Evaluation of the impact of the GRACE risk score on the management and outcome of patients hospitalised with non-ST elevation acute coronary syndrome in the UK: protocol of the UKGRIS cluster-randomised registry-based trial

Introduction For non-ST-segment elevation acute coronary syndrome (NSTEACS) there is a gap between the use of class 1 guideline recommended therapies and clinical practice. The GRACE risk score is recommended in international guidelines for the risk stratification of NSTEACS, but its impact on adherence to guideline-indicated treatments and reducing adverse clinical outcomes is unknown. The objective of the UKGRIS trial is to assess the effectiveness of the GRACE risk score tool and associated treatment recommendations on the use of guideline-indicated care and clinical outcomes. Methods and Analysis The UK GRACE Risk Score Intervention Study (UKGRIS), a parallel-group cluster randomised registry-based controlled trial, will allocate hospitals in a 1:1 ratio to manage NSTEACS by standard care or according to the GRACE risk score and associated international guidelines. UKGRIS will recruit a minimum of 3000 patients from at least 30 English National Health Service hospitals and collect healthcare data from national electronic health records. The co-primary endpoints are the use of guideline-indicated therapies, and the composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospitalisation or cardiovascular readmission at 12 months. Secondary endpoints include duration of inpatient hospital stay over 12 months, EQ-5D-5L responses and utilities, unscheduled revascularisation and the components of the composite endpoint over 12 months follow-up. Ethics and Dissemination The study has ethical approval (North East - Tyne & Wear South Research Ethics Committee ref: 4/NE/1180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the funder’s open access policy. Registration ISRCTN29731761, registered 12th January 2017

Residential Proximity to Agricultural Pesticide Use and Incidence of Breast Cancer in California, 1988–1997

California is the largest agricultural state in the United States and home to some of the world’s highest breast cancer rates. The objective of our study was to evaluate whether California breast cancer rates were elevated in areas with recent high agricultural pesticide use. We identified population-based invasive breast cancer cases from the California Cancer Registry for 1988–1997. We used California’s pesticide use reporting data to select pesticides for analysis based on use volume, carcinogenic potential, and exposure potential. Using 1990 and 2000 U.S. Census data, we derived age- and race-specific population counts for the time period of interest. We used a geographic information system to aggregate cases, population counts, and pesticide use data for all block groups in the state. To evaluate whether breast cancer rates were related to recent agricultural pesticide use, we computed rate ratios and 95% confidence intervals using Poisson regression models, adjusting for age, race/ethnicity, and neighborhood socioeconomic status and urbanization. This ecologic (aggregative) analysis included 176,302 invasive breast cancer cases and 70,968,598 person-years of observation. The rate ratios did not significantly differ from 1 for any of the selected pesticide categories or individual agents. The results from this study provide no evidence that California women living in areas of recent, high agricultural pesticide use experience higher rates of breast cancer

The 'Switch' study protocol: a randomised-controlled trial of switching to an alternative tumour-necrosis factor (TNF)-inhibitor drug or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-inhibitor drug

Background: Rheumatoid Arthritis (RA) is one of the most common autoimmune diseases, affecting approximately 1% of the UK adult population. Patients suffer considerable pain, stiffness and swelling and can sustain various degrees of joint destruction, deformity, and significant functional decline. In addition, the economic burden due to hospitalisation and loss of employment is considerable, with over 50% of patients being work-disabled within 10 years of diagnosis. Despite several biologic disease modifying anti-rheumatic drugs (bDMARD) now available, there is a lack of data to guide biologic sequencing. In the UK, second-line biologic treatment is restricted to a single option, rituximab. The aim of the SWITCH trial is to establish whether an alternative-mechanism-TNF-inhibitor (TNFi) or abatacept are as effective as rituximab in patients with RA who have failed an initial TNFi drug. Methods/Design: SWITCH is a pragmatic, phase IV, multi-centre, parallel-group design, open-label, randomised, controlled trial (RCT) comparing alternative-mechanism-TNFi and abatacept with rituximab in patients with RA who have failed an initial TNFi drug. Participants are randomised in a 1:1:1 ratio to receive alternative mechanism TNFi, (monoclonal antibodies: infliximab, adalimumab, certolizumab or golimumab or the receptor fusion protein, etanercept), abatacept or rituximab during the interventional phase (from randomisation up to week 48). Participants are subsequently followed up to a maximum of 96 weeks, which constitutes the observational phase. The primary objective is to establish whether an alternative-mechanism-TNFi or abatacept are non-inferior to rituximab in terms of disease response at 24 weeks post randomisation. The secondary objectives include the comparison of alternative-mechanism-TNFi and abatacept to rituximab in terms of disease response, quality of life, toxicity, safety and structural and bone density outcomes over a 12-month period (48 weeks) and to evaluate the cost-effectiveness of switching patients to alternative active therapies compared to current practice. Discussion: SWITCH is a well-designed trial in this therapeutic area that aims to develop a rational treatment algorithm to potentially inform personalised treatment regimens (as opposed to switching all patients to only one available (and possibly unsuccessful) therapy), which may lead to long-term improved patient outcomes and gains in population health

Modeling recursive RNA interference.

An important application of the RNA interference (RNAi) pathway is its use as a small RNA-based regulatory system commonly exploited to suppress expression of target genes to test their function in vivo. In several published experiments, RNAi has been used to inactivate components of the RNAi pathway itself, a procedure termed recursive RNAi in this report. The theoretical basis of recursive RNAi is unclear since the procedure could potentially be self-defeating, and in practice the effectiveness of recursive RNAi in published experiments is highly variable. A mathematical model for recursive RNAi was developed and used to investigate the range of conditions under which the procedure should be effective. The model predicts that the effectiveness of recursive RNAi is strongly dependent on the efficacy of RNAi at knocking down target gene expression. This efficacy is known to vary highly between different cell types, and comparison of the model predictions to published experimental data suggests that variation in RNAi efficacy may be the main cause of discrepancies between published recursive RNAi experiments in different organisms. The model suggests potential ways to optimize the effectiveness of recursive RNAi both for screening of RNAi components as well as for improved temporal control of gene expression in switch off-switch on experiments

An investigation of supervector regression for forensic voice comparison on small data

International audienceThe present paper deals with an observer design for a nonlinear lateral vehicle model. The nonlinear model is represented by an exact Takagi-Sugeno (TS) model via the sector nonlinearity transformation. A proportional multiple integral observer (PMIO) based on the TS model is designed to estimate simultaneously the state vector and the unknown input (road curvature). The convergence conditions of the estimation error are expressed under LMI formulation using the Lyapunov theory which guaranties bounded error. Simulations are carried out and experimental results are provided to illustrate the proposed observer

Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer.

Tumour hypoxia is a microenvironmental factor related to poor response to radiation, chemotherapy, genetic instability, selection for resistance to apoptosis, and increased risk of invasion and metastasis. Hypoxia-regulated carbonic anhydrase IX (CA IX) has been studied in various tumour sites and its expression has been correlated with the clinical outcome. The purpose of this study was to investigate the correlation of CA IX expression with outcome in patients with invasive breast cancer. We conducted a retrospective study examining the effects of carbonic anhydrase IX (CA IX) on survival in patients with breast cancer. To facilitate the screening of multiple tissue blocks from each patient, tissue microarrays were prepared containing between two and five representative samples of tumour per patient. Immunohistochemistry was used to examine expression of CA IX in patients with breast cancer. The study includes a cohort of 144 unselected patients with early invasive breast cancer who underwent surgery, and had CA IX expression and follow-up data available for analysis. At the time of analysis, there were 28 deaths and median follow-up of 48 months with 96% of patients having at least 2 years of follow-up. CA IX was negative for 107 patients (17 deaths) and positive for 37 patients (11 deaths). Kaplan-Meier survival curves show that survival was superior in the CA IX-negative group with a 2-year survival of 97% for negatives and 83% for positives (log-rank test P=0.01). Allowing for potential prognostic variables in a Cox regression analysis, CA IX remained a significant independent predictor of survival (P=0.035). This study showed in both univariate and multivariate analysis that survival is significantly inferior in patients with tumour expressing CA IX. Prospective studies are underway to investigate this correlation in clinical trial setting

Identification of a novel zinc metalloprotease through a global analysis of clostridium difficile extracellular proteins

Clostridium difficile is a major cause of infectious diarrhea worldwide. Although the cell surface proteins are recognized to be important in clostridial pathogenesis, biological functions of only a few are known. Also, apart from the toxins, proteins exported by C. difficile into the extracellular milieu have been poorly studied. In order to identify novel extracellular factors of C. difficile, we analyzed bacterial culture supernatants prepared from clinical isolates, 630 and R20291, using liquid chromatography-tandem mass spectrometry. The majority of the proteins identified were non-canonical extracellular proteins. These could be largely classified into proteins associated to the cell wall (including CWPs and extracellular hydrolases), transporters and flagellar proteins. Seven unknown hypothetical proteins were also identified. One of these proteins, CD630_28300, shared sequence similarity with the anthrax lethal factor, a known zinc metallopeptidase. We demonstrated that CD630_28300 (named Zmp1) binds zinc and is able to cleave fibronectin and fibrinogen in vitro in a zinc-dependent manner. Using site-directed mutagenesis, we identified residues important in zinc binding and enzymatic activity. Furthermore, we demonstrated that Zmp1 destabilizes the fibronectin network produced by human fibroblasts. Thus, by analyzing the exoproteome of C. difficile, we identified a novel extracellular metalloprotease that may be important in key steps of clostridial pathogenesis

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

The first decade of oligotrophication of Lake Constance

In Lake Constance, after several decades of cutrophication, a decrease in phosphorus loading over the last decade has lead to a partial recovery from eutrophication. Here we analyse the shift in the taxonomic composition of phytoplankton during the first decade of oligotrophication in Lake Constance. During the 1980s, spring total P concentrations decreased from ca. 130 to less than 50 mgr·l–1. This decrease was reflected by an approximately proportional decrease in summer phytoplankton biomass while spring phytoplankton biomass seemed unresponsive. Major taxonomic changes occured during both growth seasons. In spring, the proportion of diatoms, green algae and Chrysophyta increased while the proportion of Cryptophyta decreased. The summer trend was very different: the relative importance of diatoms decreased and Cryptophyta and Chrysophyta increased, while Chlorophyta reached their peak around 1985. These trends are also analysed at the genus level. Comparison with taxonomic trends during the eutrophication period shows the expected reversals in most cases. Comparison with other lakes shows general similarities, with the notable exception that Planktothrix rubescens has never been important in Lake Constance. The increase of diatoms during spring is attributed to their improved competitive performance with increasing Si:P ratios. Their decrease during summer is explained by the increasing silicate removal from the epilimnion by increasing spring populations