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\"In a future in which the privileged reside on an Earth-orbiting space station named Elysium and the less fortunate live on the surface of the blighted, overpopulated planet below, one man dares to defy the strict anti-immigration laws that separate the two disparate worlds in order to save all of mankind in this visceral sci-fi action thriller from District 9 director Neill Blomkamp. The year is 2154, and the division between social classes has grown wider than ever before. As the rich enjoy a life of luxury and access to cutting-edge medical technology on Elysium, the rest of the human race contend with poverty, crime, and disease on the surface of planet Earth. Meanwhile, hard-line immigration laws ensure that only those who have been explicitly approved will ever set foot on the elusive paradise in the stars. 36-year-old Max (Matt Damon) lives in an L.A. shantytown and earns his living by working on an Armadyne assembly line. He's had a rough past, but he's struggling to stay on the right side of the law when he realizes that his only hope for survival after being exposed to deadly radiation is to reach Elysium. Should Max succeed, he will strike a major blow for equality in the eyes of his fellow surface dwellers; should he fail, it will mean certain death. In his quest to become the hero who can restore the balance between the rich and the poor, however, Max must first do battle with Elysium's hawkish Secretary of Defense Delacourt (Jodie Foster), who has devoted her entire career to maintaining that division, and whose key enforcer Kruger (Sharlto Copley) is notorious for his brutal tactics in driving out illegals. With the fates of millions hanging in the balance, Max sets his sights on Elysium and never looks back. Alice Braga, Diego Luna, William Fichtner, and Faran Tahir co-star\"--Allmovie.com, viewed April 25, 2018.

Subnormothermic machine perfusion (SNMP) of liver grafts is currently less clinically developed than normothermic and hypothermic approaches, but may have logistical advantages. At intermediate temperatures, the oxygen demand of the graft is low enough to be satisfied with an acellular perfusate, obviating the need for oxygen carrying molecules. This intermediate metabolic rate, however, is sufficient to support the production of bile, which is emerging as an important indicator of graft injury and viability. In this study, we hypothesized that the biliary compartment would be more sensitive than perfusate in detecting graft injury during SNMP. To test this hypothesis in a rat model, we performed liver transplants with DCD and control liver grafts after 1 h of acellular room temperature machine perfusion (acRTMP) or static cold storage (SCS). Point of care liver function tests were measured in biliary and perfusate samples after 1 h of machine perfusion. Following transplantation, rats were sacrificed at 24 h for assessment of post-transplant graft function and histology. All point-of-care liver function tests were significantly more concentrated in the biliary compartment than the perfusate compartment during acRTMP. DCD liver grafts could be distinguished from control liver grafts by significantly higher markers of hepatocyte injury (AST, ALT) in the biliary compartment, but not in the perfusate compartment. Classical markers of cholangiocyte injury, such as gammy-glut amyl transferase (GGT), amylase (AML), and alkaline phosphatase were detectable in the biliary compartment, but not in the perfusate compartment. In comparison to SCS, graft preservation by acRTMP produced a significant survival benefit in DCD liver transplantation (75 vs. 0%, < 0.0030). Together, these findings demonstrate that during acRTMP, the biliary compartment may be a more sensitive indicator of graft injury than the perfusate compartment. Moreover, acRTMP provides superior graft preservation to SCS in rat DCD liver transplantation.

Purpose The purpose of this research is to identify how managers can apply the results of academic research into the concept of business models for creating and evaluating possible models for their businesses. Design/methodology/approach A review of the literature is followed by two case studies, from the airline and logistics industries, followed by recommendations based on both. Findings The findings are that there is relatively weak consensus among academics as to the definition and meaning of a business model and its components, and that the notion of generic business model applies better within rather than between industries, but that the discussion is a very fertile one for developing recommendations for managers. Practical implications The managerial implications of the study are that in their planning and strategizing, managers should factor in a proper analysis of the business model they currently use and one that they could use. Originality/value The study provides a useful addition to the literature on the practical implications of business models.

Sepsis is a deadly and debilitating condition resulting from a hyperinflammatory response to infection. Most organ systems are severely impacted, including the neurological complications for survivors of sepsis. Sepsis associated encephalopathy (SAE) is characterized by dysregulated molecular pathways of the immune response impinging upon normal central nervous system (CNS) function and ultimately resulting in lasting cognitive and behavioral impairments. Sepsis predominantly occurs in a few neonates but mostly elderly individuals where they are at high risk of sepsis-induced delirium and other neurological implications that may have overlap with neurodegenerative diseases. This study seeks to identify gene candidates that exhibit altered transcriptional expression in tissues between pigs injected with saline control vs lipopolysaccharide (LPS) to model the early inflammatory aspects of the septic response. Specifically, brain frontal cortex was examined to see which genes and pathways are altered at these early stages and could be targeted for further investigation to alter the cognitive/behavioral decline seen in sepsis survivors. This experiment uses a bulk RNA-seq approach on Yorkshire pigs to identify the variance in gene expression profile. Data analysis showed several gene candidates that were downregulated in the brain in response to LPS that point to early endothelial cell disruption, including OCLN (occludin), SLC19A3 (thiamine transporter), and SLC52A3 (riboflavin transporter). Genes that were upregulated in LPS brain samples implicate endothelial cell dysfunction as well as immune/inflammatory alterations, possibly due to alterations in microglia, the primary immune cell of the brain. Several studies are now underway to understand the cellular origin of these transcriptional changes, as well as analyzing the molecular signatures altered in response to sepsis in whole blood and kidney using bulk RNAseq. In conclusion, specific gene candidates were identified as early changes in the septic brain that could be targets to prevent long-term cognitive and behavioral changes in future studies, establishing a baseline panel to interrogate in animal models with the goal of advancing treatments for human patients who experience sepsis.

Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference −12·2, 95% CI −20·77 to −3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. Sage Therapeutics, Inc.

Our objective was to assess the cost-effectiveness of novel rapid diagnostic tests: rapid influenza diagnostic tests (RIDT), digital immunoassays (DIA), rapid nucleic acid amplification tests (NAAT), and other treatment algorithms for influenza in high-risk patients presenting to hospital with influenza-like illness (ILI). We developed a decision-analytic model to assess the cost-effectiveness of diagnostic test strategies (RIDT, DIA, NAAT, clinical judgement, batch polymerase chain reaction) preceding treatment; no diagnostic testing and treating everyone; and not treating anyone. We modeled high-risk 65-year old patients from a health payer perspective and accrued outcomes over a patient's lifetime. We reported health outcomes, quality-adjusted life years (QALYs), healthcare costs, and net health benefit (NHB) to measure cost-effectiveness per cohort of 100,000 patients. Treating everyone with no prior testing was the most cost-effective strategy, at a cost-effectiveness threshold of $50,000/QALY, in over 85% of simulations. This strategy yielded the highest NHB of 15.0344 QALYs, but inappropriately treats all patients without influenza. Of the novel rapid diagnostics, NAAT resulted in the highest NHB (15.0277 QALYs), and the least number of deaths (1,571 per 100,000). Sensitivity analyses determined that results were most impacted by the pretest probability of ILI being influenza, diagnostic test sensitivity, and treatment effectiveness. Based on our model, treating high-risk patients presenting to hospital with influenza-like illness, without performing a novel rapid diagnostic test, resulted in the highest NHB and was most cost-effective. However, consideration of whether treatment is appropriate in the absence of diagnostic confirmation should be taken into account for decision-making by clinicians and policymakers.

How local stresses propagate through polymeric fluids, and, more generally, how macromolecular dynamics give rise to viscoelasticity are open questions vital to wide-ranging scientific and industrial fields. Here, to unambiguously connect polymer dynamics to force response, and map the deformation fields that arise in macromolecular materials, we present Optical-Tweezers-integrating-Differential -Dynamic-Microscopy (OpTiDMM) that simultaneously imposes local strains, measures resistive forces, and analyzes the motion of the surrounding polymers. Our measurements with blends of ring and linear polymers (DNA) and their composites with stiff polymers (microtubules) uncover an unexpected resonant response, in which strain alignment, superdiffusivity, and elasticity are maximized when the strain rate is comparable to the entanglement rate. Microtubules suppress this resonance, while substantially increasing elastic storage, due to varying degrees to which the polymers buildup, stretch and flow along the strain path, and configurationally relax induced stress. More broadly, the rich multi-scale coupling of mechanics and dynamics afforded by OpTiDDM, empowers its interdisciplinary use to elucidate non-trivial phenomena that sculpt stress propagation dynamics–critical to commercial applications and cell mechanics alike. The authors present an approach to connect polymer dynamics to force response by integrating optical tweezers with differential dynamic microscopy. They measure blends of ring and linear DNA and observe a resonant response, which is suppressed by the presence of microtubules.

The proliferation of evidence synthesis methods makes it challenging for reviewers to select the ‘‘right’’ method. This study aimed to update the Right Review tool (a web-based decision support tool that guides users through a series of questions for recommending evidence synthesis methods) and establish a common set of questions for the synthesis of both quantitative and qualitative studies (https://rightreview.knowledgetranslation.net/). A 2-round modified international electronic modified Delphi was conducted (2022) with researchers, health-care providers, patients, and policy makers. Panel members rated the importance/clarity of the Right Review tool's guiding questions, evidence synthesis type definitions and tool output. High agreement was defined as at least 70% agreement. Any items not reaching high agreement after round 2 were discussed by the international Project Steering Group. Twenty-four experts from 9 countries completed round 1, with 12 completing round 2. Of the 46 items presented in round 1, 21 reached high agreement. Twenty-seven items were presented in round 2, with 8 reaching high agreement. The Project Steering Group discussed items not reaching high agreement, including 8 guiding questions, 9 review definitions (predominantly related to qualitative synthesis), and 2 output items. Three items were removed entirely and the remaining 16 revised and edited and/or combined with existing items. The final tool comprises 42 items; 9 guiding questions, 25 evidence synthesis definitions and approaches, and 8 tool outputs. The freely accessible Right Review tool supports choosing an appropriate review method. The design and clarity of this tool was enhanced by harnessing the Delphi technique to shape ongoing development. The updated tool is expected to be available in Quarter 1, 2025. •Right Review assists in identifying appropriate evidence synthesis methods.•Right Review was updated using an international Delphi process.•Right Review now has a single set of guiding questions.

In an effort to develop a new therapy for prostate cancer (PCa) bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wnt/β-catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels and inhibited tumor cell migration. To examine the antitumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum tartrate-resistant acid phosphatase 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia and an increase in the animal survival. Based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for PCa bone metastasis.