A Method for Reviewing the Accuracy and Reliability of a Five-Level Triage Process (Canadian Triage and Acuity Scale) in a Community Emergency Department Setting: Building the Crowding Measurement Infrastructure

Objectives. Triage data are widely used to evaluate patient flow, disease severity, and emergency department (ED) workload, factors used in ED crowding evaluation and management. We defined an indicator-based methodology that can be easily used to review the accuracy of Canadian Triage and Acuity Scale (CTAS) performance. Methods. A trained nurse reviewer (NR) retrospectively triaged two separate month's ED charts relative to a set of clinical indicators based on CTAS Chief Complaints. Interobserver reliability and accuracy were compared using Kappa and comparative statistics. Results. There were 2838 patients in Trial 1 and 3091 in Trial 2. The rate of inconsistent triage was 14% and 16% (Kappa 0.596 and 0.604). Clinical Indicators “pain scale, chest pain, musculoskeletal injury, respiratory illness, and headache” captured 68% and 62% of visits. Conclusions. We have demonstrated a system to measure the levels of process accuracy and reliability for triage over time. We identified five key clinical indicators which captured over 60% of visits. A simple method for quality review uses a small set of indicators, capturing a majority of cases. Performance consistency and data collection using indicators may be important areas to direct training efforts

Reducing Unknown Risk:The Safety Engineers’ New Horizon

A significant gap exists between accident scenarios as foreseen by company safety management systems and actual scenarios observed in major accidents. The mere fact that this gap exists is pointing at flawed risk assessments, is leaving hazards unmitigated, threatening worker safety, putting the environment at risk and endangering company continuity. This scoping review gathers perspectives reported in scientific literature about how to address these problems. Safety managers and regulators, attempting to reduce and eventually close this gap, not only encounter the pitfalls of poor safety studies, but also the acceptance of ‘unknown risk’ as a phenomenon, companies being numbed by inadequate process safety indicators, unsettled debates between paradigms on improving process safety, and inflexible recording systems in a dynamic industrial environment. The immediacy of the stagnating long term downward major accident rate trend in the Netherlands underlines the need to address these pitfalls. A method to identify and systematically reduce unknown risks is proposed. The main conclusion is that safety management can never be ready with hazard identification and risk assessment.</p

Application of a Biphasic Mathematical Model of Cancer Cell Drug Response for Formulating Potent and Synergistic Targeted Drug Combinations to Triple Negative Breast Cancer Cells

Triple negative breast cancer is a collection of heterogeneous breast cancers that are immunohistochemically negative for estrogen receptor, progesterone receptor, and ErbB2 (due to deletion or lack of amplification). No dominant proliferative driver has been identified for this type of cancer, and effective targeted therapy is lacking. In this study, we hypothesized that triple negative breast cancer cells are multi-driver cancer cells, and evaluated a biphasic mathematical model for identifying potent and synergistic drug combinations for multi-driver cancer cells. The responses of two triple negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468, to a panel of targeted therapy drugs were determined over a broad range of concentrations. The analyses of the drug responses by the biphasic mathematical model revealed that both cell lines were indeed dependent on multiple drivers, and inhibitors of individual drivers caused a biphasic response: a target-specific partial inhibition at low nM concentrations, and an off-target toxicity at μM concentrations. We further demonstrated that combinations of drugs, targeting each driver, cause potent, synergistic, and cell-specific cell killing. Immunoblotting analysis of the effects of the individual drugs and drug combinations on the signaling pathways supports the above conclusion. These results support a multi-driver proliferation hypothesis for these triple negative breast cancer cells, and demonstrate the applicability of the biphasic mathematical model for identifying effective and synergistic targeted drug combinations for triple negative breast cancer cells

Non-epileptic attack disorder: the importance of diagnosis and treatment

A 50-year-old woman was taken to hospital by emergency ambulance during her first seizure. She was admitted to hospital, treated with intravenous diazepam, diagnosed with epilepsy and started on antiepileptic drug (AED) therapy. This was ineffective so she was referred to a tertiary centre where she underwent video EEG and was diagnosed with non-epileptic attack disorder. Her experience of the diagnosis was positive; it allowed her to understand what was happening to her and to understand the link between her seizures, adverse childhood experiences and the death of her mother. She stopped taking AEDs and she was referred to a psychologist which led to a significant improvement in her functioning and quality of life. We present this case as a good example of the benefits of accurate diagnosis, clear explanation and access to specialist car

The Simple Chordate \u3cem\u3eCiona intestinalis\u3c/em\u3e Has a Reduced Complement of Genes Associated with Fanconi Anemia

Fanconi anemia (FA) is a human genetic disease characterized by congenital defects, bone marrow failure, and increased cancer risk. FA is associated with mutation in one of 24 genes. The protein products of these genes function cooperatively in the FA pathway to orchestrate the repair of DNA interstrand cross-links. Few model organisms exist for the study of FA. Seeking a model organism with a simpler version of the FA pathway, we searched the genome of the simple chordate Ciona intestinalis for homologs of the human FA-associated proteins. BLAST searches, sequence alignments, hydropathy comparisons, maximum likelihood phylogenetic analysis, and structural modeling were used to infer the likelihood of homology between C. intestinalis and human FA proteins. Our analysis indicates that C. intestinalis indeed has a simpler and potentially functional FA pathway. The C. intestinalis genome was searched for candidates for homology to 24 human FA and FA-associated proteins. Support was found for the existence of homologs for 13 of these 24 human genes in C. intestinalis. Members of each of the three commonly recognized FA gene functional groups were found. In group I, we identified homologs of FANCE, FANCL, FANCM, and UBE2T/FANCT. Both members of group II, FANCD2 and FANCI, have homologs in C. intestinalis. In group III, we found evidence for homologs of FANCJ, FANCO, FANCQ/ERCC4, FANCR/RAD51, and FANCS/BRCA1, as well as the FA-associated proteins ERCC1 and FAN1. Evidence was very weak for the existence of homologs in C. intestinalis for any other recognized FA genes. This work supports the notion that C. intestinalis, as a close relative of vertebrates, but having a much reduced complement of FA genes, offers a means of studying the function of certain FA proteins in a simpler pathway than that of vertebrate cells

Development of a knowledge-based and collaborative engineering design agent

In order to avoid errors in engineering design that affect the later product life cycle, especially the manufacturing process, an analysis or evaluation has to be performed at the earliest possible stage. As this evaluation is very knowledge-intensive and often this knowledge is not directly available to the engineer, this paper presents an approach for a knowledge-based and collaborative engineering design agent. The technology based on multi-agent systems enables problem-solving support by an autonomous knowledge-based system which has its own beliefs, goals, and intentions. The presented approach is embedded in a CAD development environment and validated on an application example from engineering design

Unfolded protein response is activated in Lewy body dementias

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Proteomic responses to elevated ocean temperature in ovaries of the ascidian \u3cem\u3eCiona intestinalis\u3c/em\u3e

Ciona intestinalis, a common sea squirt, exhibits lower reproductive success at the upper extreme of the water temperatures it experiences in coastal New England. In order to understand the changes in protein expression associated with elevated temperatures, and possible response to global temperature change, we reared C. intestinalis from embryos to adults at 18°C (a temperature at which they reproduce normally at our collection site in Rhode Island) and 22°C (the upper end of the local temperature range). We then dissected ovaries from animals at each temperature, extracted protein, and measured proteomic levels using shotgun mass spectrometry (LC-MS/MS). 1532 proteins were detected at a 1% false discovery rate present in both temperature groups by our LC-MS/MS method. 62 of those proteins are considered up- or down-regulated according to our statistical criteria. Principal component analysis shows a clear distinction in protein expression pattern between the control (18°C) group and high temperature (22°C) group. Similar to previous studies, cytoskeletal and chaperone proteins are upregulated in the high temperature group. Unexpectedly, we find evidence that proteolysis is downregulated at the higher temperature. We propose a working model for the high temperature response in C. intestinalis ovaries whereby increased temperature induces upregulation of signal transduction pathways involving PTPN11 and CrkL, and activating coordinated changes in the proteome especially in large lipid transport proteins, cellular stress responses, cytoskeleton, and downregulation of energy metabolism

TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma.

BACKGROUND: Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs). METHODS: Five unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance. RESULTS: Prolonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20-35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib. CONCLUSIONS: We have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients