Reducing Delirium and Functional Decline in Hospitalized Older Adults: Pre-Implementation of CoCare HELP

Background: Delirium is a change in consciousness characterized by rapid onset and fluctuating attention, causing impairment in the ability to process and recall information, occurring in 30% of hospitalized older adults. Delirium can increase falls, length-of-stay, mortality, and cost. The CoCare Hospital Elder Life Program® (HELP) is an evidence-based bundle of interventions targeting cognitive impairment, sleep deprivation, immobility, visual/hearing impairment, and dehydration, embedding geriatric principles in care to prevent delirium. Objectives: To further analyze the pre-implementation of the HELP in order to optimize success of program administration. Methods: Mixed methods were used to collect retrospective/prospective data (interviews (N=25], surveys [N=25], chart audits [N=500]) for an organization assessment from CoCare experts, the hospital, clinicians, and patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guided a systematic review on implementation strategies. Results: A high rate of falls (0.89/1000-days), length-of-stay (6.1 days), readmission rate (12.6%), restraint use (19197 hours), BEERs drugs prescribed (15.4%) and delirium (30.2%) were found. The review identified 10 strategies to guide implementation of HELP: engaging stakeholders/champions, educating staff/patients, clinical team creation/use, facilitation, auditing and feedback, examining satisfaction, and public relations. Products completed included: A University undergraduate course, Registered Nurse education, an Implementation Toolkit, clinician competency checklists, system budgeting plan, system sustainability plan, project analysis plan, recruitment fliers and Epic documentation format. Conclusions: Use of HELP can prevent delirium. The identification of a high rate of delirium was confirmed in the hospital. The products developed will enable the hospital to implement HELP over the next year. Implications: Delirium is prevalent among the population of interest and is associated with significant risks; however, pre-implementation of the HELP will promote a successful program launch to reduce delirium in the elderly

Sequential influence diagrams: A unified asymmetry framework

We describe a new graphical language for specifying asymmetric decision problems. The language is based on a filtered merge of several existing languages including sequential valuation networks, asymmetric influence diagrams, and unconstrained influence diagrams. Asymmetry is encoded using a structure resembling a clustered decision tree, whereas the representation of the uncertainty model is based on the (unconstrained) influence diagram framework. We illustrate the proposed language by modeling several highly asymmetric decision problems, and we describe an efficient solution procedure

ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma

Recently we identified that PREX1 overexpression is critical for metastatic but not tumorigenic growth in a mouse model of NRAS-driven melanoma. In addition, a PREX1 gene signature correlated with and was dependent on ERK mitogen-activated protein kinase (MAPK) activation in human melanoma cell lines. In the current study, the underlying mechanism of PREX1 overexpression in human melanoma was assessed. PREX1 protein levels were increased in melanoma tumor tissues and cell lines compared with benign nevi and normal melanocytes, respectively. Suppression of PREX1 by siRNA impaired invasion but not proliferation in vitro. PREX1-dependent invasion was attributable to PREX1-mediated activation of the small GTPase RAC1 but not the related small GTPase CDC42. Pharmacologic inhibition of ERK signaling reduced PREX1 gene transcription and additionally regulated PREX1 protein stability. This ERK-dependent upregulation of PREX1 in melanoma, due to both increased gene transcription and protein stability, contrasts with the mechanisms identified in breast and prostate cancers, where PREX1 overexpression was driven by gene amplification and HDAC-mediated gene transcription, respectively. Thus, although PREX1 expression is aberrantly upregulated and regulates RAC1 activity and invasion in these three different tumor types, the mechanisms of its upregulation are distinct and context-dependent

Sequential Influence Diagrams: A Unified Asymmetry Framework

We describe a new graphical language for specifying asymmetric decision problems. The language is based on a filtered merge of several existing languages including sequential valuation networks, asymmetric influence diagrams, and unconstrained influence diagrams. Asymmetry is encoded using a structure resembling a clustered decision tree, whereas the representation of the uncertainty model is based on the (unconstrained) influence diagram framework. We illustrate the proposed language by modeling several highly asymmetric decision problems, and we outline an efficient solution procedure

Using Markov chain Monte Carlo methods for estimating parameters with gravitational radiation data

We present a Bayesian approach to the problem of determining parameters for coalescing binary systems observed with laser interferometric detectors. By applying a Markov Chain Monte Carlo (MCMC) algorithm, specifically the Gibbs sampler, we demonstrate the potential that MCMC techniques may hold for the computation of posterior distributions of parameters of the binary system that created the gravity radiation signal. We describe the use of the Gibbs sampler method, and present examples whereby signals are detected and analyzed from within noisy data.Comment: 21 pages, 10 figure

Spatially Resolving a Starburst Galaxy at Hard X-ray Energies: NuSTAR, Chandra, AND VLBA Observations of NGC 253

Prior to the launch of NuSTAR, it was not feasible to spatially resolve the hard (E > 10 keV) emission from galaxies beyond the Local Group. The combined NuSTAR dataset, comprised of three ~165 ks observations, allows spatial characterization of the hard X-ray emission in the galaxy NGC 253 for the first time. As a follow up to our initial study of its nuclear region, we present the first results concerning the full galaxy from simultaneous NuSTAR, Chandra, and VLBA monitoring of the local starburst galaxy NGC 253. Above ~10 keV, nearly all the emission is concentrated within 100" of the galactic center, produced almost exclusively by three nuclear sources, an off-nuclear ultraluminous X-ray source (ULX), and a pulsar candidate that we identify for the first time in these observations. We detect 21 distinct sources in energy bands up to 25 keV, mostly consisting of intermediate state black hole X-ray binaries. The global X-ray emission of the galaxy - dominated by the off-nuclear ULX and nuclear sources, which are also likely ULXs - falls steeply (photon index >~ 3) above 10 keV, consistent with other NuSTAR-observed ULXs, and no significant excess above the background is detected at E > 40 keV. We report upper limits on diffuse inverse Compton emission for a range of spatial models. For the most extended morphologies considered, these hard X-ray constraints disfavor a dominant inverse Compton component to explain the {\gamma}-ray emission detected with Fermi and H.E.S.S. If NGC 253 is typical of starburst galaxies at higher redshift, their contribution to the E > 10 keV cosmic X-ray background is < 1%.Comment: 20 pages, 14 figures, accepted for publication in Ap

Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2

BACKGROUND: Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer’s disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer’s disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer’s disease, we tested whether loss of one functional trem2 allele would affect Aβ plaque deposition or the microglial response to Aβ pathology in APPPS1-21 mice. RESULTS: There was no significant difference in Aβ deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2(+/−) vs. TREM2(+/+) mice. CONCLUSIONS: Loss of a single copy of trem2 had no effect on Aβ pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aβ deposition but that a 50% decrease inTREM2 expression does not affect Aβ plaque burden