Filtering features for a composite event definition language

This research has enhanced a distributed, rule-based application integration environment with a composite event definition language (CEDL) and detection system. CEDL builds on existing composite event operators and selection modes, adding features to support the filtering of primitive and composite events. The filtering features include basic parameter filtering on primitive and composite events, aggregate and quantifier filters on cumulative event parameters, and time filters for defining the lifetime of the composite event detection process. This paper presents examples of CEDL, illustrating the expression of application-oriented events through the aggregation and correlation of distributed events. 1

Genomic Exploration of Distinct Molecular Phenotypes Steering Temozolomide Resistance Development in Patient-Derived Glioblastoma Cells

Chemotherapy using temozolomide is the standard treatment for patients with glioblastoma. Despite treatment, prognosis is still poor largely due to the emergence of temozolomide resistance. This resistance is closely linked to the widely recognized inter- and intra-tumoral heterogeneity in glioblastoma, although the underlying mechanisms are not yet fully understood. To induce temozolomide resistance, we subjected 21 patient-derived glioblastoma cell cultures to Temozolomide treatment for a period of up to 90 days. Prior to treatment, the cells’ molecular characteristics were analyzed using bulk RNA sequencing. Additionally, we performed single-cell RNA sequencing on four of the cell cultures to track the evolution of temozolomide resistance. The induced temozolomide resistance was associated with two distinct phenotypic behaviors, classified as “adaptive” (ADA) or “non-adaptive” (N-ADA) to temozolomide. The ADA phenotype displayed neurodevelopmental and metabolic gene signatures, whereas the N-ADA phenotype expressed genes related to cell cycle regulation, DNA repair, and protein synthesis. Single-cell RNA sequencing revealed that in ADA cell cultures, one or more subpopulations emerged as dominant in the resistant samples, whereas N-ADA cell cultures remained relatively stable. The adaptability and heterogeneity of glioblastoma cells play pivotal roles in temozolomide treatment and contribute to the tumor’s ability to survive. Depending on the tumor’s adaptability potential, subpopulations with acquired resistance mechanisms may arise.</p

Variation in population levels of sedentary time in European adults according to cross European studies: a systematic literature review within DEDIPAC

peer-reviewedBackground: Sedentary behaviour is increasingly recognized as a public health risk that needs to be monitored at the population level. Across Europe, there is increasing interest in assessing population levels of sedentary time. This systematic literature review aims to provide an overview of all existing cross-European studies that measure sedentary time in adults, to describe the variation in population levels across these studies and to discuss the impact of assessment methods. Methods: Six literature databases (PubMed, EMBASE, CINAHL, PsycINFO, SportDiscus and OpenGrey) were searched, supplemented with backward- and forward tracking and searching authors’ and experts’ literature databases. Articles were included if they reported on observational studies measuring any form of sedentary time in the general population in two or more European countries. Each record was reviewed, extracted and assessed by two independent researchers, and disagreements were resolved by a third researcher. The review protocol of this review is registered in the PROSPERO database under registration number CRD42014010335. Results: Of the 9,756 unique articles that were identified in the search, twelve articles were eligible for inclusion in this review, reporting on six individual studies and three Eurobarometer surveys. These studies represented 2 to 29 countries, and 321 to 65,790 participants. Eleven studies focused on total sedentary time, while one studied screen time. The majority of studies used questionnaires to assess sedentary time, while two studies used accelerometers. Total sedentary time was reported most frequently and varied from 150 (median) to 620 (mean) minutes per day aConclusions: One third of European countries were not included in any of the studies. Objective measures of European adults are currently limited, and most studies used single-item self-reported questions without assessing sedentary behaviour types or domains. Findings varied substantially between studies, meaning that population levels of sedentary time in European adults are currently unknown. In general, people living in northern Europe countries appear to report more sedentary time than southern Europeans. The findings of this review highlight the need for standardisation of the measurement methods and the added value of cross-European surveillance of sedentary behaviour.cross studies and countries

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers

Background: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). Methods: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. Results: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets. Conclusion:GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.</p

The Set3/Hos2 Histone Deacetylase Complex Attenuates cAMP/PKA Signaling to Regulate Morphogenesis and Virulence of Candida albicans

Candida albicans, like other pleiomorphic fungal pathogens, is able to undergo a reversible transition between single yeast-like cells and multicellular filaments. This morphogenetic process has long been considered as a key fungal virulence factor. Here, we identify the evolutionarily conserved Set3/Hos2 histone deacetylase complex (Set3C) as a crucial repressor of the yeast-to-filament transition. Cells lacking core components of the Set3C are able to maintain all developmental phases, but are hypersusceptible to filamentation-inducing signals, because of a hyperactive cAMP/Protein Kinase A signaling pathway. Strikingly, Set3C-mediated control of filamentation is required for virulence in vivo, since set3Δ/Δ cells display strongly attenuated virulence in a mouse model of systemic infection. Importantly, the inhibition of histone deacetylase activity by trichostatin A exclusively phenocopies the absence of a functional Set3C, but not of any other histone deacetylase gene. Hence, our work supports a paradigm for manipulating morphogenesis in C. albicans through alternative antifungal therapeutic strategies

Variation in population levels of sedentary time in European children and adolescents according to cross-European studies: a systematic literature review within DEDIPAC

peer-reviewedBackground: A high amount of sedentary time has been proposed as a risk factor for various health outcomes in adults. While the evidence is less clear in children and adolescents, monitoring sedentary time is important to understand the prevalence rates and how this behaviour varies over time and by place. This systematic literature review aims to provide an overview of existing cross-European studies on sedentary time in children (0-12y) and adolescents (13-18y), to describe the variation in population levels of sedentary time, and to discuss the impact of assessment methods. Methods: Six literature databases were searched (PubMed, EMBASE, CINAHL, PsycINFO, SportDiscus and OpenGrey), followed by backward- and forward tracking and searching authors’ and experts’ literature databases. Included articles were observational studies reporting on levels of sedentary time in the general population of children and/or adolescents in at least two European countries. Population levels were reported separately for children and adolescents. Data were reviewed, extracted and assessed by two researchers, with disagreements being resolved by a third researcher. The review protocol is published under registration number CRD42014013379 in the PROSPERO database. Forty-two eligible articles were identified, most were cross-sectional (n = 38). The number of included European countries per article ranged from 2 to 36. Levels of sedentary time were observed to be higher in East-European countries compared to the rest of Europe. There was a large variation in assessment methods and reported outcome variables. The majority of articles used a child-specific questionnaire (60 %). Other methods included accelerometers, parental questionnaires or interviews and ecological momentary assessment tools. Television time was reported as outcome variable in 57 % of included articles (ranging from a mean value of 1 h to 2.7 h in children and 1.3 h to 4.4 h in adolescents), total sedentary time in 24 % (ranging from a mean value of 192 min to 552 min in children and from 268 min to 506 min in adolescents). A substantial number of published studies report on levels of sedentary time in children and adolescents across European countries, but there was a large variation in assessment methods. Questionnaires (child specific) were used most often, but they mostly measured specific screen-based activities and did not assess total sedentary time. There is a need for harmonisation and standardisation of objective and subjective methods to assess sedentary time in children and adolescents to enable comparison across countries

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment