Multi Agent Diagnosis: an analysis

The paper analyzes the use of a Multi Agent System for Model Based Diagnosis. In a large dynamical system, it is often infeasible or even impossible to maintain a model of the whole system. Instead, several incomplete models of the system have to be used to detect possible faults. These models may also be physically be distributed. A Multi Agent System of diagnostic agents may offer solutions for establishing a global diagnosis. If we use a separate agent for each incomplete model of the system, establishing a global diagnosis becomes a problem cooperation and negotiation between the diagnostic agents. This raises the question whether `a set of diagnostic agents, each having an incomplete model of the system, can (efficiently) determine the same global diagnosis as an ideal single diagnostic agent having the combined knowledge of the diagnostic agents?''economics of technology ;

Alpha, Betti and the Megaparsec Universe: on the Topology of the Cosmic Web

We study the topology of the Megaparsec Cosmic Web in terms of the scale-dependent Betti numbers, which formalize the topological information content of the cosmic mass distribution. While the Betti numbers do not fully quantify topology, they extend the information beyond conventional cosmological studies of topology in terms of genus and Euler characteristic. The richer information content of Betti numbers goes along the availability of fast algorithms to compute them. For continuous density fields, we determine the scale-dependence of Betti numbers by invoking the cosmologically familiar filtration of sublevel or superlevel sets defined by density thresholds. For the discrete galaxy distribution, however, the analysis is based on the alpha shapes of the particles. These simplicial complexes constitute an ordered sequence of nested subsets of the Delaunay tessellation, a filtration defined by the scale parameter, $\alpha$. As they are homotopy equivalent to the sublevel sets of the distance field, they are an excellent tool for assessing the topological structure of a discrete point distribution. In order to develop an intuitive understanding for the behavior of Betti numbers as a function of $\alpha$, and their relation to the morphological patterns in the Cosmic Web, we first study them within the context of simple heuristic Voronoi clustering models. Subsequently, we address the topology of structures emerging in the standard LCDM scenario and in cosmological scenarios with alternative dark energy content. The evolution and scale-dependence of the Betti numbers is shown to reflect the hierarchical evolution of the Cosmic Web and yields a promising measure of cosmological parameters. We also discuss the expected Betti numbers as a function of the density threshold for superlevel sets of a Gaussian random field.Comment: 42 pages, 14 figure

О параллельной обработке потока данных, адаптированной к области бит произвольной конфигурации

Предлагается модель операции свёртки арифметических многорядных двоичных кодов (МРК), которая учитывает неравномерность распределения бит данных по разрядам. На основе этой модели разрабатываются процедуры и методы свёртки МРК, которые позволяют снизить задержку на обработку.Пропонується модель операції згортки арифметичних багаторядних двійкових кодів (БРК), яка зважає на нерівномірність розподілу біт даних за разрядами. На основі цієї моделі розроблюються процедури і методи згортки БРК, які дозволяють зменшити затримку на обробку.Model of the compressing operation of arithmetic multi-row binary codes (MRC) is offered. In this model irregularity allocation of data bit per digits is considered. Procedures and methods of compressing MRC based on this model allow diminish delay of processing are designed (developed)

Cardiac oxygen supply is compromised during the night in hypertensive patients

The enhanced heart rate and blood pressure soon after awaking increases cardiac oxygen demand, and has been associated with the high incidence of acute myocardial infarction in the morning. The behavior of cardiac oxygen supply is unknown. We hypothesized that oxygen supply decreases in the morning and to that purpose investigated cardiac oxygen demand and oxygen supply at night and after awaking. We compared hypertensive to normotensive subjects and furthermore assessed whether pressures measured non-invasively and intra-arterially give similar results. Aortic pressure was reconstructed from 24-h intra-brachial and simultaneously obtained non-invasive finger pressure in 14 hypertensives and 8 normotensives. Supply was assessed by Diastolic Time Fraction (DTF, ratio of diastolic and heart period), demand by Rate-Pressure Product (RPP, systolic pressure times heart rate, HR) and supply/demand ratio by Adia/Asys, with Adia and Asys diastolic and systolic areas under the aortic pressure curve. Hypertensives had lower supply by DTF and higher demand by RPP than normotensives during the night. DTF decreased and RPP increased in both groups after awaking. The DTF of hypertensives decreased less becoming similar to the DTF of normotensives in the morning; the RPP remained higher. Adia/Asys followed the pattern of DTF. Findings from invasively and non-invasively determined pressure were similar. The cardiac oxygen supply/demand ratio in hypertensive patients is lower than in normotensives at night. With a smaller night-day differences, the hypertensives’ risk for cardiovascular events may be more evenly spread over the 24 h. This information can be obtained noninvasively

Multiparametric Renal MRI: An Intrasubject Test-Retest Repeatability Study

BACKGROUND: Renal multiparametric magnetic resonance imaging (MRI) is a promising tool for diagnosis, prognosis, and treatment monitoring in kidney disease. PURPOSE: To determine intrasubject test-retest repeatability of renal MRI measurements. STUDY TYPE: Prospective. POPULATION: Nineteen healthy subjects aged over 40 years. FIELD STRENGTH/SEQUENCES: T1 and T2 mapping, R2 * mapping or blood oxygenation level-dependent (BOLD) MRI, diffusion tensor imaging (DTI), and intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI), 2D phase contrast, arterial spin labelling (ASL), dynamic contrast enhanced (DCE) MRI, and quantitative Dixon for fat quantification at 3T. ASSESSMENT: Subjects were scanned twice with ~1 week between visits. Total scan time was ~1 hour. Postprocessing included motion correction, semiautomated segmentation of cortex and medulla, and fitting of the appropriate signal model. STATISTICAL TEST: To assess the repeatability, a Bland-Altman analysis was performed and coefficients of variation (CoVs), repeatability coefficients, and intraclass correlation coefficients were calculated. RESULTS: CoVs for relaxometry (T1 , T2 , R2 */BOLD) were below 6.1%, with the lowest CoVs for T2 maps and highest for R2 */BOLD. CoVs for all diffusion analyses were below 7.2%, except for perfusion fraction (FP ), with CoVs ranging from 18-24%. The CoV for renal sinus fat volume and percentage were both around 9%. Perfusion measurements were most repeatable with ASL (cortical perfusion only) and 2D phase contrast with CoVs of 10% and 13%, respectively. DCE perfusion had a CoV of 16%, while single kidney glomerular filtration rate (GFR) had a CoV of 13%. Repeatability coefficients (RCs) ranged from 7.7-87% (lowest/highest values for medullary mean diffusivity and cortical FP , respectively) and intraclass correlation coefficients (ICCs) ranged from -0.01 to 0.98 (lowest/highest values for cortical FP and renal sinus fat volume, respectively). DATA CONCLUSION: CoVs of most MRI measures of renal function and structure (with the exception of FP and perfusion as measured by DCE) were below 13%, which is comparable to standard clinical tests in nephrology. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1

Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis

Objectives: To investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches. Methods: Epigenetically regulated expression of DIO2 was explored by assessing methylation of positional CpG-dinucleotides and the respective DIO2 expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced DIO2 overexpression) or decreased (iopanoic acid). Results: OA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (ß=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (ß=5.58, p=0.0006). During in vitro chondrogenesis, DIO2 overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2a/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes. Conclusions: Our findings show how genetic variation at DIO2 could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Aims To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function

An International Multicenter Cohort Study on beta-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT.Methods: From 2 international registries of patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy &lt;18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope.Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31–3.17]; and HR, 1.99 [95% CI, 1.20–3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]).Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.</p

Effective Melanoma Immunotherapy in Mice by the Skin-Depigmenting Agent Monobenzone and the Adjuvants Imiquimod and CpG

Background: Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity. Methodology and Principal Findings: We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigen-specific immune response, which abolished subcutaneous B16. F10 melanoma growth in up to 85% of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60% of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation. Conclusions: MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B-and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readily applicable in the clini