Emergency Medicine Palliative Care Access (EMPallA): Preliminary Data from a Multi-Center Randomized Controlled Trial

Introduction: Emergency department (ED)-initiated palliative care has been shown to improve patient-centered outcomes in older adults with serious illnesses, but the optimal modality for providing such interventions is unknown. The EMPallA trial compares nurse-led, telephonic case management with specialty, outpatient palliative care on: 1) patient quality of life (QOL); 2) healthcare utilization; 3) loneliness and symptom burden; and 4) caregiver strain, QOL, and bereavement. Objective: Summarize preliminary demographic and QOL data for the EMPallA cohort. Methods: A pragmatic, parallel, two-arm randomized controlled trial is enrolling 1350 ED patients across 9 EDs over 3 years to compare the effectiveness of palliative care models. Eligible patients have end-stage heart failure, renal disease, chronic obstructive pulmonary disease (COPD), or cancer. Baseline data is collected at bedside using surveys. Functional Assessment of Cancer Therapy - General (FACT-G) QOL scores are rescaled into T-scores based on general US and cancer patient samples, standardized with mean 50 and standard deviation 10. Results: 138 patients enrolled from April 16 to October 16, 2018. Average age was 69 years; 55% were female, and 55% were white. Advanced cancer was most prevalent (48%), followed by heart failure (24%), COPD (23%), and end-stage renal disease (15%). Average FACT-G T-scores were 41 (general population) and 40 (cancer patients), which are below population means of 50 by more than 5, a clinically-meaningful difference. Discussion: This gender-balanced, racially-diverse cohort stands to benefit in QOL from palliative care. When trial enrollment and follow-up are complete, the impact of interventions can be assessed

Surface modification of HVOF thermal sprayed WC–CoCr coatings by laser treatment

In this work the affects of laser characteristics on microstructure and microhardness of high velocity oxygen fuel sprayed (HVOF) WC–CoCr coatings were investigated. The coating was deposited with a Sulzer Metco WokaJet™-400 kerosene fuel and the laser surface treatments were applied using CO2 laser with 10.6 μm wavelength. Large variations in surface properties were produced from variation in the laser processing parameters. In total, four levels of peak power (100, 200, 300 and 350 W), four levels of spot diameter (0.2, 0.4, 0.6 and 1 mm) and three levels of pulse repetition frequency (PRF) were investigated. An initial set of tests were followed by a more detailed 33 factorial design of experiments. Pulse repetition frequency and duty cycle were set in order to maintain the same overlap in the x and y directions for the raster scanned sample spot impact dimensions. Overlaps of 30% were used in the initial tests and 10% in the more detailed trials. The results have shown that care must be taken to keep the irradiance at a relatively low level compared to uncoated surfaces. High irradiance can in this case result in rough and porous surfaces. Lower levels of irradiance are shown to provide more uniform microstructures, reduced porosity and increased microhardness

Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis

Copy number variations (CNVs) have been implicated in human diseases. However, it remains unclear how they affect immune dysfunction and autoimmune diseases, including rheumatoid arthritis (RA). Here, we identified a novel leukocyte-specific protein 1 (LSP1) deletion variant for RA susceptibility located in 11p15.5. We replicated that the copy number of LSP1 gene is significantly lower in patients with RA, which correlates positively with LSP1 protein expression levels. Differentially expressed genes in Lsp1-deficient primary T cells represent cell motility and immune and cytokine responses. Functional assays demonstrated that LSP1, induced by T-cell receptor activation, negatively regulates T-cell migration by reducing ERK activation in vitro. In mice with T-cell-dependent chronic inflammation, loss of Lsp1 promotes migration of T cells into the target tissues as well as draining lymph nodes, exacerbating disease severity. Moreover, patients with RA show diminished expression of LSP1 in peripheral T cells with increased migratory capacity, suggesting that the defect in LSP1 signaling lowers the threshold for T-cell activation. To our knowledge, our work is the first to demonstrate how CNVs result in immune dysfunction and a disease phenotype. Particularly, our data highlight the importance of LSP1 CNVs and LSP1 insufficiency in the pathogenesis of RA and provide previously unidentified insights into the mechanisms underlying T-cell migration toward the inflamed synovium in RA.1187Ysciescopu

Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Coordinated optimization of visual cortical maps (II) Numerical studies

It is an attractive hypothesis that the spatial structure of visual cortical architecture can be explained by the coordinated optimization of multiple visual cortical maps representing orientation preference (OP), ocular dominance (OD), spatial frequency, or direction preference. In part (I) of this study we defined a class of analytically tractable coordinated optimization models and solved representative examples in which a spatially complex organization of the orientation preference map is induced by inter-map interactions. We found that attractor solutions near symmetry breaking threshold predict a highly ordered map layout and require a substantial OD bias for OP pinwheel stabilization. Here we examine in numerical simulations whether such models exhibit biologically more realistic spatially irregular solutions at a finite distance from threshold and when transients towards attractor states are considered. We also examine whether model behavior qualitatively changes when the spatial periodicities of the two maps are detuned and when considering more than 2 feature dimensions. Our numerical results support the view that neither minimal energy states nor intermediate transient states of our coordinated optimization models successfully explain the spatially irregular architecture of the visual cortex. We discuss several alternative scenarios and additional factors that may improve the agreement between model solutions and biological observations.Comment: 55 pages, 11 figures. arXiv admin note: substantial text overlap with arXiv:1102.335

Where the Sidewalk Ends: Jets and Missing Energy Search Strategies for the 7 TeV LHC

This work explores the potential reach of the 7 TeV LHC to new colored states in the context of simplified models and addresses the issue of which search regions are necessary to cover an extensive set of event topologies and kinematic regimes. This article demonstrates that if searches are designed to focus on specific regions of phase space, then new physics may be missed if it lies in unexpected corners. Simple multiregion search strategies can be designed to cover all of kinematic possibilities. A set of benchmark models are created that cover the qualitatively different signatures and a benchmark multiregion search strategy is presented that covers these models.Comment: 30 pages, 8 Figures, 3 Tables. Version accepted at JHEP. Minor changes. Added figur

Ratio of the Isolated Photon Cross Sections at \sqrt{s} = 630 and 1800 GeV

The inclusive cross section for production of isolated photons has been measured in \pbarp collisions at $\sqrt{s} = 630$ GeV with the \D0 detector at the Fermilab Tevatron Collider. The photons span a transverse energy ($E_T$) range from 7-49 GeV and have pseudorapidity $|\eta| < 2.5$. This measurement is combined with to previous \D0 result at $\sqrt{s} = 1800$ GeV to form a ratio of the cross sections. Comparison of next-to-leading order QCD with the measured cross section at 630 GeV and ratio of cross sections show satisfactory agreement in most of the $E_T$ range.Comment: 7 pages. Published in Phys. Rev. Lett. 87, 251805, (2001

Development of cordycepin formulations for preclinical and clinical studies

There is extensive literature on in vivo studies with cordycepin but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is a promising drug candidate in multiple therapeutic areas and there is a growing interest in studies aimed at assessing the pharmacological activity of this compound in relevant animal disease models. It is likely that many reported in vivo studies used formulations in which cordycepin was incompletely soluble. This can potentially confound the interpretation of pharmacokinetics and efficacy results. Furthermore, the presence of particles in intravenously administered suspension can cause adverse effects and should be avoided. Here we present the results from our development of simple and readily applicable formulations of cordycepin based on quantitative solubility assessment. Homogeneous solutions of cordycepin were prepared in phosphate-buffered saline (PBS) at different pH levels, suitable as formulations for both intravenously and oral administration. For the purpose of high-dose oral administration we also developed propylene glycol (PPG)-based vehicles in which cordycepin is completely soluble. The stability of the newly developed formulations was also assessed, as well the feasibility of their sterilisation by filtration. Additionally, an HPLC-UV method for the determination of cordycepin in the formulations, which may also be useful for other purposes, was developed and validated. Our study could provide useful information for improvement of future preclinical and clinical studies involving cordycepin