A single-sample microarray normalization method to facilitate personalized-medicine workflows

AbstractGene-expression microarrays allow researchers to characterize biological phenomena in a high-throughput fashion but are subject to technological biases and inevitable variabilities that arise during sample collection and processing. Normalization techniques aim to correct such biases. Most existing methods require multiple samples to be processed in aggregate; consequently, each sample's output is influenced by other samples processed jointly. However, in personalized-medicine workflows, samples may arrive serially, so renormalizing all samples upon each new arrival would be impractical. We have developed Single Channel Array Normalization (SCAN), a single-sample technique that models the effects of probe-nucleotide composition on fluorescence intensity and corrects for such effects, dramatically increasing the signal-to-noise ratio within individual samples while decreasing variation across samples. In various benchmark comparisons, we show that SCAN performs as well as or better than competing methods yet has no dependence on external reference samples and can be applied to any single-channel microarray platform

Near-Peer Teaching in Radiology Symposia: A Success Story in Residents as Teachers

INTRODUCTION Peer learning and near-peer teaching have been described in many specialties, less so in Radiology. We present near-peer teaching whereby residents present a series of didactic sessions at the course outset in the form of “symposia” and perform a scholarly activity in the form of teaching. We aim to demonstrate how near-peer teaching in symposia front-loaded within an introductory radiology course can improve medical student satisfaction. METHOD A total of 169 students were enrolled over a period of 3 years, 55 before (2017-2018) and 114 (2018-2020) after the introduction of the symposium. Anonymous course evaluations were collected from all students. In addition, 240 fourth-year medical students who also attended symposium lectures received satisfaction surveys in 2019 and 2020. RESULTS All (169/169, 100%) students taking the course evaluated it. Overall evaluation scores rose from 8.3/10 to 9.0/10 post-symposia. Among student satisfaction surveys, 89/240 (37%) specifically commented on symposia; 91% (80/89) of those found symposia very or extremely informative. 29/71 (41%) of all residents were able to participate in the symposia, 20/29 in multiple years throughout residency, allowing them to fulfill the Accreditation Council for Graduate Medical Education interpersonal and communication skills core competencies and meet scholarly activity requirements. CONCLUSION Near-peer teaching in the form of resident-taught interactive didactics grouped in symposia can have a positive outcome on medical student satisfaction

The M33 Metallicity Project: Resolving the Abundance Gradient Discrepancies in M33

We present a new determination of the metallicity gradient in M33, based on Keck/LRIS measurements of oxygen abundances using the temperature-sensitive emission line [OIII] 4363 A in 61 HII regions. These data approximately triple the sample of direct oxygen abundances in M33. We find a central abundance of 12 + log(O/H) = 8.36+/-0.04 and a slope of -0.027+/-0.012 dex/kpc, in agreement with infrared measurements of the neon abundance gradient but much shallower than most previous oxygen gradient measurements. There is substantial intrinsic scatter of 0.11 dex in the metallicity at any given radius in M33, which imposes a fundamental limit on the accuracy of gradient measurements that rely on small samples of objects. We also show that the ionization state of neon does not follow the ionization state of oxygen as is commonly assumed, suggesting that neon abundance measurements from optical emission lines require careful treatment of the ionization corrections.Comment: 10 pages, Accepted to Ap

Interactive single cell RNA-Seq analysis with Single Cell Toolkit (SCTK)

I will present the Single Cell Toolkit (SCTK), an R package and interactive single cell RNA-sequencing (scRNA-Seq) analysis package that provides the first complete workflow for scRNA-Seq data analysis and visualization using a set of R functions and an interactive web interface. Users can perform analysis with modules for filtering raw results, clustering, batch correction, differential expression, pathway enrichment, and scRNA-Seq study design. The toolkit supports command line or pipeline data processing, and results can be loaded into the GUI for additional exploration and downstream analysis. We demonstrate the effectiveness of the SCTK on multiple scRNA-seq examples, including data from mucosal-associated invariant T cells, induced pluripotent stem cells, and breast cancer tumor cells. While other scRNA-Seq analysis tools exist, the SCTK is the first fully interactive analysis toolkit for scRNA-Seq data available within the R language.NIH U01CA22041

Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.

Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer

Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium

Importance: There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC). Objective: To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes. Design, Setting, and Participants: This multicenter, prospective, case-control study was conducted by the National Collegiate Athletic Association (NCAA) and the US Department of Defense Concussion Assessment, Research, and Education (CARE) Consortium from February 20, 2015, to May 31, 2018, at 6 CARE Advanced Research Core sites. A total of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport control athletes completed clinical testing and blood collection at preseason baseline, the acute postinjury period, 24 to 48 hours after injury, the point of reporting being asymptomatic, and 7 days after return to play. Data analysis was conducted from March 1 to November 30, 2019. Main Outcomes and Measures: Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain, and tau were quantified using the Quanterix Simoa multiplex assay. Clinical outcome measures included the Sport Concussion Assessment Tool-Third Edition (SCAT-3) symptom evaluation, Standardized Assessment of Concussion, Balance Error Scoring System, and Brief Symptom Inventory 18. Results: A total of 264 athletes with concussion (mean [SD] age, 19.08 [1.24] years; 211 [79.9%] male), 138 contact sport controls (mean [SD] age, 19.03 [1.27] years; 107 [77.5%] male), and 102 non-contact sport controls (mean [SD] age, 19.39 [1.25] years; 82 [80.4%] male) were included in the study. Athletes with concussion had significant elevation in GFAP (mean difference, 0.430 pg/mL; 95% CI, 0.339-0.521 pg/mL; P < .001), UCH-L1 (mean difference, 0.449 pg/mL; 95% CI, 0.167-0.732 pg/mL; P < .001), and tau levels (mean difference, 0.221 pg/mL; 95% CI, 0.046-0.396 pg/mL; P = .004) at the acute postinjury time point compared with preseason baseline. Longitudinally, a significant interaction (group × visit) was found for GFAP (F7,1507.36 = 16.18, P < .001), UCH-L1 (F7,1153.09 = 5.71, P < .001), and tau (F7,1480.55 = 6.81, P < .001); the interaction for neurofilament light chain was not significant (F7,1506.90 = 1.33, P = .23). The area under the curve for the combination of GFAP and UCH-L1 in differentiating athletes with concussion from contact sport controls at the acute postinjury period was 0.71 (95% CI, 0.64-0.78; P < .001); the acute postinjury area under the curve for all 4 biomarkers combined was 0.72 (95% CI, 0.65-0.79; P < .001). Beyond SCAT-3 symptom score, GFAP at the acute postinjury time point was associated with the classification of athletes with concussion from contact controls (β = 12.298; 95% CI, 2.776-54.481; P = .001) and non-contact sport controls (β = 5.438; 95% CI, 1.676-17.645; P = .005). Athletes with concussion with loss of consciousness or posttraumatic amnesia had significantly higher levels of GFAP than athletes with concussion with neither loss of consciousness nor posttraumatic amnesia at the acute postinjury time point (mean difference, 0.583 pg/mL; 95% CI, 0.369-0.797 pg/mL; P < .001). Conclusions and Relevance: The results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in SRC

Формування первинного капіталу в умовах кризи управління українською промисловістю (1991–1998 рр.)

Стаття присвячена історії початкового періоду ринкової трансформації в українській промисловості. Особлива увага зосереджена на формуванні первинного приватного капіталу в Україні. Розглянуті, зокрема, основні моделі цього процесу в історичній ретроспективі.The article deals with the history of Ukrainian industry market transformation, its initial stage in particular. Special attention has been paid to the private capital accumulation in Ukraine. The main models of this process have been studied in the historical retrospection