The Influence of Route Characteristics, Train Design and Maintenance Policy on Wheel Tread Damage, Wheel Life and Costs for Multiple-Unit Trains

In the UK, the use of similar vehicle types by a range of privatised operators gives the opportunity to assess the influence of different route conditions and maintenance practices on wheel tread damage, wheelset life and costs. This paper investigates these influences, using data obtained directly from the train operators and maintainers. By disseminating best practice it is expected that wheelset life can be improved on many fleets, with resultant cost savings

Association between clinical presentations before myocardial infarction and coronary mortality: a prospective population-based study using linked electronic records.

BACKGROUND: Ischaemia in different arterial territories before acute myocardial infarction (AMI) may influence post-AMI outcomes. No studies have evaluated prospectively collected information on ischaemia and its effect on short- and long-term coronary mortality. The objective of this study was to compare patients with and without prospectively measured ischaemic presentations before AMI in terms of infarct characteristics and coronary mortality. METHODS AND RESULTS: As part of the CALIBER programme, we linked data from primary care, hospital admissions, the national acute coronary syndrome registry and cause-specific mortality to identify patients with first AMI (n = 16,439). We analysed time from AMI to coronary mortality (n = 5283 deaths) using Cox regression (median 2.6 years follow-up), comparing patients with and without recent ischaemic presentations. Patients with ischaemic presentations in the 90 days before AMI experienced lower coronary mortality in the first 7 days after AMI compared with those with no prior ischaemic presentations, after adjusting for age, sex, smoking, diabetes, blood pressure and cardiovascular medications [HR: 0.64 (95% CI: 0.57-0.73) P < 0.001], but subsequent mortality was higher [HR: 1.42 (1.13-1.77) P = 0.001]. Patients with ischaemic presentations closer in time to AMI had the lowest seven day mortality (P-trend = 0.001). CONCLUSION: In the first large prospective study of ischaemic presentations prior to AMI, we have shown that those occurring closest to AMI are associated with lower short-term coronary mortality following AMI, which could represent a natural ischaemic preconditioning effect, observed in a clinical setting. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov identifier NCT01604486

Macrophage transactivation for chemokine production identified as a negative regulator of granulomatous inflammation using agent-based modeling

Cellular activation in trans by interferons, cytokines and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and / or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling and in vivo experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the Leishmania donovani-infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection to limit excessive focal inflammation

A 10-year prognostic model for patients with suspected angina attending a chest pain clinic.

BACKGROUND AND OBJECTIVE: Diagnostic models used in the management of suspected angina provide no explicit information about prognosis. We present a new prognostic model of 10-year coronary mortality in patients presenting for the first time with suspected angina to complement the Diamond-Forrester diagnostic model of disease probability. METHODS AND RESULTS: A multicentre cohort of 8762 patients with suspected angina was followed up for a median of 10 years during which 233 coronary deaths were observed. Developmental (n=4412) and validation (n=4350) prognostic models based on clinical data available at first presentation showed good performance with close agreement and the final model utilised all 8762 patients to maximise power. The prognostic model showed strong associations with coronary mortality for age, sex, chest pain typicality, smoking status, diabetes, pulse rate, and ECG findings. Model discrimination was good (C statistic 0.83), patients in the highest risk quarter accounting for 173 coronary deaths (10-year risk of death: 8.7%) compared with a total of 60 deaths in the three lower risk quarters. When the model was simplified to incorporate only Diamond-Forrester factors (age, sex and character of symptoms) it underestimated coronary mortality risk, particularly in patients with reversible risk factors. CONCLUSIONS: For the first time in patients with suspected angina, a prognostic model is presented based on simple clinical factors available at the initial cardiological assessment. The model discriminated powerfully between patients at high risk and lower risk of coronary death during 10-year follow-up. Clinical utility was reflected in the prognostic value it added to the updated Diamond-Forrester diagnostic model of disease probability

Livestock disease management for trading across different regulatory regimes

The maintenance of livestock health depends on the combined actions of many different actors, both within and across different regulatory frameworks. Prior work recognised that private risk management choices have the ability to reduce the spread of infection to trading partners. We evaluate the efficiency of farmers' alternative biosecurity choices in terms of their own-benefits from unilateral strategies and quantify the impact they may have in filtering the disease externality of trade. We use bovine viral diarrhoea (BVD) in England and Scotland as a case study, since this provides an example of a situation where contrasting strategies for BVD management occur between selling and purchasing farms. We use an agent-based bioeconomic model to assess the payoff dependence of farmers connected by trade but using different BVD management strategies. We compare three disease management actions: test-cull, test-cull with vaccination and vaccination alone. For a two-farm trading situation, all actions carried out by the selling farm provide substantial benefits to the purchasing farm in terms of disease avoided, with the greatest benefit resulting from test-culling with vaccination on the selling farm. Likewise, unilateral disease strategies by purchasers can be effective in reducing disease risks created through trade. We conclude that regulation needs to balance the trade-off between private gains from those bearing the disease management costs and the positive spillover effects on others

Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people.

BACKGROUND: The contemporary associations of type 2 diabetes with a wide range of incident cardiovascular diseases have not been compared. We aimed to study associations between type 2 diabetes and 12 initial manifestations of cardiovascular disease. METHODS: We used linked primary care, hospital admission, disease registry, and death certificate records from the CALIBER programme, which links data for people in England recorded in four electronic health data sources. We included people who were (or turned) 30 years or older between Jan 1, 1998, to March 25, 2010, who were free from cardiovascular disease at baseline. The primary endpoint was the first record of one of 12 cardiovascular presentations in any of the data sources. We compared cumulative incidence curves for the initial presentation of cardiovascular disease and used Cox models to estimate cause-specific hazard ratios (HRs). This study is registered at ClinicalTrials.gov (NCT01804439). FINDINGS: Our cohort consisted of 1 921 260 individuals, of whom 1 887 062 (98·2%) did not have diabetes and 34 198 (1·8%) had type 2 diabetes. We observed 113 638 first presentations of cardiovascular disease during a median follow-up of 5·5 years (IQR 2·1-10·1). Of people with type 2 diabetes, 6137 (17·9%) had a first cardiovascular presentation, the most common of which were peripheral arterial disease (reported in 992 [16·2%] of 6137 patients) and heart failure (866 [14·1%] of 6137 patients). Type 2 diabetes was positively associated with peripheral arterial disease (adjusted HR 2·98 [95% CI 2·76-3·22]), ischaemic stroke (1·72 [1·52-1·95]), stable angina (1·62 [1·49-1·77]), heart failure (1·56 [1·45-1·69]), and non-fatal myocardial infarction (1·54 [1·42-1·67]), but was inversely associated with abdominal aortic aneurysm (0·46 [0·35-0·59]) and subarachnoid haemorrhage (0·48 [0·26-0.89]), and not associated with arrhythmia or sudden cardiac death (0·95 [0·76-1·19]). INTERPRETATION: Heart failure and peripheral arterial disease are the most common initial manifestations of cardiovascular disease in type 2 diabetes. The differences between relative risks of different cardiovascular diseases in patients with type 2 diabetes have implications for clinical risk assessment and trial design. FUNDING: Wellcome Trust, National Institute for Health Research, and Medical Research Council

Long term health care use and costs in patients with stable coronary artery disease : a population based cohort using linked electronic health records (CALIBER)

Aims To examine long term health care utilisation and costs of patients with stable coronary artery disease (SCAD). Methods and results Linked cohort study of 94,966 patients with SCAD in England, 1st January 2001 to 31st March 2010, identified from primary care, secondary care, disease and death registries. Resource use and costs, and cost predictors by time and 5-year cardiovascular (CVD) risk profile were estimated using generalised linear models. Coronary heart disease hospitalisations were 20.5% in the first year and 66% in the year following a non-fatal (myocardial infarction, ischaemic or haemorrhagic stroke) event. Mean health care costs were £3,133 per patient in the first year and £10,377 in the year following a non-fatal event. First year predictors of cost included sex (mean cost £549 lower in females); SCAD diagnosis (NSTEMI cost £656 more than stable angina); and co-morbidities (heart failure cost £657 more per patient). Compared with lower risk patients (5-year CVD risk 3.5%), those of higher risk (5-year CVD risk 44.2%) had higher 5-year costs (£23,393 vs. £9,335) and lower lifetime costs (£43,020 vs. £116,888). Conclusion Patients with SCAD incur substantial health care utilisation and costs, which varies and may be predicted by 5-year CVD risk profile. Higher risk patients have higher initial but lower lifetime costs than lower risk patients as a result of shorter life expectancy. Improved cardiovascular survivorship among an ageing CVD population is likely to require stratified care in anticipation of the burgeoning demand

Antipsychotic drugs and risks of myocardial infarction: a self-controlled case series study.

AIM: Antipsychotics increase the risk of stroke. Their effect on myocardial infarction remains uncertain because people prescribed and not prescribed antipsychotic drugs differ in their underlying vascular risk making between-person comparisons difficult to interpret. The aim of our study was to investigate this association using the self-controlled case series design that eliminates between-person confounding effects. METHODS AND RESULTS: All the patients with a first recorded myocardial infarction and prescription for an antipsychotic identified in the Clinical Practice Research Datalink linked to the Myocardial Ischaemia National Audit Project were selected for the self-controlled case series. The incidence ratio of myocardial infarction during risk periods following the initiation of antipsychotic use relative to unexposed periods was estimated within individuals. A classical case-control study was undertaken for comparative purposes comparing antipsychotic exposure among cases and matched controls. We identified 1546 exposed cases for the self-controlled case series and found evidence of an association during the first 30 days after the first prescription of an antipsychotic, for first-generation agents [incidence rate ratio (IRR) 2.82, 95% confidence interval (CI) 2.0-3.99] and second-generation agents (IRR: 2.5, 95% CI: 1.18-5.32). Similar results were found for the case-control study for new users of first- (OR: 3.19, 95% CI: 1.9-5.37) and second-generation agents (OR: 2.55, 95% CI: 0.93-7.01) within 30 days of their myocardial infarction. CONCLUSION: We found an increased risk of myocardial infarction in the period following the initiation of antipsychotics that was not attributable to differences between people prescribed and not prescribed antipsychotics

Heterogeneous associations between smoking and a wide range of initial presentations of cardiovascular disease in 1937360 people in England: lifetime risks and implications for risk prediction.

BACKGROUND: It is not known how smoking affects the initial presentation of a wide range of chronic and acute cardiovascular diseases (CVDs), nor the extent to which associations are heterogeneous. We estimated the lifetime cumulative incidence of 12 CVD presentations, and examined associations with smoking and smoking cessation. METHODS: Cohort study of 1.93 million people aged ≥30years, with no history of CVD, in 1997-2010. Individuals were drawn from linked electronic health records in England, covering primary care, hospitalizations, myocardial infarction (MI) registry and cause-specific mortality (the CALIBER programme). RESULTS: During 11.6 million person-years of follow-up, 114859 people had an initial non-fatal or fatal CVD presentation. By age 90 years, current vs never smokers' lifetime risks varied from 0.4% vs 0.2% for subarachnoid haemorrhage (SAH), to 8.9% vs 2.6% for peripheral arterial disease (PAD). Current smoking showed no association with cardiac arrest or sudden cardiac death [hazard ratio (HR)=1.04, 95% confidence interval (CI) 0.91-1.19).The strength of association differed markedly according to disease type: stable angina (HR=1.08, 95% CI 1.01-1.15),transient ischaemic attack (HR=1.41, 95% CI 1.28-1.55), unstable angina (HR=1.54, 95% CI 1.38-1.72), intracerebral haemorrhage (HR=1.61, 95% CI 1.37-1.89), heart failure (HR=1.62, 95% CI 1.47-1.79), ischaemic stroke (HR=1.90, 95% CI 1.72-2.10), MI (HR=2.32, 95% CI 2.20-2.45), SAH (HR= 2.70, 95% CI 2.27-3.21), PAD (HR=5.16, 95% CI 4.80-5.54) and abdominal aortic aneurysm (AAA) (HR=5.18, 95% CI 4.61-5.82). Population-attributable fractions were lower for women than men for unheralded coronary death, ischaemic stroke, PAD and AAA. Ten years after quitting smoking, the risks of PAD, AAA (in men) and unheralded coronary death remained increased (HR=1.36, 1.47 and 2.74, respectively). CONCLUSIONS: The heterogeneous associations of smoking with different CVD presentations suggests different underlying mechanisms and have important implications for research, clinical screening and risk prediction