Multiple mini interview (MMI) for general practice training selection in Australia: interviewers' motivation

Background: Multiple Mini Interviews (MMIs) are being used by a growing number of postgraduate training programs and medical schools as their interview process for selection entry. The Australian General Practice and Training (AGPT) used a National Assessment Centre (NAC) approach to selection into General Practice (GP) Training, which include MMIs. Interviewing is a resource intensive process, and implementation of the MMI requires a large number of interviewers, with a number of candidates being interviewed simultaneously. In 2015, 308 interviewers participated in the MMI process – a decrease from 340 interviewers in 2014, and 310 in 2013. At the same time, the number of applicants has steadily increased, with 1930 applications received in 2013; 2254 in 2014; and 2360 in 2015. This has raised concerns regarding the increasing recruitment needs, and the need to retain interviewers for subsequent years of MMIs. In order to investigate interviewers’ reasons for participating in MMIs, we utilised self-determination theory (SDT) to consider interviewers’ motivation to take part in MMIs at national selection centres. Methods: In 2015, 308 interviewers were recruited from 17 Regional Training Providers (RTPs) to participate in the MMI process at one of 15 NACs. For this study, a convenience sample of NAC sites was used. Forty interviewers were interviewed (n = 40; 40/308 = 13%) from five NACs. Framework analysis was used to code and categorise data into themes. Results: Interviewers’ motivation to take part as interviewers were largely related to their sense of duty, their desire to contribute their expertise to the process, and their desire to have input into selection of GP Registrars; a sense of duty to their profession; and an opportunity to meet with colleagues and future trainees. Interviewers also highlighted factors hindering motivation, which sometimes included the large number of candidates seen in one day. Conclusion: Interviewers’ motivation for contributing to the MMIs was largely related to their desire to contribute to their profession, and ultimately improve future patient care. Interviewers recognised the importance of interviewing, and felt their individual roles made a crucial contribution to the profession of general practice. Good administration and leadership at each NAC is needed. By gaining an understanding of interviewers’ motivation, and enhancing this, engagement and retention of interviewers may be increased

Asbestos modulates thioredoxin-thioredoxin interacting protein interaction to regulate inflammasome activation

BACKGROUND: Asbestos exposure is related to various diseases including asbestosis and malignant mesothelioma (MM). Among the pathogenic mechanisms proposed by which asbestos can cause diseases involving epithelial and mesothelial cells, the most widely accepted one is the generation of reactive oxygen species and/or depletion of antioxidants like glutathione. It has also been demonstrated that asbestos can induce inflammation, perhaps due to activation of inflammasomes. METHODS: The oxidation state of thioredoxin was analyzed by redox Western blot analysis and ROS generation was assessed spectrophotometrically as a read-out of solubilized formazan produced by the reduction of nitrotetrazolium blue (NTB) by superoxide. Quantitative real time PCR was used to assess changes in gene transcription. RESULTS: Here we demonstrate that crocidolite asbestos fibers oxidize the pool of the antioxidant, Thioredoxin-1 (Trx1), which results in release of Thioredoxin Interacting Protein (TXNIP) and subsequent activation of inflammasomes in human mesothelial cells. Exposure to crocidolite asbestos resulted in the depletion of reduced Trx1 in human peritoneal mesothelial (LP9/hTERT) cells. Pretreatment with the antioxidant dehydroascorbic acid (a reactive oxygen species (ROS) scavenger) reduced the level of crocidolite asbestos-induced Trx1 oxidation as well as the depletion of reduced Trx1. Increasing Trx1 expression levels using a Trx1 over-expression vector, reduced the extent of Trx1 oxidation and generation of ROS by crocidolite asbestos, and increased cell survival. In addition, knockdown of TXNIP expression by siRNA attenuated crocidolite asbestos-induced activation of the inflammasome. CONCLUSION: Our novel findings suggest that extensive Trx1 oxidation and TXNIP dissociation may be one of the mechanisms by which crocidolite asbestos activates the inflammasome and helps in development of MM

Cell signaling pathways elicited by asbestos.

In recent years, it has become apparent that minerals can trigger alterations in gene expression by initiating signaling events upstream of gene transactivation. These cascades may be initiated at the cell surface after interaction of minerals with the plasma membrane either through receptorlike mechanisms or integrins. Alternatively, signaling pathways may be stimulated by active oxygen species generated both during phagocytosis of minerals and by redox reactions on the mineral surface. At least two signaling cascades linked to activation of transcription factors, i.e., DNA-binding proteins involved in modulating gene expression and DNA replication, are stimulated after exposure of lung cells to asbestos fibers in vitro. These include nuclear factor kappa B (NF kappa B) and the mitogen-activated protein kinase (MAPK) cascade important in regulation of the transcription factor, activator protein-1 (AP-1). Both NF kappa B and AP-1 bind to specific DNA sequences within the regulatory or promoter regions of genes that are critical to cell proliferation and inflammation. Unraveling the cell signaling cascades initiated by mineral dusts and pharmacologic inhibition of these events may be important for the control and treatment of mineral-associated occupational diseases

LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA.

The DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda-5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low