Development and validation of the ACE tool: Assessing medical trainees' competency in evidence based medicine

BACKGROUND: While a variety of instruments have been developed to assess knowledge and skills in evidence based medicine (EBM), few assess all aspects of EBM - including knowledge, skills attitudes and behaviour - or have been psychometrically evaluated. The aim of this study was to develop and validate an instrument that evaluates medical trainees’ competency in EBM across knowledge, skills and attitude. METHODS: The ‘Assessing Competency in EBM’ (ACE) tool was developed by the authors, with content and face validity assessed by expert opinion. A cross-sectional sample of 342 medical trainees representing ‘novice’, ‘intermediate’ and ‘advanced’ EBM trainees were recruited to complete the ACE tool. Construct validity, item difficulty, internal reliability and item discrimination were analysed. RESULTS: We recruited 98 EBM-novice, 108 EBM-intermediate and 136 EBM-advanced participants. A statistically significant difference in the total ACE score was observed and corresponded to the level of training: on a 0-15-point test, the mean ACE scores were 8.6 for EBM-novice; 9.5 for EBM-intermediate; and 10.4 for EBM-advanced (p < 0.0001). Individual item discrimination was excellent (Item Discrimination Index ranging from 0.37 to 0.84), with internal reliability consistent across all but three items (Item Total Correlations were all positive ranging from 0.14 to 0.20). CONCLUSION: The 15-item ACE tool is a reliable and valid instrument to assess medical trainees’ competency in EBM. The ACE tool provides a novel assessment that measures user performance across the four main steps of EBM. To provide a complete suite of instruments to assess EBM competency across various patient scenarios, future refinement of the ACE instrument should include further scenarios across harm, diagnosis and prognosis

MicroRNAs 1, 133, and 206: Critical factors of skeletal and cardiac muscle development, function, and disease

microRNAs (miRNAs) are a class of highly conserved small non-coding RNAs that negatively regulate gene expression post-transcriptionally. miRNAs are known to mediate myriad cell processes, including proliferation, differentiation, and apoptosis. With more than 600 miRNAs identified in humans, it is generally believed that many miRNAs function through simultaneously inhibiting multiple regulatory mRNA targets, suggesting that miRNAs participate in regulating the expression of many, if not all, genes. While many miRNAs are expressed ubiquitously, some are expressed in a tissue specific manner. The muscle specific miR-1, miR-133 and miR-206 are perhaps the most studied and best characterized miRNAs to date. Many studies demonstrate that these miRNAs are necessary for proper skeletal and cardiac muscle development and function, and have a profound influence on multiple myopathies, such as hypertrophy, dystrophy, and conduction defects

Evidence-based practice educational intervention studies: A systematic review of what is taught and how it is measured

Abstract Background Despite the established interest in evidence-based practice (EBP) as a core competence for clinicians, evidence for how best to teach and evaluate EBP remains weak. We sought to systematically assess coverage of the five EBP steps, review the outcome domains measured, and assess the properties of the instruments used in studies evaluating EBP educational interventions. Methods We conducted a systematic review of controlled studies (i.e. studies with a separate control group) which had investigated the effect of EBP educational interventions. We used citation analysis technique and tracked the forward and backward citations of the index articles (i.e. the systematic reviews and primary studies included in an overview of the effect of EBP teaching) using Web of Science until May 2017. We extracted information on intervention content (grouped into the five EBP steps), and the outcome domains assessed. We also searched the literature for published reliability and validity data of the EBP instruments used. Results Of 1831 records identified, 302 full-text articles were screened, and 85 included. Of these, 46 (54%) studies were randomised trials, 51 (60%) included postgraduate level participants, and 63 (75%) taught medical professionals. EBP Step 3 (critical appraisal) was the most frequently taught step (63 studies; 74%). Only 10 (12%) of the studies taught content which addressed all five EBP steps. Of the 85 studies, 52 (61%) evaluated EBP skills, 39 (46%) knowledge, 35 (41%) attitudes, 19 (22%) behaviours, 15 (18%) self-efficacy, and 7 (8%) measured reactions to EBP teaching delivery. Of the 24 instruments used in the included studies, 6 were high-quality (achieved ≥3 types of established validity evidence) and these were used in 14 (29%) of the 52 studies that measured EBP skills; 14 (41%) of the 39 studies that measured EBP knowledge; and 8 (26%) of the 35 studies that measured EBP attitude. Conclusions Most EBP educational interventions which have been evaluated in controlled studies focus on teaching only some of the EBP steps (predominantly critically appraisal of evidence) and did not use high-quality instruments to measure outcomes. Educational packages and instruments which address all EBP steps are needed to improve EBP teaching

Long-term safety and effectiveness of canakinumab therapy in patients with cryopyrin-associated periodic syndrome: results from the β-Confident Registry.

OBJECTIVE: To report the long-term safety and effectiveness of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), in a real-world setting. METHODS: From December 2009 to December 2015, the β-Confident Registry prospectively enrolled patients with CAPS and non-CAPS conditions who received canakinumab per routine care and were prospectively followed for up to 6 years. The registry protocol did not mandate specific visits or procedures; however, all observed adverse events (AEs) and serious adverse events (SAEs) had to be recorded. Canakinumab effectiveness was evaluated by Physician's Global Assessment (PGA). RESULTS: Of 288 patients enrolled, 3 were excluded due to missing informed consent. Among the remaining 285 patients, 243 (85.3%) were patients with CAPS and 42 (14.7%) had atypical CAPS (6.3%) or other conditions (8.4%). The median age was 26.6 years. Based on PGA, 58 of 123 (47.2%) patients with CAPS had no disease activity at 48 months, and 65 of 123 (52.8%) experienced mild/moderate disease activity at 48 months. Among CAPS phenotypes, AE incidence rates per 100 patient-years were lowest for FCAS (73.1; 95% CI 60.3 to 87.8) compared with those with MWS (105.0; 95% CI 97.2 to 113.2) or NOMID (104.6; 95% CI 86.6 to 125.2). One hundred twenty-eight SAEs were reported in 68 patients with CAPS (incidence rate/100 patient-years, 14.0; 95% CI 11.6 to 16.6). One death (metastatic rectal adenocarcinoma in a patient with MWS) was reported. CONCLUSIONS: The response to canakinumab was sustained for up to 6 years. Canakinumab demonstrated a favourable safety profile over long-term treatment in patients with CAPS. TRIAL REGISTRATION NUMBER: NCT01213641

Projected t-SNE for batch correction

Motivation: Low-dimensional representations of high-dimensional data are routinely employed in biomedical research to visualize, interpret and communicate results from different pipelines. In this article, we propose a novel procedure to directly estimate t-SNE embeddings that are not driven by batch effects. Without correction, interesting structure in the data can be obscured by batch effects. The proposed algorithm can therefore significantly aid visualization of high-dimensional data. Results: The proposed methods are based on linear algebra and constrained optimization, leading to efficient algorithms and fast computation in many high-dimensional settings. Results on artificial single-cell transcription profiling data show that the proposed procedure successfully removes multiple batch effects from t-SNE embeddings, while retaining fundamental information on cell types. When applied to single-cell gene expression data to investigate mouse medulloblastoma, the proposed method successfully removes batches related with mice identifiers and the date of the experiment, while preserving clusters of oligodendrocytes, astrocytes, and endothelial cells and microglia, which are expected to lie in the stroma within or adjacent to the tumours. Contact: [email protected]

The Ubiquitin Ligase ASB4 Promotes Trophoblast Differentiation through the Degradation of ID2

Vascularization of the placenta is a critical developmental process that ensures fetal viability. Although the vascular health of the placenta affects both maternal and fetal well being, relatively little is known about the early stages of placental vascular development. The ubiquitin ligase Ankyrin repeat, SOCS box-containing 4 (ASB4) promotes embryonic stem cell differentiation to vascular lineages and is highly expressed early in placental development. The transcriptional regulator Inhibitor of DNA binding 2 (ID2) negatively regulates vascular differentiation during development and is a target of many ubiquitin ligases. Due to their overlapping spatiotemporal expression pattern in the placenta and contrasting effects on vascular differentiation, we investigated whether ASB4 regulates ID2 through its ligase activity in the placenta and whether this activity mediates vascular differentiation. In mouse placentas, ASB4 expression is restricted to a subset of cells that express both stem cell and endothelial markers. Placentas that lack Asb4 display immature vascular patterning and retain expression of placental progenitor markers, including ID2 expression. Using JAR placental cells, we determined that ASB4 ubiquitinates and represses ID2 expression in a proteasome-dependent fashion. Expression of ASB4 in JAR cells and primary isolated trophoblast stem cells promotes the expression of differentiation markers. In functional endothelial co-culture assays, JAR cells ectopically expressing ASB4 increased endothelial cell turnover and stabilized endothelial tube formation, both of which are hallmarks of vascular differentiation within the placenta. Co-transfection of a degradation-resistant Id2 mutant with Asb4 inhibits both differentiation and functional responses. Lastly, deletion of Asb4 in mice induces a pathology that phenocopies human pre-eclampsia, including hypertension and proteinuria in late-stage pregnant females. These results indicate that ASB4 mediates vascular differentiation in the placenta via its degradation of ID2