Delivering Trauma Mastery with an International Trauma Masters

This is a file of an unedited manuscript that has been accepted for publication.As a service to our customers we are providing this early version of the manuscript.The manuscript will undergo copy editing, typesetting, and review of the resulting proof before it is published in its final formINTRODUCTION Trauma is a global problem. The goal of optimising multidisciplinary trauma care through speciality education is a challenge. No single pathway exists to educate care providers in trauma knowledge, management and skills. Queen Mary University of London (QMUL) devised an online electronic learning (e-learning) Master’s degree (MSc) in Trauma Sciences in 2011. E-learning is increasingly popular however low progression rates question effectiveness. The further post-graduate impact is unknown. Our goal was to establish whether this program is a successful method of delivering multidisciplinary trauma education to an international community. We hypothesized that graduating students make a global impact in trauma care, education and research. METHODS The Trauma Sciences MSc programs launched in 2011. Electronic surveys were distributed worldwide to students who successfully completed the program between 2013 to 2016. Graduation rates, degree/qualification awarded, clinical involvement in trauma management, presentation of MSc work, academic progression and roles in trauma education were explored. Supporting demographics were extracted from the QMUL student database. RESULTS A total of 176 students, of 29 nationalities, enrolled in the two year course between 2011 and 2014. Clinical backgrounds included multi-speciality physicians (83.5%), nurses (9.6%) and paramedics (6.8%). 119 (67.6%) graduated within the study period, 108 (60.8%) with the full masters award. Completion was independent of clinical background (p = 0.20) and age (p = 0.99). Highest completion rates were seen in students from Australia and New Zealand, Asia and Europe (p = 0.03). All survey responders were currently providing regular clinical care to trauma patients. 73% (n = 36) were delivering trauma education, many at national or international level. 49% (n = 24) had presented work from the MSc and 23% (n = 11) published their dissertation.12% (n = 6) subsequently enrolled in a PhD program. CONCLUSION Compared with other e-learning courses this Masters program has an enviable completion rate. Graduates go on to make an international multidisciplinary impact with diverse roles in clinical management, research and trauma education. This programme provides a robust trauma education curriculum. The QMUL Trauma Sciences MSc program is an excellent resource for clinicians participating in any form of trauma care or who wish to augment sub-speciality training in trauma

A System for Scoring Proverb Interpretations Provided by Non-Brain-Damaged and Aphasic Adults

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Sox9 Inhibits -Trcp-Mediated Protein Degradation To Promote Nuclear Gli1 Expression And Cancer Stem Cell Properties

The high mobility group box protein SOX9 and the GLI1 transcription factor play protumorigenic roles in pancreatic ductal adenocarcinoma (PDA). In Kras transgenic mice, each of these factors are crucial for the development of PDA precursor lesions. SOX9 transcription is directly regulated by GLI1, but how SOX9 functions downstream of GLI1 is unclear. We observed positive feedback, such that SOX9-deficient PDA cells have severely repressed levels of endogenous GLI1, attributed to loss of GLI1 protein stability. SOX9 associated with the F-box domain of the SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase component, β-TrCP (also known as F-box/WD repeat-containing protein 1A), and suppressed its association with SKP1 and GLI1, a substrate of SCF-β-TrCP. SOX9 also tethered β-TrCP within the nucleus and promoted its degradation. SOX9 bound to β-TrCP through the SOX9 C-terminal PQA/S domain that mediates transcriptional activation. Suppression of β-TrCP in SOX9-deficient PDA cells restored GLI1 levels and promoted SOX9-dependent cancer stem cell properties. These studies identify SOX9–GLI1 positive feedback as a major determinant of GLI1 protein stability and implicate β-TrCP as a latent SOX9-bound tumor suppressor with the potential to degrade oncogenic proteins in tumor cells

Model-based lamotrigine clearance changes during pregnancy: clinical implication

Objective: The objective of the study was to characterize changes in the oral clearance (CL/F) of lamotrigine (LTG) over the course of pregnancy and the postpartum period through a model-based approach incorporating clinical characteristics that may influence CL/F, in support of developing clinical management guidelines. Methods: Women receiving LTG therapy who were pregnant or planning pregnancy were enrolled. Maternal blood samples were collected at each visit. A pharmacokinetic analysis was performed using a population-based, nonlinear, mixed-effects model. Results: A total of 600 LTG concentrations from 60 women (64 pregnancies) were included. The baseline LTG CL/F was 2.16 L/h with a between-subject variability of 40.6%. The influence of pregnancy on CL/F was described by gestational week. Two subpopulations of women emerged based on the rate of increase in LTG CL/F during pregnancy. The gestational age-associated increase in CL/F displayed a 10-fold higher rate in 77% of the women (0.118 L/h per week) compared to 23% (0.0115 L/h per week). The between-subject variability in these slopes was 43.0%. The increased CL/F at delivery declined to baseline values with a half-life of 0.55 weeks. Interpretation The majority of women had a substantial increase in CL/F from 2.16 to 6.88 L/h by the end of pregnancy, whereas 23% of women had a minimal increase. An increase in CL/F may correspond to decreases in LTG blood concentrations necessitating the need for more frequent dosage adjustments and closer monitoring in some pregnant women with epilepsy. Postpartum doses should be tapered to preconception dose ranges within 3 weeks of delivery

Mobility of the SecA 2-helix-finger is not essential for polypeptide translocation via the SecYEG complex

The bacterial ATPase SecA and protein channel complex SecYEG form the core of an essential protein translocation machinery. The nature of the conformational changes induced by each stage of the hydrolytic cycle of ATP and how they are coupled to protein translocation are not well understood. The structure of the SecA–SecYEG complex revealed a 2-helix-finger (2HF) of SecA in an ideal position to contact the substrate protein and push it through the membrane. Surprisingly, immobilization of this finger at the edge of the protein channel had no effect on translocation, whereas its imposition inside the channel blocked transport. This analysis resolves the stoichiometry of the active complex, demonstrating that after the initiation process translocation requires only one copy each of SecA and SecYEG. The results also have important implications on the mechanism of energy transduction and the power stroke driving transport. Evidently, the 2HF is not a highly mobile transducing element of polypeptide translocation

Exercise Blocks Ethanol-Induced Kappa Opioid Receptor Sensitization in Nucleus Accumbens and Ventral Tegmental Area

Exercise has been increasingly used as an adjunctive therapy in the treatment of alcohol use disorder (AUD). Despite this, the mechanism by which it influences the mesolimbic circuitry changes underlying alcohol addiction is not well understood. Previous studies have shown alcohol dependence to lead to upregulation of the Dynorphin-Kappa Opioid Receptor (KOR) system, making it a potential target for therapeutics. Thus, gaining a better understanding of these pathways will help develop evidence-based guidelines for integrating exercise into therapies for the treatment of AUD