First-Order Provenance Games

We propose a new model of provenance, based on a game-theoretic approach to query evaluation. First, we study games G in their own right, and ask how to explain that a position x in G is won, lost, or drawn. The resulting notion of game provenance is closely related to winning strategies, and excludes from provenance all "bad moves", i.e., those which unnecessarily allow the opponent to improve the outcome of a play. In this way, the value of a position is determined by its game provenance. We then define provenance games by viewing the evaluation of a first-order query as a game between two players who argue whether a tuple is in the query answer. For RA+ queries, we show that game provenance is equivalent to the most general semiring of provenance polynomials N[X]. Variants of our game yield other known semirings. However, unlike semiring provenance, game provenance also provides a "built-in" way to handle negation and thus to answer why-not questions: In (provenance) games, the reason why x is not won, is the same as why x is lost or drawn (the latter is possible for games with draws). Since first-order provenance games are draw-free, they yield a new provenance model that combines how- and why-not provenance

Drug-drug interactions with tyrosine-kinase inhibitors:A clinical perspective

In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice

Extreme precipitation and extreme streamflow in the Dongjiang River Basin in southern China

International audienceExtreme hydro-meteorological events have become the focus of more and more studies in the last decade. Due to the complexity of the spatial pattern of changes in precipitation processes, it is still hard to establish a clear view of how precipitation has changed and how it will change in the future. In the present study, changes in extreme precipitation and streamflow processes in the Dongjiang River Basin in southern China are investigated. It was shown that little change is observed in annual extreme precipitation in terms of various indices, but some significant changes are found in the precipitation processes on a monthly basis. The result indicates that when detecting climate changes, besides annual indices, seasonal variations in extreme events should be considered as well. Despite of little change in annual extreme precipitation series, significant changes are detected in several annual extreme flood flow and low-flow series, mainly at the stations along the main channel of Dongjiang River, which are affected significantly by the operation of several major reservoirs. The result highlights the importance of evaluating the impacts of human activities in assessing the changes of extreme streamflows. In addition, three non-parametric methods that are not-commonly used by hydro-meteorology community, i.e., Kolmogorov?Smirnov test, Levene's test and quantile test, are introduced and assessed by Monte Carlo simulation in the present study to test for changes in the distribution, variance and the shift of tails of different groups of dataset. Monte Carlo simulation result shows that, while all three methods work well for detecting changes in two groups of data with large data size (e.g., over 200 points in each group) and big difference in distribution parameters (e.g., over 100% increase of scale parameter in Gamma distribution), none of them are powerful enough for small data sets (e.g., less than 100 points) and small distribution parameter difference (e.g., 50% increase of scale parameter in Gamma distribution)

Stroke risk in patients with device-detected atrial high-rate episodes

Cardiovascular implantable electronic devices (CIEDs) can detect atrial arrhythmias, i.e. atrial high-rate episodes (AHRE). The thrombo-embolic risk in patients showing AHRE appears to be lower than in patients with clinical atrial fibrillation (AF) and it is unclear whether the former will benefit from oral anticoagulants. Based on currently available evidence, it seems reasonable to consider antithrombotic therapy in patients without documented AF showing AHRE >24 hours and a CHA(2)DS(2)-VASc score (congestive heart failure, hypertension, age >= 75 years [doubled], diabetes mellitus, prior stroke [doubled], vascular disease, age 65-74 years and female sex) >= 1, awaiting definite answers from ongoing randomised clinical trials. In patients with AHR

Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients

There is controversy regarding the prognostic value of cathepsin-D in primary breast cancer. An increased level of cathepsin-D in tumour extracts has been found to be associated with a poor relapse-free and overall survival. Studies performed with immunohistochemistry or Western blotting have produced diverse results. We have analysed 2810 cytosolic extracts obtained from human primary breast tumours for cathepsin-D expression, and have correlated their levels with prognosis. The median follow-up of the patients still alive was 88 months. Patients with high cathepsin-D levels had a significantly worse relapse-free and overall survival, also in multivariate analysis (P < 0.0001). Adjuvant therapy which was associated with an improved prognosis in node-positive patients in univariate analysis, also significantly added to the multivariate models for relapse-free and overall survival. There were no statistically significant interactions between the levels of cathepsin-D and any of the classical prognostic factors in analysis for relapse-free survival, suggesting that the prognostic value of cathepsin-D is not different in the various subgroups of patients. Indeed, multivariate analyses in subgroups of node-negative and -positive patients, pre- and post-menopausal patients, and their combinations, showed that tumours with high cathepsin-D values had a significantly poor relapse-free survival, with relative hazard rates ranging from 1.3 to 1.5, compared with tumours with low cathepsin-D levels. The results presented here on 2810 patients confirm that high cytosolic cathepsin-D values are associated with poor prognosis in human primary breast cancer. © 1999 Cancer Research Campaig

Gut-microbe derived TMAO and its association with more progressed forms of AF:Results from the AF-RISK study

Introduction: The importance of gut microbiome in cardiovascular disease has been increasingly recognized. Trimethylamine N-oxide (TMAO) is a gut microbe-derived metabolite that is associated with cardiovascular disease, including atrial fibrillation (AF). The role of TMAO in clinical AF progression however remains unknown. Methods and results: In this study we measured TMAO and its precursor (betaine, choline, and L- carnitine) levels in 78 patients using plasma samples from patients that participated in the AF-RISK study. 56 patients suffered from paroxysmal AF and 22 had a short history of persistent AF. TMAO levels were significantly higher in patients with persistent AF, as compared to those with paroxysmal AF (median [IQR] 5.65 [4.7–9.6] m/z versus 4.31 [3.2–6.2] m/z, p < 0.05), while precursor levels did not differ. In univariate analysis, we observed that for every unit increase in TMAO, the odds for having persistent AF increased with 0.44 [0.14–0.73], p < 0.01. Conclusion: These results suggest that higher levels of TMAO are associated with more progressed forms of AF. We therefore hypothesize that increased TMAO levels may reflect disease progression in humans. Larger studies are required to validate these preliminary findings.Trial Registration number: Clinicaltrials.gov NCT01510210

Evidence on continuous flow peritoneal dialysis: A review

Clinical application of continuous flow peritoneal dialysis (CFPD) has been explored since the 1960s, but despite anticipated clinical benefits, CFPD has failed to gain a foothold in clinical practice, among others due to the typical use of two catheters (or a dual-lumen catheter) and large dialysate volumes required per treatment. Novel systems applying CFPD via the existing single-lumen catheter using rapid dialysate cycling may solve one of these hurdles. Novel on-demand peritoneal dialysate generation systems and sorbent-based peritoneal dialysate regeneration systems may considerably reduce the storage space for peritoneal dialysate and/or the required dialysate volume. This review provides an overview of current evidence on CFPD in vivo. The available (pre)clinical evidence on CFPD is limited to case reports/series with inherently nonuniform study procedures, or studies with a small sample size, short follow-up, and no hard endpoints. Small solute clearance appears to be higher in CFPD compared to conventional PD, in particular at dialysate flows ≥100 mL/min using two single-lumen catheters or a double-lumen catheter. Results of CFPD using rapid cycling via a single-lumen catheter are too preliminary to draw any conclusions. Continuous addition of glucose to dialysate with CFPD appears to be effective in reducing the maximum intraperitoneal glucose concentration while increasing ultrafiltration efficiency (mL/g absorbed glucose). Patient tolerance may be an issue since abdominal discomfort and sterile peritonitis were reported with continuous circulation of the peritoneal dialysate. Thus, well-designed clinical trials of longer duration and larger sample size, in particular applying CFPD via the existing catheter, are urgently required