Identification of a Serum-Induced Transcriptional Signature Associated With Type 1 Diabetes in the BioBreeding Rat

OBJECTIVE - Inflammatory mediators associated with type 1 diabetes are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing preonset risk, and monitoring therapeutic interventions. RESEARCH DESIGN AND METHODS - We previously utilized a novel bioassay in which human type 1 diabetes sera were used to induce a disease-specific transcriptional signature in unrelated, healthy peripheral blood mononuclear cells (PBMCs). Here, we apply this strategy to investigate the inflammatory state associated with type 1 diabetes in biobreeding (BB) rats. RESULTS - Consistent with their common susceptibility, sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induced transcription of cytokines, immune receptors, and signaling molecules in PBMCs of healthy donor rats compared with control sera. Like the human type 1 diabetes signature, the DRlyp/lyp signature, which is associated with progression to diabetes, was differentiated from that of the DR+/+ by induction of many interleukin (IL)-1-regulated genes. Supplementing cultures with an IL-1 receptor antagonist (IL-1Ra) modulated the DRlyp/lyp signature (P < 10-6), while administration of IL-1Ra to DRlyp/lyp rats delayed onset (P = 0.007), and sera of treated animals did not induce the characteristic signature. Consistent with the presence of immunoregulatory cells in DR+/+ rats was induction of a signature possessing negative regulators of transcription and inflammation. CONCLUSIONS - Paralleling our human studies, serum signatures in BB rats reflect processes associated with progression to type 1 diabetes. Furthermore, these studies support the potential utility of this approach to detect changes in the inflammatory state during therapeutic intervention

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.

PURPOSE: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions. METHODS: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation. RESULTS: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression. CONCLUSION: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers

The ABC130 barrel module prototyping programme for the ATLAS strip tracker

For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector, consisting of silicon pixel, silicon strip and transition radiation sub-detectors, will be replaced with an all new 100 % silicon tracker, composed of a pixel tracker at inner radii and a strip tracker at outer radii. The future ATLAS strip tracker will include 11,000 silicon sensor modules in the central region (barrel) and 7,000 modules in the forward region (end-caps), which are foreseen to be constructed over a period of 3.5 years. The construction of each module consists of a series of assembly and quality control steps, which were engineered to be identical for all production sites. In order to develop the tooling and procedures for assembly and testing of these modules, two series of major prototyping programs were conducted: an early program using readout chips designed using a 250 nm fabrication process (ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm processing (ABC130 and HCC130 chips). This second generation of readout chips was used for an extensive prototyping program that produced around 100 barrel-type modules and contributed significantly to the development of the final module layout. This paper gives an overview of the components used in ABC130 barrel modules, their assembly procedure and findings resulting from their tests.Comment: 82 pages, 66 figure

Implementing evidence-based supported employment in Sussex for people with severe mental illness

Introduction: The aim of this research was to evaluate a large-scale implementation of evidence-based supported employment for people with severe mental illness, at 17 locations throughout Sussex, England. Method: A parallel group observational design was used to evaluate an implementation of the individual placement and support approach to supported employment. Three sites provided both a comparison pre-individual placement and support cohort (n=140), and a new post-individual placement and support cohort (n=107) as part of the individual placement and support implementation (n=446). All individual placement and support sites involved community mental health teams forming partnerships with Southdown Supported Employment to co-locate an employment specialist into each mental health team. The primary outcome was the proportion of participants commencing competitive employment during the follow-up period. Results: The new individual placement and support sites attained higher fidelity with respect to individual placement and support principles and practices (mean 97 of 125) than the pre-individual placement and support sites (mean 77 of 125). Significantly more individual placement and support participants commenced competitive employment than pre-individual placement and support participants (24.9% vs 14.3%). Individual placement and support participants experienced less delay before commencing their first job (153 vs 371 days), and when employed, worked more hours per week (24.3 vs 15.4 hours). Conclusion: This implementation of individual placement and support in Sussex improved on the previous vocational services. Although progress is encouraging there is much room for improvement. More resources appear needed to support programme development, specifically to strengthen site-level management, training, technical support, fidelity assessment, programme monitoring, and outcome evaluation

Emergency department performance indicators that encompass the patient journey

Objective: The study aimed to provide a recommended list of performance indicators from routinely collected data that measure most aspects of the patient journey through the emergency department (ED). Methods: Data from a large tertiary ED were used to investigate the proposed performance indicators, which fell into 7 categories: background information, time from arrival to triage, time from triage to treatment, length of stay, readmission rate, left without being seen, and deaths in the ED. Main Results: Category 1 patients were triaged, treated, and discharged rapidly. For category 2 patients, the times from arrival to triage increased but times from triage to treatment were relatively stable. Patients in categories 3 and 4 were not triaged rapidly and both the arrival to triage and triage to treatment processes were unstable and deteriorating. The average time to treatment for patients treated outside recommended times was unstable and increasing for categories 2, 3, and 4. The number of patients who left without being seen was stable except for 2 periods, and the readmission rate was stable except for 1 period of increase. Conclusion: The performance indicators use only routinely collected data and clearly identify the areas in which this ED performed poorly

The utility of item level fidelity scores for developing evidence based practices in supported employment

BACKGROUND: Fidelity scales are an important way to control the quality of implementation of psychosocial interventions such as supported employment programs. However, little is known about the utility of item level scores for informing the implementation of supported employment programs. OBJECTIVE: To explore the utility of item level scores from the IPS-25 fidelity scale for developing evidence based practices in supported employment for people with severe mental illnesses in Sussex, United Kingdom (UK). METHODS: Fidelity was assessed in 18 sites representing 34 independent cohorts where IPS was implemented by one organisation. Item-level fidelity scores were examined descriptively. Nine item level correlations were selected a-priori and examined with respect to two employment milestones and program attrition. RESULTS: Mean total fidelity score was associated with commencing competitive employment (r = 0.36, p = 0.04). None of the three items selected as likely to be related to either commencing employment or to employment duration, were correlated as expected. Of the three items selected as likely to influence attrition, only one 'Rapid commencement of job searching' was correlated as expected (r = 0.38, p = 0.02). CONCLUSIONS: Individual fidelity score items appear useful for improving supported employment programs, in terms of item response characteristics and expected correlations with particular program outcomes

Opera Workshop Dido & Aeneas April 9, 2017

Concert ProgramConcert Program for Opera Workshop Dido & Aeneas April 9, 201

Claudin-8 expression in Sertoli cells and putative spermatogonial stem cells in the bovine testis

Adhesion molecules are expressed by both adult and embryonic stem cells, with different classes of adhesion molecules involved in cell-membrane and intercellular contacts. In this study the expression of the adhesion molecule claudin-8 (CLDN8), a tight-junction protein, was investigated as a potential marker for undifferentiated spermatogonia in the bovine testis. We found that CLDN8 was expressed by both spermatogonia and a subset of Sertoli cells in the bovine testis. We also showed co-expression of GFRα1 in testis cells with CLDN8 and with 'Dolichos biflorus' agglutinin-fluorescein isothiocyanate (DBA-FITC) staining. We observed co-enrichment of spermatogonia and CLDN8-expressing Sertoli cells in DBA-FITC-assisted magnetic-activated cell sorting (MACS), an observation supported by results from fluorescence-activated cell sorting analysis, which showed CLDN8-expressing cells were over-represented in the MACS-positive cell fraction, leading to the hypothesis that CLDN8 may play a role in the spermatogonial stem-cell niche