Using tools to help cost estimating and pricing: examination of costing model's and cost breakdown's workability and their capability to cooperative work

Tämä diplomityö käsittelee työkaluja, jotka on suunniteltu kustannusten ennakointiin ja hinnan asetantaan. Aluksi on käyty läpi perinteisen ja toimintoperusteisen kustannuslaskennan perusteita. Näiden menetelmien välisiä eroja on tarkasteltu ja toimintoperusteisen kustannuslaskennan paremmin sopivuus nykypäivän yrityksille on perusteltu. Toisena käsitellään hinnoittelu. Hinnan merkitys, hinnoittelumenetelmät ja päätös lopullisesta hinnasta on käyty läpi. Hinnoittelun jälkeen esitellään kustannusjärjestelmät ja kustannusten arviointi. Nämä asiat todistavat, että tarkat kustannusarviot ovat elintärkeitä yritykselle. Tuotteen kustannusarviointi, hinnan asetanta ja tarjoaminen ovat erittäin merkityksellisiä asioita ottaen huomioon koko projektin elinkaaren ja tulevat tuotot. Nykyään on yleistä käyttää työkaluja kustannusarvioinnissa ja joskus myös hinnoittelussa. Työkalujen luotettavuus on tiedettävä, ennenkuin työkalut otetaan käyttöön. Myös työkalujen käyttäjät täytyy perehdyttää hyvin. Muuten yritys todennäköisesti kohtaa odottamattomia ja epämiellyttäviä yllätyksiä.

Predicting human resting-state functional connectivity from structural connectivity

In the cerebral cortex, the activity levels of neuronal populations are continuously fluctuating. When neuronal activity, as measured using functional MRI (fMRI), is temporally coherent across 2 populations, those populations are said to be functionally connected. Functional connectivity has previously been shown to correlate with structural (anatomical) connectivity patterns at an aggregate level. In the present study we investigate, with the aid of computational modeling, whether systems-level properties of functional networks-including their spatial statistics and their persistence across time-can be accounted for by properties of the underlying anatomical network. We measured resting state functional connectivity (using fMRI) and structural connectivity (using diffusion spectrum imaging tractography) in the same individuals at high resolution. Structural connectivity then provided the couplings for a model of macroscopic cortical dynamics. In both model and data, we observed (i) that strong functional connections commonly exist between regions with no direct structural connection, rendering the inference of structural connectivity from functional connectivity impractical; (ii) that indirect connections and interregional distance accounted for some of the variance in functional connectivity that was unexplained by direct structural connectivity; and (iii) that resting-state functional connectivity exhibits variability within and across both scanning sessions and model runs. These empirical and modeling results demonstrate that although resting state functional connectivity is variable and is frequently present between regions without direct structural linkage, its strength, persistence, and spatial statistics are nevertheless constrained by the large-scale anatomical structure of the human cerebral cortex.

Classifying minimally disabled multiple sclerosis patients from resting state functional connectivity.

Multiple sclerosis (MS), a variable and diffuse disease affecting white and gray matter, is known to cause functional connectivity anomalies in patients. However, related studies published to-date are post hoc; our hypothesis was that such alterations could discriminate between patients and healthy controls in a predictive setting, laying the groundwork for imaging-based prognosis. Using functional magnetic resonance imaging resting state data of 22 minimally disabled MS patients and 14 controls, we developed a predictive model of connectivity alterations in MS: a whole-brain connectivity matrix was built for each subject from the slow oscillations (<0.11Hz) of region-averaged time series, and a pattern recognition technique was used to learn a discriminant function indicating which particular functional connections are most affected by disease. Classification performance using strict cross-validation yielded a sensitivity of 82% (above chance at p<0.005) and specificity of 86% (p<0.01) to distinguish between MS patients and controls. The most discriminative connectivity changes were found in subcortical and temporal regions, and contralateral connections were more discriminative than ipsilateral connections. The pattern of decreased discriminative connections can be summarized post hoc in an index that correlates positively (ρ=0.61) with white matter lesion load, possibly indicating functional reorganisation to cope with increasing lesion load. These results are consistent with a subtle but widespread impact of lesions in white matter and in gray matter structures serving as high-level integrative hubs. These findings suggest that predictive models of resting state fMRI can reveal specific anomalies due to MS with high sensitivity and specificity, potentially leading to new non-invasive markers.

Correlations of glycogen synthase and phosphorylase activities with glycogen concentration in human muscle biopsies. Evidence for a double-feedback mechanism regulating glycogen synthesis and breakdown.

The purpose of this study was to verify in man the relationships of muscle glycogen synthase and phosphorylase activities with glycogen concentration that were reported in animal studies. The upper level of glycogen concentration in muscle is known to be tightly controlled, and glycogen concentration was reported to have an inhibitory effect on synthase activity and a stimulatory effect on phosphorylase activity. Glycogen synthase and phosphorylase activity and glycogen concentration were measured in muscle biopsies in a group of nine normal subjects after stimulating an increase of their muscle glycogen concentration through either an intravenous glucose-insulin infusion to stimulate glycogen synthesis, or an Intralipid (Vitrum, Stockholm, Sweden) infusion in the basal state to inhibit glycogen mobilization by favoring lipid oxidation at the expense of glucose oxidation. Phosphorylase activity increased from 71.3 +/- 21.0 to 152.8 +/- 20.0 nmol/min/mg protein (P < .005) after the glucose-insulin infusion. Phosphorylase activity was positively correlated with glycogen concentration (P = .005 and P = .0001) after the glucose-insulin and Intralipid infusions, respectively. Insulin-stimulated glycogen synthase activity was significantly negatively correlated with glycogen concentration at the end of the Intralipid infusion (P < .005). In conclusion, by demonstrating a negative correlation of glycogen concentration with glycogen synthase and a positive correlation with phosphorylase, this study might confirm in man the double-feedback mechanism by which changes in glycogen concentration regulate glycogen synthase and phosphorylase activities. It suggests that this mechanism might play an important role in the regulation of glucose storage.

A parameterization method for the computation of invariant tori and their whiskers in quasi-periodic maps: explorations and mechanisms for the breakdown of hyperbolicity

In two previous papers [J. Differential Equations, 228 (2006), pp. 530 579; Discrete Contin. Dyn. Syst. Ser. B, 6 (2006), pp. 1261 1300] we have developed fast algorithms for the computations of invariant tori in quasi‐periodic systems and developed theorems that assess their accuracy. In this paper, we study the results of implementing these algorithms and study their performance in actual implementations. More importantly, we note that, due to the speed of the algorithms and the theoretical developments about their reliability, we can compute with confidence invariant objects close to the breakdown of their hyperbolicity properties. This allows us to identify a mechanism of loss of hyperbolicity and measure some of its quantitative regularities. We find that some systems lose hyperbolicity because the stable and unstable bundles approach each other but the Lyapunov multipliers remain away from 1. We find empirically that, close to the breakdown, the distances between the invariant bundles and the Lyapunov multipliers which are natural measures of hyperbolicity depend on the parameters, with power laws with universal exponents. We also observe that, even if the rigorous justifications in [J. Differential Equations, 228 (2006), pp. 530-579] are developed only for hyperbolic tori, the algorithms work also for elliptic tori in Hamiltonian systems. We can continue these tori and also compute some bifurcations at resonance which may lead to the existence of hyperbolic tori with nonorientable bundles. We compute manifolds tangent to nonorientable bundles.

APOE status modulates the changes in network connectivity induced by brain stimulation in non-demented elders.

Behavioral consequences of a brain insult represent an interaction between the injury and the capacity of the rest of the brain to adapt to it. We provide experimental support for the notion that genetic factors play a critical role in such adaptation. We induced a controlled brain disruption using repetitive transcranial magnetic stimulation (rTMS) and show that APOE status determines its impact on distributed brain networks as assessed by functional MRI (fMRI).Twenty non-demented elders exhibiting mild memory dysfunction underwent two fMRI studies during face-name encoding tasks (before and after rTMS). Baseline task performance was associated with activation of a network of brain regions in prefrontal, parietal, medial temporal and visual associative areas. APOE ε4 bearers exhibited this pattern in two separate independent components, whereas ε4-non carriers presented a single partially overlapping network. Following rTMS all subjects showed slight ameliorations in memory performance, regardless of APOE status. However, after rTMS APOE ε4-carriers showed significant changes in brain network activation, expressing strikingly similar spatial configuration as the one observed in the non-carrier group prior to stimulation. Similarly, activity in areas of the default-mode network (DMN) was found in a single component among the ε4-non bearers, whereas among carriers it appeared disaggregated in three distinct spatiotemporal components that changed to an integrated single component after rTMS. Our findings demonstrate that genetic background play a fundamental role in the brain responses to focal insults, conditioning expression of distinct brain networks to sustain similar cognitive performance.

Basal ganglia-cortical structural connectivity in Huntington's disease.

Huntington's disease is an incurable neurodegenerative disease caused by inheritance of an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat within the Huntingtin gene. Extensive volume loss and altered diffusion metrics in the basal ganglia, cortex and white matter are seen when patients with Huntington's disease (HD) undergo structural imaging, suggesting that changes in basal ganglia-cortical structural connectivity occur. The aims of this study were to characterise altered patterns of basal ganglia-cortical structural connectivity with high anatomical precision in premanifest and early manifest HD, and to identify associations between structural connectivity and genetic or clinical markers of HD. 3-Tesla diffusion tensor magnetic resonance images were acquired from 14 early manifest HD subjects, 17 premanifest HD subjects and 18 controls. Voxel-based analyses of probabilistic tractography were used to quantify basal ganglia-cortical structural connections. Canonical variate analysis was used to demonstrate disease-associated patterns of altered connectivity and to test for associations between connectivity and genetic and clinical markers of HD; this is the first study in which such analyses have been used. Widespread changes were seen in basal ganglia-cortical structural connectivity in early manifest HD subjects; this has relevance for development of therapies targeting the striatum. Premanifest HD subjects had a pattern of connectivity more similar to that of controls, suggesting progressive change in connections over time. Associations between structural connectivity patterns and motor and cognitive markers of disease severity were present in early manifest subjects. Our data suggest the clinical phenotype in manifest HD may be at least partly a result of altered connectivity. Hum Brain Mapp 36:1728-1740, 2015. © 2015 Wiley Periodicals, Inc.

Reliable computation of robust response tori on the verge of breakdown

We prove the existence and local uniqueness of invariant tori on the verge of breakdown for two systems: the quasi-periodically driven logistic map and the quasi-periodically forced standard map. These systems exemplify two scenarios: the Heagy-Hammel route for the creation of strange non- chaotic attractors and the nonsmooth bifurcation of saddle invariant tori. Our proofs are computer- assisted and are based on a tailored version of the Newton-Kantorovich theorem. The proofs cannot be performed using classical perturbation theory because the two scenarios are very far from the perturbative regime, and fundamental hypotheses such as reducibility or hyperbolicity either do not hold or are very close to failing. Our proofs are based on a reliable computation of the invariant tori and a careful study of their dynamical properties, leading to the rigorous validation of the numerical results with our novel computational techniques.

Structural Brain Connectivity in School-Age Preterm Infants Provides Evidence for Impaired Networks Relevant for Higher Order Cognitive Skills and Social Cognition.

Extreme prematurity and pregnancy conditions leading to intrauterine growth restriction (IUGR) affect thousands of newborns every year and increase their risk for poor higher order cognitive and social skills at school age. However, little is known about the brain structural basis of these disabilities. To compare the structural integrity of neural circuits between prematurely born controls and children born extreme preterm (EP) or with IUGR at school age, long-ranging and short-ranging connections were noninvasively mapped across cortical hemispheres by connection matrices derived from diffusion tensor tractography. Brain connectivity was modeled along fiber bundles connecting 83 brain regions by a weighted characterization of structural connectivity (SC). EP and IUGR subjects, when compared with controls, had decreased fractional anisotropy-weighted SC (FAw-SC) of cortico-basal ganglia-thalamo-cortical loop connections while cortico-cortical association connections showed both decreased and increased FAw-SC. FAw-SC strength of these connections was associated with poorer socio-cognitive performance in both EP and IUGR children.

Metabolic connectivity as index of verbal working memory.

Positron emission tomography (PET) data are commonly analyzed in terms of regional intensity, while covariant information is not taken into account. Here, we searched for network correlates of healthy cognitive function in resting state PET data. PET with [(18)F]-fluorodeoxyglucose and a test of verbal working memory (WM) were administered to 35 young healthy adults. Metabolic connectivity was modeled at a group level using sparse inverse covariance estimation. Among 13 WM-relevant Brodmann areas (BAs), 6 appeared to be robustly connected. Connectivity within this network was significantly stronger in subjects with above-median WM performance. In respect to regional intensity, i.e., metabolism, no difference between groups was found. The results encourage examination of covariant patterns in FDG-PET data from non-neurodegenerative populations.

Endoscopic epiglottopexy using Lichtenberger's needle carrier to avoid breakdown of repair.

Severe type III laryngomalacia LM is represented by a retroflexed epiglottis that touches the posterior pharyngeal wall and obstructs the laryngeal inlet. Endoscopic epiglottopexy is advised in such cases wherein pexy sutures are passed between the epiglottis and base of tongue. Using conventional needle carriers, it is difficult to pass such sutures that go deep enough into the tongue base. Such a pexy is prone to a break down. We describe a novel technique of placing these glossoepiglottic sutures using the Lichtenberger's needle carrier. We used this technique in three patients with excellent results and report no complications. We propose to use this technique in cases of epiglottic prolapse seen in severe LM and certain hypotonic conditions.

Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth.

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts.