Level-Based Analysis of the Population-Based Incremental Learning Algorithm

The Population-Based Incremental Learning (PBIL) algorithm uses a convex combination of the current model and the empirical model to construct the next model, which is then sampled to generate offspring. The Univariate Marginal Distribution Algorithm (UMDA) is a special case of the PBIL, where the current model is ignored. Dang and Lehre (GECCO 2015) showed that UMDA can optimise LeadingOnes efficiently. The question still remained open if the PBIL performs equally well. Here, by applying the level-based theorem in addition to Dvoretzky--Kiefer--Wolfowitz inequality, we show that the PBIL optimises function LeadingOnes in expected time $\mathcal{O}(n\lambda \log \lambda + n^2)$ for a population size $\lambda = \Omega(\log n)$, which matches the bound of the UMDA. Finally, we show that the result carries over to BinVal, giving the fist runtime result for the PBIL on the BinVal problem.Comment: To appea

CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis

Background: Although the etiology of idiopathic pulmonary fibrosis (IPF) remains perplexing, adaptive immune activation is evident among many afflicted patients. Repeated cycles of antigen-induced proliferation cause T-cells to lose surface expression of CD28, and we hypothesized this process might also occur in IPF. Methodology/Principal Findings: Peripheral blood CD4 T-cells from 89 IPF patients were analyzed by flow cytometry and cytokine multiplex assays, and correlated with clinical events. In comparison to autologous CD4 +CD28+cells, the unusual CD4+CD28 null lymphocytes seen in many IPF patients had discordant expressions of activation markers, more frequently produced cytotoxic mediators perforin (2.4±0.8% vs. 60.0±7.4%, p<0.0001) and granzyme B (4.5±2.8% vs.74.9±6.5%, p<0.0001), produced greater amounts of many pro-inflammatory cytokines, and less frequently expressed the regulatory T-cell marker FoxP3 (12.9±1.1% vs. 3.3±0.6% p<0.0001). Infiltration of CD4+CD28null T-cells in IPF lungs was confirmed by confocal microscopy. Interval changes of CD28 expression among subjects who had replicate studies were correlated with conterminous changes of their forced vital capacities (rs = 0.49, p = 0.012). Most importantly, one-year freedom from major adverse clinical events (either death or lung transplantation) was 56±6% among 78 IPF patients with CD4 +CD28+/CD4total≥82%, compared to 9±9% among those with more extensive CD28 down-regulation (CD4+CD28 +/CD4total<82%) (p = 0.0004). The odds ratio for major adverse events among those with the most extensive CD28 down-regulation was 13.0, with 95% confidence intervals 1.6-111.1. Conclusions/Significance: Marked down-regulation of CD28 on circulating CD4 T-cells, a result of repeated antigen-driven proliferations, is associated with poor outcomes in IPF patients. The CD4+CD28null cells of these patients have potentially enhanced pathogenic characteristics, including increased productions of cytotoxic mediators and pro-inflammatory cytokines. These findings show proliferative T-cell responses to antigen(s) resulting in CD28 down-regulation are associated with progression and manifestations of IPF, and suggest assays of circulating CD4 T-cells may identify patients at greatest risk for clinical deterioration. © 2010 Gilani et al

Carbohydrate supplementation during prolonged cycling exercise spares muscle glycogen but does not affect intramyocellular lipid use

Using contemporary stable-isotope methodology and fluorescence microscopy, we assessed the impact of carbohydrate supplementation on whole-body and fiber-type-specific intramyocellular triacylglycerol (IMTG) and glycogen use during prolonged endurance exercise. Ten endurance-trained male subjects were studied twice during 3 h of cycling at 63 ± 4% of maximal O2 uptake with either glucose ingestion (CHO trial; 0.7 g CHO kg−1 h−1) or without (CON placebo trial; water only). Continuous infusions with [U-13C] palmitate and [6,6-2H2] glucose were applied to quantify plasma free fatty acids (FFA) and glucose oxidation rates and to estimate intramyocellular lipid and glycogen use. Before and after exercise, muscle biopsy samples were taken to quantify fiber-type-specific IMTG and glycogen content. Plasma glucose rate of appearance (Ra) and carbohydrate oxidation rates were substantially greater in the CHO vs CON trial. Carbohydrate supplementation resulted in a lower muscle glycogen use during the first hour of exercise in the CHO vs CON trial, resulting in a 38 ± 19 and 57 ± 22% decreased utilization in type I and II muscle-fiber glycogen content, respectively. In the CHO trial, both plasma FFA Ra and subsequent plasma FFA concentrations were lower, resulting in a 34 ± 12% reduction in plasma FFA oxidation rates during exercise (P < 0.05). Carbohydrate intake did not augment IMTG utilization, as fluorescence microscopy revealed a 76 ± 21 and 78 ± 22% reduction in type I muscle-fiber lipid content in the CHO and CON trial, respectively. We conclude that carbohydrate supplementation during prolonged cycling exercise does not modulate IMTG use but spares muscle glycogen use during the initial stages of exercise in endurance-trained men

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with &#60;5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Estimation of airway obstruction using oximeter plethysmograph waveform data

BACKGROUND: Validated measures to assess the severity of airway obstruction in patients with obstructive airway disease are limited. Changes in the pulse oximeter plethysmograph waveform represent fluctuations in arterial flow. Analysis of these fluctuations might be useful clinically if they represent physiologic perturbations resulting from airway obstruction. We tested the hypothesis that the severity of airway obstruction could be estimated using plethysmograph waveform data. METHODS: Using a closed airway circuit with adjustable inspiratory and expiratory pressure relief valves, airway obstruction was induced in a prospective convenience sample of 31 healthy adult subjects. Maximal change in airway pressure at the mouthpiece was used as a surrogate measure of the degree of obstruction applied. Plethysmograph waveform data and mouthpiece airway pressure were acquired for 60 seconds at increasing levels of inspiratory and expiratory obstruction. At each level of applied obstruction, mean values for maximal change in waveform area under the curve and height as well as maximal change in mouth pressure were calculated for sequential 7.5 second intervals. Correlations of these waveform variables with mouth pressure values were then performed to determine if the magnitude of changes in these variables indicates the severity of airway obstruction. RESULTS: There were significant relationships between maximal change in area under the curve (P < .0001) or height (P < 0.0001) and mouth pressure. CONCLUSION: The findings suggest that mathematic interpretation of plethysmograph waveform data may estimate the severity of airway obstruction and be of clinical utility in objective assessment of patients with obstructive airway diseases

The renin‐angiotensin‐aldosterone system and its suppression

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/1/jvim15454-sup-0001-supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/2/jvim15454-sup-0002-figures.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/3/jvim15454-sup-0005-TableS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/4/jvim15454-sup-0004-TableS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/5/jvim15454-sup-0007-TableS5.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/6/jvim15454_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/7/jvim15454.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/8/jvim15454-sup-0006-TableS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148403/9/jvim15454-sup-0003-TableS1.pd

Production properties of K*(892) vector mesons and their spin alignment as measured in the NOMAD experiment

First measurements of K*(892) mesons production properties and their spin alignment in nu_mu charged current (CC) and neutral current (NC) interactions are presented. The analysis of the full data sample of the NOMAD experiment is performed in different kinematic regions. For K*+ and K*- mesons produced in nu_mu CC interactions and decaying into K0 pi+/- we have found the following yields per event: (2.6 +/- 0.2 (stat.) +/- 0.2 (syst.))% and (1.6 +/- 0.1 (stat.) +/- 0.1 (syst.))% respectively, while for the K*+ and K*- mesons produced in nu NC interactions the corresponding yields per event are: (2.5 +/- 0.3 (stat.) +/- 0.3 (syst.))% and (1.0 +/- 0.3 (stat.) +/- 0.2 (syst.))%. The results obtained for the rho00 parameter, 0.40 +/- 0.06 (stat) +/- 0.03 (syst) and 0.28 +/- 0.07 (stat) +/- 0.03 (syst) for K*+ and K*- produced in nu_mu CC interactions, are compared to theoretical predictions tuned on LEP measurements in e+e- annihilation at the Z0 pole. For K*+ mesons produced in nu NC interactions the measured rho00 parameter is 0.66 +/- 0.10 (stat) +/- 0.05 (syst).Comment: 20 p

Reliability of a tool for measuring theory of planned behaviour constructs for use in evaluating research use in policymaking

<p>Abstract</p> <p>Background</p> <p>Although measures of knowledge translation and exchange (KTE) effectiveness based on the theory of planned behavior (TPB) have been used among patients and providers, no measure has been developed for use among health system policymakers and stakeholders. A tool that measures the intention to use research evidence in policymaking could assist researchers in evaluating the effectiveness of KTE strategies that aim to support evidence-informed health system decision-making. Therefore, we developed a 15-item tool to measure four TPB constructs (intention, attitude, subjective norm and perceived control) and assessed its face validity through key informant interviews.</p> <p>Methods</p> <p>We carried out a reliability study to assess the tool's internal consistency and test-retest reliability. Our study sample consisted of 62 policymakers and stakeholders that participated in deliberative dialogues. We assessed internal consistency using Cronbach's alpha and generalizability (G) coefficients, and we assessed test-retest reliability by calculating Pearson correlation coefficients (<it>r</it>) and G coefficients for each construct and the tool overall.</p> <p>Results</p> <p>The internal consistency of items within each construct was good with alpha ranging from 0.68 to alpha = 0.89. G-coefficients were lower for a single administration (G = 0.34 to G = 0.73) than for the average of two administrations (G = 0.79 to G = 0.89). Test-retest reliability coefficients for the constructs ranged from <it>r </it>= 0.26 to <it>r </it>= 0.77 and from G = 0.31 to G = 0.62 for a single administration, and from G = 0.47 to G = 0.86 for the average of two administrations. Test-retest reliability of the tool using G theory was moderate (G = 0.5) when we generalized across a single observation, but became strong (G = 0.9) when we averaged across both administrations.</p> <p>Conclusion</p> <p>This study provides preliminary evidence for the reliability of a tool that can be used to measure TPB constructs in relation to research use in policymaking. Our findings suggest that the tool should be administered on more than one occasion when the intervention promotes an initial 'spike' in enthusiasm for using research evidence (as it seemed to do in this case with deliberative dialogues). The findings from this study will be used to modify the tool and inform further psychometric testing following different KTE interventions.</p

Altered Dopamine and Serotonin Metabolism in Motorically Asymptomatic R6/2 Mice

The pattern of cerebral dopamine (DA) abnormalities in Huntington disease (HD) is complex, as reflected by the variable clinical benefit of both DA antagonists and agonists in treating HD symptoms. In addition, little is known about serotonin metabolism despite the early occurrence of anxiety and depression in HD. Post-mortem enzymatic changes are likely to interfere with the in vivo profile of biogenic amines. Hence, in order to reliably characterize the regional and chronological profile of brain neurotransmitters in a HD mouse model, we used a microwave fixation system that preserves in vivo concentrations of dopaminergic and serotoninergic amines. DA was decreased in the striatum of R6/2 mice at 8 and 12 weeks of age while DA metabolites, 3-methoxytyramine and homovanillic acid, were already significantly reduced in 4-week-old motorically asymptomatic R6/2 mice. In the striatum, hippocampus and frontal cortex of 4, 8 and 12-week-old R6/2 mice, serotonin and its metabolite 5-hydroxyindoleacetic acid were significantly decreased in association with a decreased turnover of serotonin. In addition, automated high-resolution behavioural analyses displayed stress-like behaviours such as jumping and grooming and altered spatial learning in R6/2 mice at age 4 and 6 weeks respectively. Therefore, we describe the earliest alterations of DA and serotonin metabolism in a HD murine model. Our findings likely underpin the neuropsychological symptoms at time of disease onset in HD