The Effect of a Translating Research into Practice (TRIP)‐Cancer Intervention on Cancer Pain Management in Older Adults in Hospice

Background.  Pain is a major concern for individuals with cancer, particularly older adults who make up the largest segment of individuals with cancer and who have some of the most unique pain challenges. One of the priorities of hospice is to provide a pain‐free death, and while outcomes are better in hospice, patients still die with poorly controlled pain. Objective.  This article reports on the results of a Translating Research into Practice intervention designed to promote the adoption of evidence‐based pain practices for older adults with cancer in community‐based hospices. Setting.  This Institutional Human Subjects Review Board‐approved study was a cluster randomized controlled trial implemented in 16 Midwestern hospices. Methods.  Retrospective medical records from newly admitted patients were used to determine the intervention effect. Additionally, survey and focus group data gathered from hospice staff at the completion of the intervention phase were analyzed. Results.  Improvement on the Cancer Pain Practice Index, an overall composite outcome measure of evidence‐based practices for the experimental sites, was not significantly greater than control sites. Decrease in patient pain severity from baseline to post‐intervention in the experimental group was greater; however, the result was not statistically significant ( P  = 0.1032). Conclusions.  Findings indicate a number of factors that may impact implementation of multicomponent interventions, including unique characteristics and culture of the setting, the level of involvement with the change processes, competing priorities and confounding factors, and complexity of the innovation (practice change). Our results suggest that future study is needed on specific factors to target when implementing a community‐based hospice intervention, including determining and measuring intervention fidelity prospectively.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93516/1/j.1526-4637.2012.01405.x.pd

Executive deficits are related to the inferior frontal junction in early dementia

Executive functions describe a wide variety of higher order cognitive processes that allow the flexible modification of thought and behaviour in response to changing cognitive or environmental contexts. Their impairment is common in neurodegenerative disorders. Executive deficits negatively affect everyday activities and hamper the ability to cope with other deficits, such as memory impairment in Alzheimer's disease or behavioural disorders in frontotemporal lobar degeneration. Our study aimed to characterize the neural correlates of executive functions by relating respective deficits to regional hypometabolism in early dementia. Executive functions were assessed with two classical tests, the Stroop and semantic fluency test and various subtests of the behavioural assessment of the dysexecutive syndrome test battery capturing essential aspects of executive abilities relevant to daily living. Impairments in executive functions were correlated with reductions in brain glucose utilization as measured by [18F]fluorodeoxyglucose positron emission tomography and analysed voxelwise using statistical parametric mapping in 54 subjects with early dementia, mainly Alzheimer's disease and frontotemporal lobar degeneration, and its prodromal stages: subjective and mild cognitive impairment. Although the analysis revealed task-specific frontoparietal networks, it consistently showed that hypometabolism in one region in the left lateral prefrontal cortex—the inferior frontal junction area—was related to performance in the various neuropsychological tests. This brain region has recently been related to the three component processes of cognitive control—working memory, task switching and inhibitory control. Group comparisons additionally showed hypometabolism in this area in Alzheimer's disease and frontotemporal lobar degeneration. Our study underlines the importance of the inferior frontal junction area for cognitive control in general and for executive deficits in early dementia

The association of cardioprotective medications with pneumonia-related outcomes

Introduction: Little research has examined whether cardiovascular medications, other than statins, are associated with improved outcomes after pneumonia. Our aim was to examine the association between the use of beta-blockers, statins, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) with pneumonia-related outcomes. Materials and Methods: We conducted a retrospective population-based study on male patients ≥65 years of age hospitalized with pneumonia and who did not have pre-existing cardiac disease. Our primary analyses were multilevel regression models that examined the association between cardiovascular medication classes and either mortality or cardiovascular events. Results: Our cohort included 21,985 patients: 22% died within 90 days of admission, and 22% had a cardiac event within 90 days. The cardiovascular medications studied that were associated with decreased 90-day mortality included: statins (OR 0.70, 95% CI 0.63-0.77), ACE inhibitors (OR 0.82, 95% CI 0.74-0.91), and ARBs (OR 0.58, 95% CI 0.44-0.77). However, none of the medications were significantly associated with decreased cardiovascular events. Discussion: While statins, ACE inhibitors, and ARBs, were associated with decreased mortality, there was no significant association with decreased CV events. These results indicate that this decreased mortality is unlikely due to their potential cardioprotective effects

Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNFα by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A2A receptor activation did not reverse ibudilast's inhibition of Tat-induced TNFα production. Interestingly, ibudilast reduced Tat-mediated transcription of TNFα, via modulation of nuclear factor-kappa B (NF-κB) signaling, as shown by transcriptional activity of NF-κB and analysis of inhibitor of kappa B alpha (IκBα) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNFα production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND

Nuclear Factor-Kappa B Family Member RelB Inhibits Human Immunodeficiency Virus-1 Tat-Induced Tumor Necrosis Factor-Alpha Production

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is likely neuroinflammatory in origin, believed to be triggered by inflammatory and oxidative stress responses to cytokines and HIV protein gene products such as the HIV transactivator of transcription (Tat). Here we demonstrate increased messenger RNA for nuclear factor-kappa B (NF-κB) family member, transcription factor RelB, in the brain of doxycycline-induced Tat transgenic mice, and increased RelB synthesis in Tat-exposed microglial cells. Since genetic ablation of RelB in mice leads to multi-organ inflammation, we hypothesized that Tat-induced, newly synthesized RelB inhibits cytokine production by microglial cells, possibly through the formation of transcriptionally inactive RelB/RelA complexes. Indeed, tumor necrosis factor-alpha (TNFα) production in monocytes isolated from RelB deficient mice was significantly higher than in monocytes isolated from RelB expressing controls. Moreover, RelB overexpression in microglial cells inhibited Tat-induced TNFα synthesis in a manner that involved transcriptional repression of the TNFα promoter, and increased phosphorylation of RelA at serine 276, a prerequisite for increased RelB/RelA protein interactions. The Rel-homology-domain within RelB was necessary for this interaction. Overexpression of RelA itself, in turn, significantly increased TNFα promoter activity, an effect that was completely blocked by RelB overexpression. We conclude that RelB regulates TNFα cytokine synthesis by competitive interference binding with RelA, which leads to downregulation of TNFα production. Moreover, because Tat activates both RelB and TNFα in microglia, and because Tat induces inflammatory TNFα synthesis via NF-κB, we posit that RelB serves as a cryoprotective, anti-inflammatory, counter-regulatory mechanism for pathogenic NF-κB activation. These findings identify a novel regulatory pathway for controlling HIV-induced microglial activation and cytokine production that may have important therapeutic implications for the management of HAND

Dreams and nightmares of liberal international law: capitalist accumulation, natural rights and state hegemony

This article develops a line of theorising the relationship between peace, war and commerce and does so via conceptualising global juridical relations as a site of contestation over questions of economic and social justice. By sketching aspects of a historical interaction between capitalist accumulation, natural rights and state hegemony, the article offers a critical account of the limits of liberal international law, and attempts to recover some ground for thinking about the emancipatory potential of international law more generally

Staffing decisions for heterogeneous workers with turnover

In this paper we consider a firm that employs heterogeneous workers to meet demand for its product or service. Workers differ in their skills, speed, and/or quality, and they randomly leave, or turn over. Each period the firm must decide how many workers of each type to hire or fire in order to meet randomly changing demand forecasts at minimal expense. When the number of workers of each type can by continuously varied, the operational cost is jointly convex in the number of workers of each type, hiring and firing costs are linear, and a random fraction of workers of each type leave in each period, the optimal policy has a simple hire- up-to/fire-down-to structure. However, under the more realistic assumption that the number of workers of each type is discrete, the optimal policy is much more difficult to characterize, and depends on the particular notion of discrete convexity used for the cost function. We explore several different notions of discrete convexity and their impact on structural results for the optimal policy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45844/1/186_2005_Article_33.pd

NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis

While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNα and IFNβ, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds to bacterial peptidoglycan, and this event requires membrane damage that is actively inflicted by the bacterium. Unexpectedly, this recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depend entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the Nod2/Rip2/Irf5 pathway. Thus, the Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system

CKD-MBD after kidney transplantation

Successful kidney transplantation corrects many of the metabolic abnormalities associated with chronic kidney disease (CKD); however, skeletal and cardiovascular morbidity remain prevalent in pediatric kidney transplant recipients and current recommendations from the Kidney Disease Improving Global Outcomes (KDIGO) working group suggest that bone disease—including turnover, mineralization, volume, linear growth, and strength—as well as cardiovascular disease be evaluated in all patients with CKD. Although few studies have examined bone histology after renal transplantation, current data suggest that bone turnover and mineralization are altered in the majority of patients and that biochemical parameters are poor predictors of bone histology in this population. Dual energy X-ray absorptiometry (DXA) scanning, although widely performed, has significant limitations in the pediatric transplant population and values have not been shown to correlate with fracture risk; thus, DXA is not recommended as a tool for the assessment of bone density. Newer imaging techniques, including computed tomography (quantitative CT (QCT), peripheral QCT (pQCT), high resolution pQCT (HR-pQCT) and magnetic resonance imaging (MRI)), which provide volumetric assessments of bone density and are able to discriminate bone microarchitecture, show promise in the assessment of bone strength; however, future studies are needed to define the value of these techniques in the diagnosis and treatment of renal osteodystrophy in pediatric renal transplant recipients

Snowmass Neutrino Frontier: DUNE Physics Summary

The Deep Underground Neutrino Experiment (DUNE) is a next-generation long-baseline neutrino oscillation experiment with a primary physics goal of observing neutrino and antineutrino oscillation patterns to precisely measure the parameters governing long-baseline neutrino oscillation in a single experiment, and to test the three-flavor paradigm. DUNE's design has been developed by a large, international collaboration of scientists and engineers to have unique capability to measure neutrino oscillation as a function of energy in a broadband beam, to resolve degeneracy among oscillation parameters, and to control systematic uncertainty using the exquisite imaging capability of massive LArTPC far detector modules and an argon-based near detector. DUNE's neutrino oscillation measurements will unambiguously resolve the neutrino mass ordering and provide the sensitivity to discover CP violation in neutrinos for a wide range of possible values of δCP. DUNE is also uniquely sensitive to electron neutrinos from a galactic supernova burst, and to a broad range of physics beyond the Standard Model (BSM), including nucleon decays. DUNE is anticipated to begin collecting physics data with Phase I, an initial experiment configuration consisting of two far detector modules and a minimal suite of near detector components, with a 1.2 MW proton beam. To realize its extensive, world-leading physics potential requires the full scope of DUNE be completed in Phase II. The three Phase II upgrades are all necessary to achieve DUNE's physics goals: (1) addition of far detector modules three and four for a total FD fiducial mass of at least 40 kt, (2) upgrade of the proton beam power from 1.2 MW to 2.4 MW, and (3) replacement of the near detector's temporary muon spectrometer with a magnetized, high-pressure gaseous argon TPC and calorimeter