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Commercial off-the-shelf (COTS) multicore platforms are often used to enable the execution of mixed-criticality real-time applications. In these systems, the memory subsystem is one of the most notable sources of interference and unpredictability, with the memory controller (MC) being a key component orchestrating the data flow between processing units and main memory. The worst-case response times of real-time tasks is indeed particularly affected by memory contention and, in turn, by the MC behavior as well. This article presents FrATM2, a Framework to Automatically learn the Timing Models of the Memory subsystem. The framework automatically generates and executes micro-benchmarks on bare-metal hardware to profile the platform behavior in a large number of memory-contention scenarios. After aggregating and filtering the collected measurements, FrATM2 trains MC models to bound memory-related interference. The MC models can be used to enable response-time analysis. The framework was evaluated on an AMD/Xilinx Ultrascale+ SoC, collecting gigabytes of raw experimental data by testing tents of thousands of contention scenarios.

ObjectiveWe have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. Here we sought to develop a blood-based test that could identify these subgroups without cell separation, and thus be suitable for clinical use in Crohn’s disease (CD) and ulcerative colitis (UC).DesignPatients with active IBD were recruited before treatment. Transcriptomic analyses were performed on purified CD8 T cells and/or whole blood. Phenotype data were collected prospectively. IBD1/IBD2 patient subgroups were identified by consensus clustering of CD8 T cell transcriptomes. In a training cohort, machine learning was used to identify groups of genes (‘classifiers’) whose differential expression in whole blood recreated the IBD1/IBD2 subgroups. Genes from the best classifiers were quantitative (q)PCR optimised, and further machine learning was used to identify the optimal qPCR classifier, which was locked down for further testing. Independent validation was sought in separate cohorts of patients with CD (n=66) and UC (n=57).ResultsIn both validation cohorts, a 17-gene qPCR-based classifier stratified patients into two distinct subgroups. Irrespective of the underlying diagnosis, IBDhi patients (analogous to the poor prognosis IBD1 subgroup) experienced significantly more aggressive disease than IBDlo patients (analogous to IBD2), with earlier need for treatment escalation (hazard ratio=2.65 (CD), 3.12 (UC)) and more escalations over time (for multiple escalations within 18 months: sensitivity=72.7% (CD), 100% (UC); negative predictive value=90.9% (CD), 100% (UC)).ConclusionThis is the first validated prognostic biomarker that can predict prognosis in newly diagnosed patients with IBD and represents a step towards personalised therapy.

The molecular mechanisms underlying the acquisition of retinal precursor identity are scarcely defined. Although the homeobox gene Rx1(also known as Rax) plays a major role in specifying retinal precursors and maintaining their multipotent state, the involved mechanisms remain to be largely deciphered. Here, following a highthroughput screen for genes regulated by Rx1, we found that this transcription factor specifies the fate of retinal progenitors by repressing genes normally activated in adjacent ectodermal territories. Unexpectedly, we also observed that Rx1, mainly through the activation of the transcriptional repressors TLE2 and Hes4, is necessary and sufficient to inhibit endomesodermal gene expression in retinal precursors of the eye field. In particular, Rx1 knockdown leads retinogenic blastomeres to adopt an endomesodermal fate, indicating a previously undescribed function for Rx1 in preventing the expression of endomesoderm determinants known to inhibit retinal fate. Altogether these data suggest that an essential requirement to establish a retinal precursor identity is the active inhibition of pathways leading to alternative fates. StemCells2013;31:2842–2847

Background: Currently, there is no specific pharmacological therapy with established efficacy for the treatment of cocaine dependence. The aim of this study was to determine the safety, tolerability and the effects of aripiprazole and ropinirole in patients with cocaine dependence. Methods: This randomized clinical trial of 12-week duration was carried out on 28 consecutive patients with cocaine dependence presenting for treatment. The diagnostic assessment was performed using ICD-9-CM criteria and Mini International Neuropsychiatric Interview. The Clinical Global Impression Scale, a Visual Analogue Scale to assess craving and a self-report questionnaire on the use of cocaine were administered at baseline and then weekly throughout the study. Urinalyses were carried out three times per weeks to search for benzoylecgonine. Results: Of the 28 study participants, 14 completed the protocol. Treatment discontinuation was unrelated with side effects. One patient required a dosage reduction of ropinirole because of sleepiness and one patient assigned to aripiprazole who reported moderate akathysia had the dosage reduced to 5 mg/day. Routine blood works did not show significant changes from baseline and the overall proportion of positive urinalyses for benzoylecgnonine did not differ significantly between treatments. Using linear mixed-effect models a significant decrease in craving was found in the overall sample (p<0.001). The mean number of cocaine administrations exhibited a faster decrease with aripiprazole compared with ropinirole (p0.009). Conclusions: Our pilot study indicates that cocaine craving decreases with both aripiprazole and ropinirole treatment but aripiprazole is more efficacious in reducing cocaine use.

ABSTRACTRotavirus P[8]G9 was recognized as the most widespread genotype during a sentinel-based survey in Italy; phylogenetic analysis of the VP7 and VP4 genes showed that Italian isolates constituted a closely related genetic cluster distinct from the other G9 strains recently isolated in other European countries, America, and Asia.

For decades, acupuncture and electroneedling treatments have been used, predominately in the Eastern countries, in the management of patients with compromised cardiovascular and digestive functions. Similarly, neuromuscular electrical stimulation is commonly employed in Western countries to modulate pain, augment muscle strength and enhance blood flow in patients with peripheral vascular disease. Many rehabilitation specialists believe that electrical stimulation of acupuncture points with surface electrodes can elicit the same physiological and therapeutic effects as those produced by acupuncture and electroneedling techniques. Electrical stimulation of acupuncture points with surface electrodes is a relatively new and non-invasive treatment with potential clinical application in the management of patients with peripheral vascular disease. Presently, there are controversies in the literature as to the effects of traditional acupuncture, electroneedling and neuromuscular electrical stimulation treatments on peripheral haemodynamic functioning. This paper provides a detailed review of published studies on the above promising therapies. An attempt was made to clarify the pitfalls in the extant literature and delineate the fact from the fiction. Areas for further research were proposed.

The lateral coherence length is of the order of 100 µm at the `long' (145 m) ID19 beamline of the ESRF, which is mainly devoted to imaging. Most of the optical elements located along the X‐ray path can thus act as `phase objects', and lead to spurious contrast and/or to coherence degradation, which shows up as an enhanced effective angular size of the source. Both the spurious contrast and the coherence degradation are detrimental for the images (diffraction topographs, tomographs, phase‐contrast images) produced at this beamline. The problems identified and the way they were solved during the commissioning of ID19 are reported. More particularly, the role of the protection foils located in the front end, the beryllium windows, the filters and the monochromator defects (scratches, dust, small vibrations) is discussed.

Abstract: The clinical usefulness of glycated hemoglobin (HbA1c) depends crucially on the accuracy and precision of its assay. When we compared an immunological bench-top analyzer (DCA 2000, Bayer Diagnostici, Milan) to the high-performance liquid chromatography (HPLC) reference method used in a routine hospital laboratory (Diamat and Fast Diamat, Bio-Rad Lab., Milan) by assaying multiple control sera, we found so many sources of systematic analytical errors in the routine use of HPLC as to compromise between-assay precision. DCA 2000 showed intra- and interassay coefficients of variation (CV) of 1.1% and 2.3% with the normal standard serum, 1.0% and 4.2% with the pathological one; Diamat yielded CVs of 1.3% and 7.0%, 1.3% and 5.7%, respectively. Although the measurement of 161 blood samples showed that Diamat usually overestimated HbA1c (paired t-test, P<0.001), a great variability of Diamat performance became evident when the relationship Diamat vs DCA was evaluated day by day over 17 days of observation (analysis of variance, ANOVA, P<0.001). Intra- and interassay CVs of Fast Diamat initially (new instrument still on approval) were 0.6% and 2.5% (normal standard serum), 0.3% and 1.9% (high standard serum), yet after 6 months of routine laboratory use, they became 3.1% and 3.2%, 1% and 12.3%, respectively. Main sources of error were: inaccurate autodilution, unsuitable parameter settings, disregard of the maintenance schedule. We conclude that the tendency to overlook major critical aspects in the routine use of HPLC is detrimental to the quality of HbA1c determination and implies the loss of HbA1c value in clinical practice. Both carefully supervising laboratory quality and checking the likelihood of the analytical result with the clinical setting appear even more important.

A new high‐power front‐end has been developed and installed at the European Synchrotron Radiation Facility. The new design consists of the replacement of the X‐ray absorber and the filtering system. An upstream pre‐slit and a compact high‐heat‐load absorber have replaced the X‐ray absorber. A chemical‐vapour‐deposition diamond window has replaced the beryllium window and graphite filters usually employed. Commissioning has been successfully performed on the ID23 test front‐end equipped with three U34 undulators producing synchrotron radiation with a total power of 11 kW and a peak power density of 1200 W mm−2at normal incidence.

IntroductionThe course of Crohn’s disease (CD) varies substantially between affected individuals, but reliable prognostic markers are not available in clinical practice. This hinders disease management because patients with aggressive disease will be undertreated by conventional “step-up” therapy, while those with indolent disease would be exposed to the risks of unnecessary immunosuppression of a “top-down” approach. Previously, we have described a transcriptional signature that is detectable within peripheral blood CD8 T cells at diagnosis and which correlates with subsequent disease course. To translate this work to the bedside and overcome the technical challenges of separating cell populations, we sought to develop a whole blood qPCR-based biomarker that can re-capitulate the CD8 subgroups without the need for cell separation. Here we describe the development and validation of this biomarker and the upcoming biomarker-stratified trial that will test whether it can deliver personalised medicine in CD.MethodFrom a training cohort of 69 newly diagnosed IBD patients, we simultaneously obtained a whole blood PAXgene RNA tube and peripheral blood CD8 T cell sample. Gene expression in both samples was measured by microarray. After confirming that the CD8 transcriptional signature was detectable and correlated with prognosis, we used machine learning to identify a transcriptional classifier in whole blood gene expression data that would re-capitulate the CD8 transcriptional subgroups. Model selection was performed using Bayesian Information Criterion and the genes identified were subsequently tested by qPCR and optimised to produce an 18 gene qPCR assay.ResultsIndependent validation of this biomarker was established using a second, independent cohort of 85 newly diagnosed patients with CD from 4 sites around the United Kingdom. This validated the biomarker and confirmed that the subgroups it identified had significantly different disease courses (analogous to those observed with the CD8 T cell subgroups). The hazard ratio for time to treatment escalation in this validation cohort was 3.52 (1.84–6.76, 95% confidence intervals, p=0.0002). We now propose to conduct the first ever biomarker-stratified trial in any inflammatory disease to determine whether this biomarker can deliver personalised medicine in CD.ConclusionWe have developed, optimised and validated a whole blood qPCR classifier that is able to predict disease course from diagnosis in IBD patients. This represents a major step towards personalised therapy in IBD, and we will soon investigate whether this could make personalised medicine a reality in CD.Disclosure of InterestNone Declared

The title dimer (III) prepared according to the scheme is the first example of an arene‐Ru complex having planar chirality with respect to the face of the coordinated arenes.