Characterizing Cytokine Transport in Hemoadsorption Beads Used to Treat Sepsis

Extracorporeal blood purification is a promising therapeutic modality for sepsis, a potentially fatal, dysfunctional immune disorder caused by infection. During sepsis, dysregulation of the innate immune system leads to excessive release of inflammatory mediators known as cytokines into the bloodstream. Removal of cytokines from the circulating blood may attenuate hyper-inflammatory signaling and promote immunologic homeostasis. We are developing an extracorporeal blood purification device to remove cytokines from the blood using biocompatible, porous, polymeric beads. Hemoadsorption therapy using our device has demonstrated improved survival in a murine sepsis model, and may serve as a novel adjuvant therapy to improve patient outcomes in the setting of severe sepsis and septic shock.We developed a mathematical model to characterize cytokine adsorption dynamics within the device, and used confocal laser scanning microscopy (CLSM) to quantify cytokine transport within single sorbent beads. Finite element modeling was utilized to estimate model parameters based on best fits to CLSM data, and the fitted model was used to simulate cytokine adsorption behavior under clinically relevant conditions. We investigated intraparticle cytokine transport under competitive and non-competitive adsorption conditions, and demonstrated that effects due to coadsorption of serum solutes are likely negligible under physiologic cytokine concentrations. CLSM results indicate that less than 20% of available sorbent surface area is utilized for cytokine adsorption. Tumor necrosis factor (TNF) is a pleiotropic, pro-inflammatory cytokine, and serves as a primary initiator of systemic inflammation during sepsis. Removal of TNF within the device is slow, putatively due to hindered diffusion of the large TNF molecule (51kD) within the sorbent pores. We induced deoligomerization of trimeric TNF into its monomeric subunits, and demonstrated significantly accelerated capture of monomerized TNF within the device, compared to native TNF. We investigated small molecules capable of facilitating TNF deoligomerization, and proposed techniques to immobilize such molecules on the sorbent surface. Functionalized sorbent beads capable of locally dissociating TNF at the bead surface may significantly accelerate capture of TNF from the circulating blood. This concept could be expanded to enhance capture of oligomeric biomolecules using size exclusion filtration materials for a variety of disease states

A profile in FIRE: resolving the radial distributions of satellite galaxies in the Local Group with simulations

While many tensions between Local Group (LG) satellite galaxies and LCDM cosmology have been alleviated through recent cosmological simulations, the spatial distribution of satellites remains an important test of physical models and physical versus numerical disruption in simulations. Using the FIRE-2 cosmological zoom-in baryonic simulations, we examine the radial distributions of satellites with Mstar > 10^5 Msun around 8 isolated Milky Way- (MW) mass host galaxies and 4 hosts in LG-like pairs. We demonstrate that these simulations resolve the survival and physical destruction of satellites with Mstar >~ 10^5 Msun. The simulations broadly agree with LG observations, spanning the radial profiles around the MW and M31. This agreement does not depend strongly on satellite mass, even at distances <~ 100 kpc. Host-to-host variation dominates the scatter in satellite counts within 300 kpc of the hosts, while time variation dominates scatter within 50 kpc. More massive host galaxies within our sample have fewer satellites at small distances, likely because of enhanced tidal destruction of satellites via the baryonic disks of host galaxies. Furthermore, we quantify and provide fits to the tidal depletion of subhalos in baryonic relative to dark matter-only simulations as a function of distance. Our simulated profiles imply observational incompleteness in the LG even at Mstar >~ 10^5 Msun: we predict 2-10 such satellites to be discovered around the MW and possibly 6-9 around M31. To provide cosmological context, we compare our results with the radial profiles of satellites around MW analogs in the SAGA survey, finding that our simulations are broadly consistent with most SAGA systems.Comment: 18 pages, 10 figures, plus appendices. Main results in figures 2, 3, and 4. Accepted versio

Nature Tourism: A Guidebook for Evaluating Enterprise Opportunities.

86 p

Museum object handling: a health promoting community-based activity for dementia care

In a quasi-experimental design (N = 80), this study examined the wellbeing impact of handling museum artefacts, by testing for differences across domain, time, gender and stages of dementia. Results indicated people with early and moderate impairment showed positive increases in wellbeing, regardless of the type of dementia but those with early stage dementia showed larger positive increases in wellbeing. We can feel confident that for most people with early to middle stage dementia, handling museum objects in a supportive group environment, increases subjective wellbeing and should be considered part of a health promotion strategy in dementia care

The genomic basis of adaptive evolution in threespine sticklebacks

Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine–freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine–freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature.National Human Genome Research Institute (U.S.)National Human Genome Research Institute (U.S.) (NHGRI CEGS Grant P50-HG002568

Numerical modelling of a two-phase twin-screw expander for Trilateral Flash Cycle applications

This paper presents numerical investigations of a twin-screw expander for low grade (≤100°C) heat to power conversion applications based on the bottoming Trilateral Flash Cycle. After a thorough description of the modeling procedure, a first set of simulations shows the effect of different inlet qualities of the R245fa working fluid and of the revolution speed on the expander performance. In particular, at 3750 RPM and an inlet absolute pressure of 5 bar, the volumetric and adiabatic efficiencies will increase from 24.8% and 37.6% to 61.2% and 83.1% if the inlet quality in the intake duct of the expander increased from 0 to 0.1. To further assess the effects of inlet quality, inlet pressure and revolution speed on the expander performance, parametric analyses were carried out in the ranges 0-1 inlet quality, 5-10 bar pressure and 1500-6000RPM speed respectively. © 2018 The Author(s).European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 680599, (ii) Innovate UK (project no. 61995-431253, (iii) Engineering and Physical Sciences Research Council UK (EPSRC), grant no. EP/P510294/1 and (iv) Research Councils UK (RCUK), grant no. EP/K011820/1

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.</p> <p>Methods</p> <p>The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.</p> <p>Results</p> <p>Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.</p> <p>Conclusions</p> <p>In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.</p

STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement

Julian Little and colleagues present the STREGA recommendations, which are aimed at improving the reporting of genetic association studies