Death in the Emergency Department: A Retrospective Analysis of Mortality in a Swiss University Hospital.

Acute treatment in emergency medicine revolves around the management and stabilization of sick patients, followed by a transfer to the relevant medical specialist, be it outpatient or inpatient. However, when patients are too sick to be stabilized, i.e., when the care provided in the Emergency Department (ED) may not be sufficient to enable transfer, death may occur. This aspect of emergency medicine is often overlooked, and very few public data exist regarding who dies in the ED. The following retrospective analysis of the mortality figures of a Swiss university hospital from January 1st 2013 to December 31st 2016 attests to the fact that with an incidence of 2.6/1,000, death does occur in the ED. With a broad range of aetiologies, clinical severity at presentation has a high correlation with mortality, a finding that reinforces the necessity of good triage system. Our analysis goes on to show that however (in)frequent death in the ED may be, there exists a lack of advanced directives in a majority of patients (present in only 14.8% of patients during the time of study), a worrying and often challenging situation for Emergency Medicine (EM) teams faced with premorbid patients. Furthermore, a lack of such directives may hinder access to palliative care, as witnessed in part by the fact that palliative measures were only started in 16.6% of patients during the study. The authors hope this study will serve as a stepping stone to promote further research and discussion into early identification methods for patients at risk of death in the ED, as well as motivate a discussion into the integration of palliative care within the ED and EM training curriculum

A Process Mining Approach to Statistical Analysis: Application to a Real-World Advanced Melanoma Dataset

AbstractThanks to its ability to offer a time-oriented perspective on the clinical events that define the patient's path of care, Process Mining (PM) is assuming an emerging role in clinical data analytics. PM's ability to exploit time-series data and to build processes without any a priori knowledge suggests interesting synergies with the most common statistical analyses in healthcare, in particular survival analysis. In this work we demonstrate contributions of our process-oriented approach in analyzing a real-world retrospective dataset of patients treated for advanced melanoma at the Lausanne University Hospital. Addressing the clinical questions raised by our oncologists, we integrated PM in almost all the steps of a common statistical analysis. We show: (1) how PM can be leveraged to improve the quality of the data (data cleaning/pre-processing), (2) how PM can provide efficient data visualizations that support and/or suggest clinical hypotheses, also allowing to check the consistency between real and expected processes (descriptive statistics), and (3) how PM can assist in querying or re-expressing the data in terms of pre-defined reference workflows for testing survival differences among sub-cohorts (statistical inference). We exploit a rich set of PM tools for querying the event logs, inspecting the processes using statistical hypothesis testing, and performing conformance checking analyses to identify patterns in patient clinical paths and study the effects of different treatment sequences in our cohort

Child maltreatment and NR3C1 exon 1F methylation, link with deregulated hypothalamus-pituitary-adrenal axis and psychopathology: A systematic review

Background Epigenetics offers one promising method for assessing the psychobiological response to stressful experiences during childhood. In particular, deoxyribonucleic acid (DNA) methylation has been associated with an altered hypothalamus–pituitary–adrenal (HPA) axis and the onset of mental disorders. Equally, there are promising leads regarding the association between the methylation of the glucocorticoid receptor gene (NR3C1-1F) and child maltreatment and its link with HPA axis and psychopathology. Objective The current study aimed to assess the evidence of a link among child maltreatment, NR3C1-1F methylation, HPA axis deregulation, and symptoms of psychopathology. Methods We followed the Prisma guidelines and identified 11 articles that met our inclusion criteria. Results We found that eight studies (72.72%) reported increased NR3C1-1F methylation associated with child maltreatment, specifically physical abuse, emotional abuse, sexual abuse, neglect, and exposure to intimate partner violence, while three studies (27.27%) found no significant association. Furthermore, a minority of studies (36.36%) provided additional measures of symptoms of psychopathology or cortisol in order to examine the link among NR3C1-1F methylation, HPA axis deregulation, and psychopathology in a situation of child maltreatment. These results suggest that NR3C1-1F hypermethylation is positively associated with higher HPA axis activity, i.e. increased production of cortisol, as well as symptoms of psychopathology, including emotional lability-negativity, externalizing behavior symptoms, and depressive symptoms. Conclusion NR3C1-1F methylation could be one mechanism that links altered HPA axis activity with the development of psychopathology

Trametinib Induces the Stabilization of a Dual GNAQ p.Gly48Leu- and FGFR4 p.Cys172Gly-Mutated Uveal Melanoma. The Role of Molecular Modelling in Personalized Oncology.

We report a case of an uveal melanoma patient with GNAQ p.Gly48Leu who responded to MEK inhibition. At the time of the molecular analysis, the pathogenicity of the mutation was unknown. A tridimensional structural analysis showed that Gα <sub>q</sub> can adopt active and inactive conformations that lead to substantial changes, involving three important switch regions. Our molecular modelling study predicted that GNAQ p.Gly48Leu introduces new favorable interactions in its active conformation, whereas little or no impact is expected in its inactive form. This strongly suggests that GNAQ p.Gly48Leu is a possible tumor-activating driver mutation, consequently triggering the MEK pathway. In addition, we also found an FGFR4 p.Cys172Gly mutation, which was predicted by molecular modelling analysis to lead to a gain of function by impacting the Ig-like domain 2 folding, which is involved in FGF binding and increases the stability of the homodimer. Based on these analyses, the patient received the MEK inhibitor trametinib with a lasting clinical benefit. This work highlights the importance of molecular modelling for personalized oncology

Systematic comparison with autoimmune liver disease identifies specific histological features of immune checkpoint inhibitor-related adverse events.

Immune checkpoint inhibitors (ICIs) have become a mainstay of cancer treatment. Their immune-boosting quality has one major drawback, their proclivity to induce a broad array of immune-related adverse events (irAEs) affecting, among others, the liver and sharing some similarities with classic autoimmune liver diseases (AILD).We aimed to compare clinical, laboratory and histological features of patients with liver-related irAEs and AILD. We systematically compared liver irAEs with AILD, namely autoimmune hepatitis (AIH) and primary biliary cholangitis, regarding their clinical, laboratory, and histological features. Twenty-seven patients with liver irAEs (ICI group) and 14 patients with AILD were identified. We observed three distinct ICI-induced histological liver injury patterns: hepatitic (52%), cholangitic (19%), and mixed (29%). When comparing the ICI and AILD groups, centrilobular injury as well as granuloma formation were more prevalent in the former (p=0.067 and 0.002, respectively). CD4+/CD8+ T cell ratios were heterogeneous between the two groups, without statistically significant difference but with a trend toward increased CD8+ T cells among hepatitic irAEs as compared with AIH. Pattern of liver function test alteration was predictive for the type of irAEs but did not correlate with histological severity. Liver irAEs have broad clinical, laboratory and histological presentations. Histological features of irAEs and AILD are distinct, likely underpinning their different immunological mechanisms

The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles

Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Loss of CK in the arista, border cells or proneural clusters of the wing imaginal discs affects DRONC-dependent patterning. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-β to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. Similarly, the mammalian CK counterpart, MYO7A, binds to and impinges on CASPASE-8, revealing a new regulatory axis affecting receptor interacting protein kinase-1 (RIPK1)>CASPASE-8 signalling. Together, our results expose a conserved role for unconventional myosins in transducing caspase-dependent regulation of kinases, allowing them to take part in specific signalling events