Evaluation of the accuracy of serum MMP-9 as a test for colorectal cancer in a primary care population

Background Bowel cancer is common and is a major cause of death. Meta-analysis of randomised controlled trials estimates that screening for colorectal cancer using faecal occult blood (FOB) test reduces mortality from colorectal cancer by 16%. However, FOB testing has a low positive predictive value, with associated unnecessary cost, risk and anxiety from subsequent investigation, and is unacceptable to a proportion of the target population. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP-9) have been found to be associated with colorectal cancer, and this can be measured from a blood sample. Serum MMP-9 is potentially an accurate, low risk and cost-effective population screening tool. This study aims to evaluate the accuracy of serum MMP-9 as a test for colorectal cancer in a primary care population. Methods/Design People aged 50 to 69 years, who registered in participating general practices in the West Midlands Region, will be asked to complete a questionnaire that asks about symptoms. Respondents who describe any colorectal symptoms (except only abdominal bloating and/or anal symptoms) and are prepared to provide a blood sample for MMP9 estimation and undergo a colonoscopy (current gold standard investigation) will be recruited at GP based clinics by a research nurse. Those unfit for colonoscopy will be excluded. Colonoscopies will be undertaken in dedicated research clinics. The accuracy of MMP-9 will be assessed by comparing the MMP-9 level with the colonoscopy findings, and the combination of factors (e.g. symptoms and MMP-9 level) that best predict a diagnosis of malignancy (invasive disease or polyps) will be determined. Discussion Colorectal cancer is a major cause of morbidity and mortality. Most colorectal cancers arise from adenomas and there is a period for early detection by screening, but available tests have risks, are unacceptable to many, have high false positive rates or are expensive. This study will establish the potential of serum MMP-9 as a screening test for colorectal cancer. If it is confirmed as accurate and acceptable, this serum marker has the potential to assist with reducing the morbidity and mortality from colorectal cancer

Meaningful characterisation of perturbative theoretical uncertainties

We consider the problem of assigning a meaningful degree of belief to uncertainty estimates of perturbative series. We analyse the assumptions which are implicit in the conventional estimates made using renormalisation scale variations. We then formulate a Bayesian model that, given equivalent initial hypotheses, allows one to characterise a perturbative theoretical uncertainty in a rigorous way in terms of a credibility interval for the remainder of the series. We compare its outcome to the conventional uncertainty estimates in the simple case of the calculation of QCD corrections to the e+e- -> hadrons process. We find comparable results, but with important conceptual differences. This work represents a first step in the direction of a more comprehensive and rigorous handling of theoretical uncertainties in perturbative calculations used in high energy phenomenology.Comment: 28 pages, 5 figures. Language modified in order to make it more 'bayesian'. No change in results. Version published in JHE

On direct measurement of the W production charge asymmetry at the LHC

The prospects for making a direct measurement of the W production charge asymmetry at the LHC are discussed. A modification to the method used at the Tevatron is proposed for measurements at the LHC. The expected sensitivity for such a measurement to parton distribution functions is compared to that for a measurement of the lepton charge asymmetry. The direct measurement approach is found to be less useful for placing constraints on parton distribution functions at the LHC than a measurement of the lepton charge asymmetry.Comment: 18 pages, 10 figures, v2: references and keywords updated v3: Additional paragraph discussing inclusion of W asymmetry in global fits adde

Accuracy of monitors used for blood pressure checks in English retail pharmacies::a cross-sectional observational study

BACKGROUND: Free blood pressure (BP) checks offered by community pharmacies provide a potentially useful opportunity to diagnose and/or manage hypertension, but the accuracy of the sphygmomanometers in use is currently unknown. AIM: To assess the accuracy of validated automatic BP monitors used for BP checks in a UK retail pharmacy chain. DESIGN AND SETTING: Cross-sectional, observational study in 52 pharmacies from one chain in a range of locations (inner city, suburban, and rural) in central England. METHOD: Monitor accuracy was compared with a calibrated reference device (Omron PA-350), at 50 mmHg intervals across the range 0–300 mmHg (static pressure test), with a difference from the reference monitor of +/− 3 mmHg at any interval considered a failure. The results were analysed by usage rates and length of time in service. RESULTS: Of 61 BP monitors tested, eight (13%) monitors failed (that is, were >3 mmHg from reference), all of which underestimated BP. Monitor failure rate from the reference monitor of +/− 3 mmHg at any testing interval varied by length of time in use (2/38, 5% <18 months; 4/14, 29% >18 months, P = 0.038) and to some extent, but non-significantly, by usage rates (4/22, 18% in monitors used more than once daily; 2/33, 6% in those used less frequently, P = 0.204). CONCLUSION: BP monitors within a pharmacy setting fail at similar rates to those in general practice. Annual calibration checks for blood pressure monitors are needed, even for new monitors, as these data indicate declining performance from 18 months onwards

Fitting Parton Distribution Data with Multiplicative Normalization Uncertainties

We consider the generic problem of performing a global fit to many independent data sets each with a different overall multiplicative normalization uncertainty. We show that the methods in common use to treat multiplicative uncertainties lead to systematic biases. We develop a method which is unbiased, based on a self--consistent iterative procedure. We demonstrate the use of this method by applying it to the determination of parton distribution functions with the NNPDF methodology, which uses a Monte Carlo method for uncertainty estimation.Comment: 33 pages, 5 figures: published versio

Different systolic blood pressure targets for people with history of stroke or transient ischaemic attack: PAST-BP (Prevention After Stroke--Blood Pressure) randomised controlled trial.

OBJECTIVE: To assess whether using intensive blood pressure targets leads to lower blood pressure in a community population of people with prevalent cerebrovascular disease. DESIGN: Open label randomised controlled trial. SETTING: 99 general practices in England, with participants recruited in 2009-11. PARTICIPANTS: People with a history of stroke or transient ischaemic attack whose systolic blood pressure was 125 mm Hg or above. INTERVENTIONS: Intensive systolic blood pressure target (<130 mm Hg or 10 mm Hg reduction from baseline if this was <140 mm Hg) or standard target (<140 mm Hg). Apart from the different target, patients in both arms were actively managed in the same way with regular reviews by the primary care team. MAIN OUTCOME MEASURE: Change in systolic blood pressure between baseline and 12 months. RESULTS: 529 patients (mean age 72) were enrolled, 266 to the intensive target arm and 263 to the standard target arm, of whom 379 were included in the primary analysis (182 (68%) intensive arm; 197 (75%) standard arm). 84 patients withdrew from the study during the follow-up period (52 intensive arm; 32 standard arm). Mean systolic blood pressure dropped by 16.1 mm Hg to 127.4 mm Hg in the intensive target arm and by 12.8 mm Hg to 129.4 mm Hg in the standard arm (difference between groups 2.9 (95% confidence interval 0.2 to 5.7) mm Hg; P=0.03). CONCLUSIONS: Aiming for target below 130 mm Hg rather than 140 mm Hg for systolic blood pressure in people with cerebrovascular disease in primary care led to a small additional reduction in blood pressure. Active management of systolic blood pressure in this population using a <140 mm Hg target led to a clinically important reduction in blood pressure.Trial registration Current Controlled Trials ISRCTN29062286.This report is independent research funded by the National Institute for Health Research (Stroke Prevention in Primary Care, Programme Grant for Applied Research, RP-PG-0606-1153), and by an NIHR Professorship (Prof McManus). FDRH is part funded as Director of the National Institute for Health Research (NIHR) School for Primary Care Research (SPCR), Theme Leader of the NIHR Oxford Biomedical Research Centre (BRC), and Director of the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) Oxford. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS. The study sponsor was the University of Birmingham. The study funder and sponsor had no role in the study design, collection, analysis or interpretation of data, in the writing of the report, or in the decision to submit to publication. The researchers are independent of the funders.This is the final version of the article. It first appeared from the BMJ Publishing Group via http://dx.doi.org/10.1136/bmj.i70

Spin and Statistics and First Principles

It was shown in the early Seventies that, in Local Quantum Theory (that is the most general formulation of Quantum Field Theory, if we leave out only the unknown scenario of Quantum Gravity) the notion of Statistics can be grounded solely on the local observable quantities (without assuming neither the commutation relations nor even the existence of unobservable charged field operators); one finds that only the well known (para)statistics of Bose/Fermi type are allowed by the key principle of local commutativity of observables. In this frame it was possible to formulate and prove the Spin and Statistics Theorem purely on the basis of First Principles. In a subsequent stage it has been possible to prove the existence of a unique, canonical algebra of local field operators obeying ordinary Bose/Fermi commutation relations at spacelike separations. In this general guise the Spin - Statistics Theorem applies to Theories (on the four dimensional Minkowski space) where only massive particles with finite mass degeneracy can occur. Here we describe the underlying simple basic ideas, and briefly mention the subsequent generalisations; eventually we comment on the possible validity of the Spin - Statistics Theorem in presence of massless particles, or of violations of locality as expected in Quantum Gravity.Comment: Survey based on a talk given at the Meeting on "Theoretical and experimental aspects of the spin - statistics connection and related symmetries", Trieste, Italy - October 21-25, 200

A prospective study to assess the value of MMP-9 in improving the appropriateness of urgent referrals for colorectal cancer

Background Bowel cancer is common and is a major cause of death. Most people with bowel symptoms who meet the criteria for urgent referral to secondary care will not be found to have bowel cancer, and some people who are found to have cancer will have been referred routinely rather than urgently. If general practitioners could better identify people who were likely to have bowel cancer or conditions that may lead to bowel cancer, the pressure on hospital clinics may be reduced, enabling these patients to be seen more quickly. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP-9) have been found to be associated with such conditions, and this can be measured from a blood sample. This study aims to find out whether measuring MMP-9 levels could improve the appropriateness of urgent referrals for patients with bowel symptoms. Methods People aged 18 years or older referred to a colorectal clinic will be asked to complete a questionnaire about symptoms, recent injuries or chronic illnesses (these can increase the level of matrix metalloproteinases) and family history of bowel cancer. A blood sample will be taken from people who consent to take part to assess MMP-9 levels, and the results of examination at the clinic and/or investigations arising from the clinic visit will be collected from hospital records. The accuracy of MMP-9 will be assessed by comparing the MMP-9 level with the resulting diagnosis. The combination of factors (e.g. symptoms and MMP-9 level) that best predict a diagnosis of malignancy (invasive disease or polyps) will be determined. Discussion Although guidelines are in place to facilitate referrals to colorectal clinics, symptoms alone do not adequately distinguish people with malignancy from people with benign conditions. This study will establish whether MMP-9 could assist this process. If this were the case, measurement of MMP-9 levels could be used by general practitioners to assist in the identification of people who were most likely to have bowel cancer or conditions that may lead to bowel cancer, and who should, therefore, be referred most urgently to secondary car

W boson production at hadron colliders: the lepton charge asymmetry in NNLO QCD

We consider the production of W bosons in hadron collisions, and the subsequent leptonic decay W->lnu_l. We study the asymmetry between the rapidity distributions of the charged leptons, and we present its computation up to the next-to-next-to-leading order (NNLO) in QCD perturbation theory. Our calculation includes the dependence on the lepton kinematical cuts that are necessarily applied to select W-> lnu_l events in actual experimental analyses at hadron colliders. We illustrate the main differences between the W and lepton charge asymmetry, and we discuss their physical origin and the effect of the QCD radiative corrections. We show detailed numerical results on the charge asymmetry in ppbar collisions at the Tevatron, and we discuss the comparison with some of the available data. Some illustrative results on the lepton charge asymmetry in pp collisions at LHC energies are presented.Comment: 37 pages, 21 figure

When Anomaly Mediation is UV Sensitive

Despite its successes---such as solving the supersymmetric flavor problem---anomaly mediated supersymmetry breaking is untenable because of its prediction of tachyonic sleptons. An appealing solution to this problem was proposed by Pomarol and Rattazzi where a threshold controlled by a light field deflects the anomaly mediated supersymmetry breaking trajectory, thus evading tachyonic sleptons. In this paper we examine an alternate class of deflection models where the non-supersymmetric threshold is accompanied by a heavy, instead of light, singlet. The low energy form of this model is the so-called extended anomaly mediation proposed by Nelson and Weiner, but with potential for a much higher deflection threshold. The existence of this high deflection threshold implies that the space of anomaly mediated supersymmetry breaking deflecting models is larger than previously thought.Comment: 14 pages, 1 figure (version to appear in JHEP