Primary prevention of ischaemic cardiovascular disorders with antiplatelet agents.

In those who have already survived myocardial infarction (MI) or stroke, or have had a transient ischaemic episode (TIA), daily low dose aspirin (ASA) reduces the risk of recurrences by an amount that greatly exceeds the risk of serious bleeding (secondary prevention). ASA is therefore recommended for these people. However, in primary prevention-reducing risk in those so far free of clinically manifest episodes-the benefit is of the same order as the bleeding hazard, (which is much the same in both primary and secondary prevention contexts). The use of other effective agents such as statins further emphasises the even balance between benefit and hazard in primary prevention. Six primary prevention trials are reviewed, first singly and then in a meta-analysis based on individual patient data. ASA reduced non-fatal myocardial infarction by about 25%. However, death from coronary heart disease (CHD) was not significantly reduced (by 5%), nor was any vascular death (3%). There was a non- significant reduction in strokes of 5%, this being the net result of an 8% reduction in non-fatal stroke and a 21% increase in stroke death (mainly from haemorrhagic events), both effects being non-significant. Serious vascular events (MI, stroke or vascular death) were significantly reduced by 12%, mainly due to the large effect on non-fatal MI. About 1650 people would need to be treated with ASA for a year to avoid one serious vascular event, which contrasts with the 10-20 events avoided in secondary prevention by treating 1,000 patients for a year. Other primary prevention trials not included in the meta-analysis have also reported no benefits in MI or stroke, but the findings of still unpublished trials are awaited. Recently, however, encouraging results have come from meta-analyses of the effects of ASA on cancer incidence and mortality and on its effects on cancer metastasis, particularly for adenocarcinomas. Typically, reductions in these measures have been around 30% following treatment for four or five years, but more in several instances. These results alter the balance in primary prevention between benefit and hazard as it appears for arterial events alone, tipping it towards the use of ASA. Consequently, new guidelines on advice and decisions on ASA in primary prevention are now needed. Low dose ASA, eg. 75 mg daily is as effective as higher doses for all the vascular and cancer benefits established in the meta-analyses, and it causes less serious bleeding than higher doses

Distinguishing between those dying suddenly or not suddenly from coronary heart disease: long-term prospective results from the Northwick Park Heart Study.

AIM: To establish whether ECG findings are associated with subsequent risk of sudden death from coronary heart disease (CHD). METHODS AND RESULTS: Potential risk factors for CHD were measured at entry to the first Northwick Park Heart Study of 2167 men. ECG findings were coded as high or low risk for CHD according to definitions in the Minnesota code. Sudden or non-sudden deaths were defined as occurring in less than or more than 24 hours, respectively. The only factor independently associated with sudden death among the 262 men dying of CHD was high-risk ECG. Of 184 sudden CHD deaths, 34 men (18.5%) had had high-risk ECGs at entry to the study compared with 5 (6.4%) of 78 men who experienced non-sudden deaths (adjusted OR 3.94 (95% CI 1.33 to 11.67)) (p=0.006). Findings were also compared among all 2167 men, where high-risk ECGs were again associated with sudden death. T-wave changes were the main abnormalities associated with a high risk of sudden death. CONCLUSIONS: In a group of men who had not previously experienced major episodes of CHD but who subsequently died from it, there was strong evidence that high-risk ECG changes, mainly T-wave abnormalities, differentiated between those who later died sudden deaths and those who survived for >24 hours

Recent respiratory infection and risk of venous thromboembolism: case–control study through a general practice database

Background The association between respiratory infection and risk of heart attacks and strokes is well established. However, less evidence exists for an association between respiratory infection and venous thromboembolism (VTE). In this article, we describe the associations between respiratory infection and VTE

UV friendly T-parity in the SU(6)/Sp(6) little Higgs model

Electroweak precision tests put stringent constraints on the parameter space of little Higgs models. Tree-level exchange of TeV scale particles in a generic little Higgs model produce higher dimensional operators that make contributions to electroweak observables that are typically too large. To avoid this problem a discrete symmetry dubbed T-parity can be introduced to forbid the dangerous couplings. However, it was realized that in simple group models such as the littlest Higgs model, the implementation of T-parity in a UV completion could present some challenges. The situation is analogous to the one in QCD where the pion can easily be defined as being odd under a new $Z_2$ symmetry in the chiral Lagrangian, but this $Z_2$ is not a symmetry of the quark Lagrangian. In this paper we examine the possibility of implementing a T-parity in the low energy $SU(6)/Sp(6)$ model that might be easier to realize in the UV. In our model, the T-parity acts on the low energy non-linear sigma model field in way which is different to what was originally proposed for the Littlest Higgs, and lead to a different low energy theory. In particular, the Higgs sector of this model is a inert two Higgs doublets model with an approximate custodial symmetry. We examine the contributions of the various sectors of the model to electroweak precision data, and to the dark matter abundance.Comment: 21 pages,4 figures. Clarifications added, typos corrected and references added. Published in JHE

Cardiovascular Risk Factors Associated With Venous Thromboembolism

Importance It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). Objective To estimate associations between major cardiovascular risk factors and VTE, i.e., deep-vein thrombosis (DVT) and pulmonary embolism (PE). Design Analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 731,728 participants; 75 cohorts; latest date of follow-up 2015), and UK Biobank (UKBB; 421,537 participants; latest date of follow-up 2016). Setting Approximately population-based prospective cohort studies. Participants Individuals without cardiovascular disease at baseline. Exposures A panel of several established cardiovascular risk factors. Main Outcomes and Measures Hazard ratios (HRs) per 1-SD higher risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (n=1041 VTE, n=25,131 CHD) and incident fatal/non-fatal outcomes in UKBB (n=2321 VTE, n=3385 CHD). HRs were adjusted for age, sex, smoking status, diabetes mellitus, and body-mass index. Results Adjusted HRs for VTE were: 2.67 (2.45-2.91) in ERFC and 1.81 (1.71-1.92) in UKBB per decade older age; 1.38 (1.20-1.58) in ERFC and 1.23 (1.08-1.40) in UKBB with smoking; 1.43 (1.35-1.50) in ERFC and 1.37 (1.32-1.41) in UKBB per 1-SD higher body-mass index; and 0.75 (0.61-0.93) in ERFC and 0.82 (0.71-0.94) in UKBB with current alcohol consumption. For the preceding factors, there were similar HRs for pulmonary embolism versus deep vein thrombosis in UKBB (except adiposity was more strongly associated with PE; P<0.01), and similar HRs for unprovoked versus provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than coronary heart disease. We noted inconsistent associations with diabetes and blood pressure for VTEs across ERFC and UKBB, and had limited ability to study lipid and inflammation markers. Conclusions and Relevance Older age, smoking, adiposity, and lower alcohol consumption were consistently associated with higher VTE risk.A study website (http://www.phpc.cam.ac.uk/ceu/erfc/list-of-studies/) includes a list that investigators have provided of funding agencies that have supported individual cohorts in the ERFC contributing to the present consortium. This research has been conducted using the UK Biobank resource (application 26865)

An ontology-based nurse call management system (oNCS) with probabilistic priority assessment

<p>Abstract</p> <p>Background</p> <p>The current, place-oriented nurse call systems are very static. A patient can only make calls with a button which is fixed to a wall of a room. Moreover, the system does not take into account various factors specific to a situation. In the future, there will be an evolution to a mobile button for each patient so that they can walk around freely and still make calls. The system would become person-oriented and the available context information should be taken into account to assign the correct nurse to a call.</p> <p>The aim of this research is (1) the design of a software platform that supports the transition to mobile and wireless nurse call buttons in hospitals and residential care and (2) the design of a sophisticated nurse call algorithm. This algorithm dynamically adapts to the situation at hand by taking the profile information of staff members and patients into account. Additionally, the priority of a call probabilistically depends on the risk factors, assigned to a patient.</p> <p>Methods</p> <p>The <it>ontology-based Nurse Call System (oNCS) </it>was developed as an extension of a <it>Context-Aware Service Platform</it>. An ontology is used to manage the profile information. Rules implement the novel nurse call algorithm that takes all this information into account. Probabilistic reasoning algorithms are designed to determine the priority of a call based on the risk factors of the patient.</p> <p>Results</p> <p>The <it>oNCS </it>system is evaluated through a prototype implementation and simulations, based on a detailed dataset obtained from Ghent University Hospital. The arrival times of nurses at the location of a call, the workload distribution of calls amongst nurses and the assignment of priorities to calls are compared for the <it>oNCS </it><it>system </it>and the current, place-oriented nurse call system. Additionally, the performance of the system is discussed.</p> <p>Conclusions</p> <p>The execution time of the nurse call algorithm is on average 50.333 ms. Moreover, the <it>oNCS system </it>significantly improves the assignment of nurses to calls. Calls generally have a nurse present faster and the workload-distribution amongst the nurses improves.</p

RAMPART : a model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting

AstraZeneca LP have provided an educational grant for the trial and free of charge durvalumab and tremelimumab. A small grant is also provided by Kidney Cancer UK. MRC CTU at UCL provides funding for staff working on the trial.The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations.Publisher PDFPeer reviewe

RAMPART : a phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

AstraZeneca LP have provided an educational grant for the trial and free of charge durvalumab and tremelimumab. A small grant is also provided by Kidney Cancer UK. MRC CTU at UCL also provides funding for staff working on the trial. The TransRAMPART sample collection is being funded by a Prospective Sample Collection award from Cancer Research UK.Background 20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. Methods/design RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART).Publisher PDFPeer reviewe

Model for estimating the population prevalence of chronic obstructive pulmonary disease: cross sectional data from the Health Survey for England

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major but neglected public health problem. Currently 1.4% of the England population has a clinical diagnosis of COPD, but the true burden of the disease has not been known with certainty, as many cases remain undiagnosed. METHODS: A mathematical model based on cross sectional data from a representative sample of the population in England (the Heath Survey for England 2001, n = 10,750) was developed allowing estimates on the prevalence of COPD (defined based on the presence of airflow obstruction) to be obtained. Logistic regression analysis was used to investigate and choose risk factors for inclusion in the model and to derive the prevalence estimates based on the strength of association between selected risk factors and the outcome COPD. The model allows the prevalence to be estimated in populations at national level and also at regional and large local areas, based on their compositions according to age, sex, smoking and ethnicity, and on area degrees of urbanisation and deprivation. We applied the model to measure the prevalence of COPD in England and in some sub-groups of the population within the country. RESULTS: The prevalence of COPD in England is estimated as 3.1% (3.9% in men and 2.4% in women) in the population over 15 years of age, and 5.3% (6.8% in men and 3.9% in women) in 45 year-olds and over. There was a 7-fold variation in the prevalence across subgroups of the population, with lowest values in Asian women from wealthy rural areas (1.7%), and highest in black men from deprived urban areas (12.5%). CONCLUSION: The model can be used to estimate population prevalence of COPD from large general practices to national level, and as a tool to identify areas of high levels of unmet needs for COPD priority health actions. The results from the model highlight the importance of including variables other than age, sex and smoking, i.e. levels of deprivation, urbanisation and ethnicity, when estimating population prevalence of COPD. The model should be validated at local level and incorporated into case-finding strategies

The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial

BACKGROUND: At the time of feasibility work and final design of the trial there was no randomised control trial evidence for the long-term risks and benefits of hormone replacement therapy. Observational studies had suggested that long term use of estrogen was likely to be associated, amongst other things, with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer. Concomitant use of progestogens had been shown to protect against endometrial cancer, but there were few data showing how progestogen might affect estrogen actions on other conditions. Disease specific risks from observational studies suggested that, overall, long-term HRT was likely to be beneficial. Several studies showed that mortality from all causes was lower in HRT users than in non-users. Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women. The WISDOM trial was designed to compare combined estrogen and progestogen versus placebo, and estrogen alone versus combined estrogen and progestogen. During the development of WISDOM the Women's Health Initiative trial was designed, funded and started in the US. DESIGN: Randomised, placebo, controlled, trial. METHODS: The trial was set in general practices in the UK (384), Australia (94), and New Zealand (24). In these practices 284175 women aged 50–69 years were registered with 226282 potentially eligible. We sought to randomise 22300 postmenopausal women aged 50 – 69 and treat for ten years. The interventions were: conjugated equine estrogens, 0.625 mg orally daily; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily; matched placebo. Primary outcome measures were: major cardiovascular disease, osteoporotic fractures, breast cancer and dementia. Secondary outcomes were: other cancers, all cause death, venous thromboembolism and cerebro-vascular disease. RESULTS: The trial was prematurely closed during recruitment following publication of early results from the Women's Health Initiative. At the time of closure, 56583 had been screened, 8980 entered run-in, and 5694 (26% of target of 22,300) randomised. Those women randomised had received a mean of one year of therapy, mean age was 62.8 years and total follow-up time was 6491 person years. DISCUSSION: The WISDOM experience leads to some simple messages. The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery. When a trial is very costly and beyond the resources of one country, funders and investigators should make every effort to develop international collaboration with joint funding