The Effects of Myelin on Macrophage Activation Are Phenotypic Specific via cPLA\u3csub\u3e2\u3c/sub\u3e in the Context of Spinal Cord Injury Inflammation

Spinal cord injury (SCI) produces chronic, pro-inflammatory macrophage activation that impairs recovery. The mechanisms driving this chronic inflammation are not well understood. Here, we detail the effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA2) in myelin-mediated potentiation of pro-inflammatory macrophage activation. We hypothesized that cPLA2 and myelin debris are key mediators of persistent pro-inflammatory macrophage responses after SCI. To test this, we examined spinal cord tissue 28-days after thoracic contusion SCI in 3-month-old female mice and observed both cPLA2 activation and intracellular accumulation of lipid-rich myelin debris in macrophages. In vitro, we utilized bone marrow-derived macrophages to determine myelin’s effects across a spectrum of activation states. We observed phenotype-specific responses with myelin potentiating only pro-inflammatory (LPS + INF-γ; M1) macrophage activation, whereas myelin did not induce pro-inflammatory responses in unstimulated or anti-inflammatory (IL-4; M2) macrophages. Specifically, myelin increased levels of pro-inflammatory cytokines, reactive oxygen species, and nitric oxide production in M1 macrophages as well as M1-mediated neurotoxicity. PACOCF3 (cPLA2 inhibitor) blocked myelin’s detrimental effects. Collectively, we provide novel spatiotemporal evidence that myelin and cPLA2 play an important role in the pathophysiology of SCI inflammation and the phenotype-specific response to myelin implicate diverse roles of myelin in neuroinflammatory conditions

Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies

This is the final version. Available from IOS Press via the DOI in this record.BACKGROUND: Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear. OBJECTIVE: To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia. METHODS: We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality. RESULTS: We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer's disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects. CONCLUSIONS: Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors.This work was supported by the Mary Kinross Charitable Trust (DJL and EK), Halpin Trust (DJL, EK and IL), the James Tudor Foundation (DJL and EK), National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula (IL, JTC, AB and DJL) and the National Institute on Aging of the National Institutes of Health under Award Number RF1AG055654 (DJL)

Rapid phenotypic and genomic change in response to therapeutic pressure in prostate cancer inferred by high content analysis of single circulating tumor cells

Timely characterization of a cancer's evolution is required to predict treatment efficacy and to detect resistance early. High content analysis of single Circulating Tumor Cells (CTCs) enables sequential characterization of genotypic, morphometric and protein expression alterations in real time over the course of cancer treatment. This concept was investigated in a patient with castrate-resistant prostate cancer progressing through both chemotherapy and targeted therapy. In this case study, we integrate across four timepoints 41 genome-wide copy number variation (CNV) profiles plus morphometric parameters and androgen receptor (AR) protein levels. Remarkably, little change was observed in response to standard chemotherapy, evidenced by the fact that a unique clone (A), exhibiting highly rearranged CNV profiles and AR+ phenotype was found circulating before and after treatment. However, clinical response and subsequent progression after targeted therapy was associated with the drastic depletion of clone A, followed by the sequential emergence of two distinct CTC sub-populations that differed in both AR genotype and expression phenotype. While AR- cells with flat or pseudo-diploid CNV profiles (clone B) were identified at the time of response, a new tumor lineage of AR+ cells (clone C) with CNV altered profiles was detected during relapse. We showed that clone C, despite phylogenetically related to clone A, possessed a unique set of somatic CNV alterations, including MYC amplification, an event linked to hormone escape. Interesting, we showed that both clones acquired AR gene amplification by deploying different evolutionary paths. Overall, these data demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the multi-scale analysis of fluid biopsies to quantify and monitor disease evolution in individual patients

HIV Testing, Care Referral, and Linkage to Care Intervals Affect Time to Engagement in Care for Newly Diagnosed HIV-Infected Adolescents in 15 Adolescent Medicine Clinics in the United States

OBJECTIVE: To examine how the time from HIV testing to care referral and from referral to care linkage influenced time to care engagement for newly diagnosed HIV-infected adolescents. METHODS: We evaluated the Care Initiative, a care linkage and engagement program for HIV-infected adolescents in 15 US clinics. We analyzed client-level factors, provider type, and intervals from HIV testing to care referral and from referral to care linkage as predictors of care engagement. Engagement was defined as a second HIV-related medical visit within 16 weeks of initial HIV-related medical visit (linkage). RESULTS: At 32 months, 2143 youth had been referred. Of these, 866 were linked to care through the Care Initiative within 42 days and thus eligible for study inclusion. Of the linked youth, 90.8% were ultimately engaged in care. Time from HIV testing to referral (eg, ≤7 days versus >365 days) was associated with engagement [adjusted odds ratio = 2.91; 95% confidence interval (CI): 1.43 to 5.94] and shorter time to engagement (adjusted hazard ratio = 1.41; 95% CI: 1.11 to 1.79). Individuals with shorter care referral to linkage intervals (eg, ≤7 days versus 22-42 days) engaged in care faster (adjusted hazard ratio = 2.90; 95% CI: 2.34 to 3.60) and more successfully (adjusted odds ratio = 2.01; 95% CI: 1.04 to 3.89). CONCLUSIONS: These data address a critical piece of the care continuum and can offer suggestions of where and with whom to intervene to best achieve the care engagement goals outlined in the US National HIV/AIDS Strategy. These results may also inform programs and policies that set concrete milestones and strategies for optimal care linkage timing for newly diagnosed adolescents

Factors affecting linkage to care and engagement in care for newly diagnosed HIV-positive adolescents within fifteen adolescent medicine clinics in the United States

Early linkage to care and engagement in care are critical for initiation of medical interventions. However, over 50 % of newly diagnosed persons do not receive HIV-related care within 6 months of diagnosis. We evaluated a linkage to care and engagement in care initiative for HIV-positive adolescents in 15 U.S.-based clinics. Structural and client-level factors (e.g. demographic and behavioral characteristics, clinic staff and location) were evaluated as predictors of successful linkage and engagement. Within 32 months, 1,172/1,679 (69.8 %) of adolescents were linked to care of which 1,043/1,172 (89 %) were engaged in care. Only 62.1 % (1,043/1,679) of adolescents were linked and engaged in care. Linkage to care failure was attributed to adolescent, provider, and clinic-specific factors. Many adolescents provided incomplete data during the linkage process or failed to attend appointments, both associated with failure to linkage to care. Additional improvements in HIV care will require creative approaches to coordinated data sharing, as well as continued outreach services to support newly diagnosed adolescents

Query-Driven Visualization of Time-Varying Adaptive Mesh Refinement Data

The visualization and analysis of AMR-based simulations is integral to the process of obtaining new insight in scientific research. We present a new method for performing query-driven visualization and analysis on AMR data, with specific emphasis on time-varying AMR data. Our work introduces a new method that directly addresses the dynamic spatial and temporal properties of AMR grids which challenge many existing visualization techniques. Further, we present the first implementation of query-driven visualization on the GPU that uses a GPU-based indexing structure to both answer queries and efficiently utilize GPU memory. We apply our method to two different science domains to demonstrate its broad applicability

Visualization at Supercomputing Centers: The Tale of Little Big Iron and the Three Skinny Guys

Supercomputing Centers (SC's) are unique resources that aim to enable scientific knowledge discovery through the use of large computational resources, the Big Iron. Design, acquisition, installation, and management of the Big Iron are activities that are carefully planned and monitored. Since these Big Iron systems produce a tsunami of data, it is natural to co-locate visualization and analysis infrastructure as part of the same facility. This infrastructure consists of hardware (Little Iron) and staff (Skinny Guys). Our collective experience suggests that design, acquisition, installation, and management of the Little Iron and Skinny Guys does not receive the same level of treatment as that of the Big Iron. The main focus of this article is to explore different aspects of planning, designing, fielding, and maintaining the visualization and analysis infrastructure at supercomputing centers. Some of the questions we explore in this article include:"How should the Little Iron be sized to adequately support visualization and analysis of data coming off the Big Iron?" What sort of capabilities does it need to have?" Related questions concern the size of visualization support staff:"How big should a visualization program be (number of persons) and what should the staff do?" and"How much of the visualization should be provided as a support service, and how much should applications scientists be expected to do on their own?&quot

Corporate governance and financial constraints on strategic turnarounds

The paper extends the Robbins and Pearce (1992) two-stage turnaround response model to include governance factors. In addition to the retrenchment and recovery, the paper proposes the addition of a realignment stage, referring specifically to the re-alignment of expectations of principal and agent groups. The realignment stage imposes a threshold that must be crossed before the retrenchment and hence recovery stage can be entered. Crossing this threshold is problematic to the extent that the interests of governance-stakeholder groups diverge in a crisis situation. The severity of the crisis impacts on the bases of strategy contingent asset valuation leading to the fragmentation of stakeholder interests. In some cases the consequence may be that management are prevented from carrying out turnarounds by governance constraints. The paper uses a case study to illustrate these dynamics, and like the Robbins and Pearce study, it focuses on the textile industry. A longitudinal approach is used to show the impact of the removal of governance constraints. The empirical evidence suggests that such financial constraints become less serious to the extent that there is a functioning market for corporate control. Building on governance research and turnaround literature, the paper also outlines the general case necessary and sufficient conditions for successful turnarounds

Thirty Years After Michael E. Porter: What Do We Know About Business Exit?

Although a business exit is an important corporate change initiative, the buyer’s side seems to be more appealing to management researchers than the seller’s because acquisitions imply growth, i.e., success. Yet from an optimistic viewpoint, business exit can effectively create value for the selling company. In this paper we attempt to bring the relevance of the seller’s side back into our consciousness by asking: What do we know about business exit? We start our exploration with Porter (1976), focusing on literature that investigates the antecedents of, barriers to, and outcomes of business exit. We also include studies from related fields such as finance and economics.1 Through this research we determine three clusters of findings: factors promoting business exit, exit barriers, and exit outcomes. Overall, it is the intention of this paper to highlight the importance of business exit for research and practice. Knowing what we know about business exits and their high financial value we should bear in mind that exit need not mean failure but a new beginning for a corporation

Prediction and validation of exenatide risk marker effects on progression of renal disease:Insights from EXSCEL

Aim To assess whether the previously developed multivariable risk prediction framework (PRE score) could predict the renal effects observed in the EXSCEL cardiovascular outcomes trial using short-term changes in cardio-renal risk markers. Materials and Methods Changes from baseline to 6 months in HbA1c, systolic blood pressure (SBP), body mass index (BMI), haemoglobin, total cholesterol, and new micro- or macroalbuminuria were evaluated. The renal outcomes were defined as a composite of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). Relationships between risk markers and long-term renal outcomes were determined in patients with type 2 diabetes from the ALTITUDE study using multivariable Cox regression analysis, and then applied to short-term changes in risk markers observed in EXSCEL to predict the exenatide-induced impact on renal outcomes. Results Compared with placebo, mean HbA1c, BMI, SBP and total cholesterol were lower at 6 months with exenatide, as was the incidence of new microalbuminuria. The PRE score predicted a relative risk reduction for the 30% eGFR decline + ESRD endpoint of 11.3% (HR 0.89; 95% CI 0.83-0.94), compared with 12.7% (HR 0.87; 0.77-0.99) observed risk reduction. For the 40% eGFR decline + ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 0.82-0.97) and 13.7% (HR 0.86, 0.72-1.04), respectively. Conclusions Integrating short-term risk marker changes into a multivariable risk score predicted the magnitude of renal risk reduction observed in EXSCEL