 patients attended the specialised burn service for assessment and admission in England and Wales. Of these, 57 801 were admitted to the services. Males accounted for 63% of the total workload in specialised burn injury services, and females for 37%. The median (IQR) burn surface area was 1.5% (3.5%). The most frequent reason for burn injury was scald (38%). The median (IQR) age for all the referred workload for both genders was 21 (40). The overall mortality of the admitted patients was 1.51% and the median (IQR) LOS was 1 (5) days. Conclusions: Mortality from burn injuries in England and Wales is decreasing in line with western world trends. There is an observed increase in admissions to burn services but that could be explained in various ways. These results are vital for service development and planning, as well as the development and monitoring of prevention strategies and for healthcare commissioning. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the relationship between performance on the UK Quality and Outcomes Framework pay-for-performance scheme and choice of clinical computer system. Design: Retrospective longitudinal study. Setting: Data for 2007-2008 to 2010-2011, extracted from the clinical computer systems of general practices in England. Participants: All English practices participating in the pay-for-performance scheme: average 8257 each year, covering over 99% of the English population registered with a general practice. Main outcome measures: Levels of achievement on 62 quality-of-care indicators, measured as: reported achievement (levels of care after excluding inappropriate patients); population achievement (levels of care for all patients with the relevant condition) and percentage of available quality points attained. Multilevel mixed effects multiple linear regression models were used to identify population, practice and clinical computing system predictors of achievement. Results: Seven clinical computer systems were consistently active in the study period, collectively holding approximately 99% of the market share. Of all population and practice characteristics assessed, choice of clinical computing system was the strongest predictor of performance across all three outcome measures. Differences between systems were greatest for intermediate outcomes indicators (eg, control of cholesterol levels). Conclusions: Under the UK's pay-for-performance scheme, differences in practice performance were associated with the choice of clinical computing system. This raises the question of whether particular system characteristics facilitate higher quality of care, better data recording or both. Inconsistencies across systems need to be understood and addressed, and researchers need to be cautious when generalising findings from samples of providers using a single computing system. [ABSTRACT FROM AUTHOR]

Background Mutations in BRCA1/2 genes confer ovarian, alongside breast, cancer risk. We examined the risk of developing ovarian cancer in BRCA1/2-positive families and if this risk is extended to BRCA negative families. Patients and Methods A prospective study involving women seen at a single family history clinic in Manchester, UK. Patients were excluded if they had ovarian cancer or oophorectomy prior to clinic. Follow-up was censored at the latest date of: 31/12/2010; ovarian cancer diagnosis; oophorectomy; or death. We used person-years at risk to assess ovarian cancer rates in the study population, subdivided by genetic status (BRCA1, BRCA2, BRCA negative, BRCA untested) compared with the general population. Results We studied 8005 women from 895 families. Women from BRCA2 mutation families showed a 17-fold increased risk of invasive ovarian cancer (relative risk (RR) 16.67; 95% CI 5.41 to 38.89). This risk increased to 50-fold in women from families with BRCA1 mutations (RR 50.00; 95% CI 26.62 to 85.50). No association was found for women in families tested negative for BRCA1/2, where there was 1 observed invasive ovarian cancer in 1613 women when 2.74 were expected (RR 0.37; 95% CI 0.01 to 2.03). There was no association with ovarian cancer in families untested for BRCA1/2 (RR 0.99; 95% CI 0.45 to 1.88). Discussion This study showed no increased risk of ovarian cancer in families that tested negative for BRCA1/2 or were untested. These data help counselling women from BRCA1/2 negative families with breast cancer that their risk of invasive ovarian cancer is not higher than the general population. [ABSTRACT FROM AUTHOR]

Background There is a public health need to balance timely generation of hypotheses with cautious causal inference. For rare cancers this is particularly challenging because standard epidemiological study designs may not be able to elucidate causal factors in an early period of newly emerging risks. Alternative methodologies need to be considered for generating and shaping hypotheses prior to definitive investigation. Objectives To evaluate whether open-access databases can be used to explore links between potential risk factors and cancers at an ecological level, using the case study of brain and nervous system cancers as an example. Methods National age-adjusted cancer incidence rates were obtained from the GLOBOCAN 2008 resource and combined with data from the United Nations Development Report and the World Bank list of development indicators. Data were analysed using multivariate regression models. Results Cancer rates, potential confounders and environmental risk factors were available for 165 of 208 countries. 2008 national incidences of brain and nervous system cancers were associated with continent, gross national income in 2008 and Human Development Index Score. The only exogenous risk factor consistently associated with higher incidence was the penetration rate of mobile/cellular telecommunications subscriptions, although other factors were highlighted. According to these ecological results the latency period is at least 11-12 years, but probably more than 20 years. Missing data on cancer incidence and for other potential risk factors prohibit more detailed investigation of exposure- response associations and/or explore other hypotheses. Conclusions Readily available ecological data may be underused, particularly for the study of risk factors for rare diseases and those with long latencies. The results of ecological analyses in general should not be overinterpreted in causal inference, but equally they should not be ignored where alternative signals of aetiology are lacking. [ABSTRACT FROM AUTHOR]

Developed countries have enjoyed substantial falls in cardiovascular disease (CVD) mortality. However, low and middle income countries are drowning in a rising tide of CVD and other non-communicable diseases. Current and future trends in CVD mortality will therefore require increasing attention in the 21st century. The success of clinical cardiology in providing evidence-based cost-effective treatments should be celebrated. However, the growing understanding of CVD mortality trends highlights the crucial role of tobacco, diet, alcohol and inactivity as key drivers. Pro-active public health approaches focused on 'upstream' population-wide policies are increasingly recognised as being potentially powerful, rapid, equitable and cost-saving. However, the future political challenges could be substantial. [ABSTRACT FROM AUTHOR]

Objective: The original EuroSCORE models are poorly calibrated for predicting mortality in contemporary cardiac surgery. EuroSCORE II has been proposed as a new risk model. The objective of this study was to assess the performance of EuroSCORE II in UK cardiac surgery Design: A cross-sectional analysis of prospectively collected multi-centre clinical audit data, from the Society for Cardiothoracic Surgery in Great Britain and Ireland Database Setting: All NHS hospitals, and some UK private hospitals performing adult cardiac surgery Patients: 23 740 procedures at 41 hospitals between July 2010 and March 2011 Main outcome measures: The main outcome measure was in-hospital mortality. Model calibration (HosmereLemeshow test, calibration plot) and discrimination (area under receiver operating characteristic curve) were assessed in the overall cohort and clinically defined sub-groups Results: The mean age at procedure was 67.1 years (SD 11.8) and 27.7% were women. The overall mortality was 3.1% with a EuroSCORE II predicted mortality of 3.4%. Calibration was good overall but the model failed the HosmereLemeshow test (p¼0.003) mainly due to overprediction in the highest and lowest-risk patients. Calibration was poor for isolated coronary artery bypass graft surgery (HosmereLemeshow, p<0.001). The model had good discrimination overall (area under receiver operating characteristic curve 0.808, 95% CI 0.793 to 0.824) and in all clinical sub-groups analysed Conclusions: EuroSCORE II performs well overall in the UK and is an acceptable contemporary generic cardiac surgery risk model. However, the model is poorly calibrated for isolated coronary artery bypass graft surgery and in both the highest and lowest risk patients. Regular revalidation of EuroSCORE II will be needed to identify calibration drift or clinical inconsistencies, which commonly emerge in clinical prediction models [ABSTRACT FROM AUTHOR]

The article discusses the importance of public support to the use of large scale health data which can benefit patient care, public health and research. Topics covered include the problem encountered in initiatives intended to improve the accessibility of healthcare records, the key elements for success of big health data projects and the need for the public to access clear, high quality summaries of healthcare improvements.

Discusses the communication of population risk to policy makers and the public. Application of population impact numbers; Impact of smoking and social mobility on death from any cause; Impact of blood cholesterol concentrations on death from coronary heart disease; Calculating the population impact number of eliminating a risk factor (PIN-ER-t); Potential limitations of data and PIN-ER-t.

Studies the changes in prescribing among general practice fundholders and non-fundholders in England. General measures of prescribing; Practice characteristics; Alterations in prescribing practices; Management of prescribing cost.

Conclusions: 1989 to 1998 there was a highly significant increase in weight and body mass index in children under 4 years of age. Routinely collected data are valuable in identifying anthropometric trends in populations. [ABSTRACT FROM AUTHOR]

Presents a study to assess the extent to which the outcome of depression among primary care attenders in Liverpool, England, affected by medical diagnosis or by feedback of questionnaire results in unrecognized cases. Study design; Subjects; Interventions; Main outcome measures; Results.

A letter to the editor is presented with regards to the association between overall Quality and Outcomes Framework performance and mortality.

Presents a letter to the editor about the Reilly et al study on early life risk factors for obesity and reports flaws in the findings relating to breast feeding and weaning.

The article discusses results of a study that examines the rates and trends in the mortality of the north of England with the south from 1965. The study design and methodology are given. Since 1965, the northern excess mortality remained at a substantial average of 13.8 percent, with the geographical inequality more pronounced in males than for females. Economic recession has been identified as the driving force in the reduction in northern excess mortality in the late 1980s while the increase in 2000 was attributed to the economic boom. It concludes that the economic and income disparity between the north and south continues.