Reference Cluster Normalization Improves Detection of Frontotemporal Lobar Degeneration by Means of FDG-PET.

Positron emission tomography with [18F] fluorodeoxyglucose (FDG-PET) plays a well-established role in assisting early detection of frontotemporal lobar degeneration (FTLD). Here, we examined the impact of intensity normalization to different reference areas on accuracy of FDG-PET to discriminate between patients with mild FTLD and healthy elderly subjects. FDG-PET was conducted at two centers using different acquisition protocols: 41 FTLD patients and 42 controls were studied at center 1, 11 FTLD patients and 13 controls were studied at center 2. All PET images were intensity normalized to the cerebellum, primary sensorimotor cortex (SMC), cerebral global mean (CGM), and a reference cluster with most preserved FDG uptake in the aforementioned patients group of center 1. Metabolic deficits in the patient group at center 1 appeared 1.5, 3.6, and 4.6 times greater in spatial extent, when tracer uptake was normalized to the reference cluster rather than to the cerebellum, SMC, and CGM, respectively. Logistic regression analyses based on normalized values from FTLD-typical regions showed that at center 1, cerebellar, SMC, CGM, and cluster normalizations differentiated patients from controls with accuracies of 86%, 76%, 75% and 90%, respectively. A similar order of effects was found at center 2. Cluster normalization leads to a significant increase of statistical power in detecting early FTLD-associated metabolic deficits. The established FTLD-specific cluster can be used to improve detection of FTLD on a single case basis at independent centers - a decisive step towards early diagnosis and prediction of FTLD syndromes enabling specific therapies in the future.

Projectes de modelatge i simulació avançada de sistemes mitjançant l'entorn ARENA

RESUM En l’exercici de les funcions típiques de qualsevol activitat humana, l’home ha de prendre decisions d’un o altre tipus permanentment i aquesta situació porta afegit, per lo general risc i incertesa, el que compromet la qualitat i l’èxit de la decisió. Per ajudar i contrarestar aquesta situació, l’home ha desenvolupat a través del temps una diversitat d’eines que li permeten minimitzar el risc i la incertesa en la presa de decisions. La simulació és una d’aquestes eines. Mitjançant la seva aplicació no només s’aconsegueix la comesa anterior, sinó que també es minimitzen els costos involucrats en la decisió mitjançant un millor ús dels recursos, la disminució del temps emprat per a la seva realització i la minimització de les probabilitats de risc. Aquest projecte representa la continuació d’un primer estudi introductori de la simulació anomenat: Estudi i guia docent per a modelatge i simulació de sistemes mitjançant l’entorn ARENA [9]. Realitzat per l’alumna d’Enginyeria en Organització Industrial de la Universitat de Vic, Montse Carbonell Crosas, l’any 2008 i sota la codirecció del director d’aquest segon projecte, el professor Juli Ordeix Rigo. Aquest nou projecte s’inicia amb una primera part teòrica, continguda dins del primer volum, la qual reforça els conceptes teòrics referents a la simulació amb ARENA, ja vistos en l’anterior projecte. Complementant aquells considerats bàsics i els de més utilitat i finalitza introduint nous conceptes avançats. Els nous capítols de temàtica avançada, junt als primers més bàsics de la primera part són exercitats dins de la segona, formant el segon volum d’aquest projecte. El mateix requereix la participació activa de l’alumne, per tal de realitzar cadascun dels 89 exercicis pràctics que es plantegen i poder onsolidar l’aprenentatge teòric d’aquesta eina avançada de simulació fent consultes als apartats teòrics recomanats dins de cada exercici. La complexitat dels exercicis anirà augmentant gradualment i s’insisteix en seguir la metodologia presentada en el projecte per a realitzar-los tots de forma ordenada i ascendent. L’ alumne quan acabi la part pràctica, haurà consolidat tota la part teòrica i serà capaç d’exercir com analista per tal de generar els seus propis projecte de simulació.

Social Cognition is not Reducible to Theory of Mind. When Children use Deontic Rules to Predict Others' Behaviors

The objective of this paper is to discuss whether children have a capacity for deonticreasoning that is irreducible to mentalizing. The results of two experiments point tothe existence of such non-mentalistic understanding and prediction of the behaviourof others. In Study 1, young children (3- and 4-year-olds) were told different versionsof classic false-belief tasks, some of which were modified by the introduction of a ruleor a regularity. When the task (a standard change of location task) included a rule, theperformance of 3-year-olds, who fail traditional false-belief tasks, significantly improved.In Study 2, 3-year-olds proved to be able to infer a rule from a social situation and touse it in order to predict the behaviour of a character involved in a modified versionof the false-belief task. These studies suggest that rules play a central role in the socialcognition of young children and that deontic reasoning might not necessarily involvemind reading.

Genome-wide arrays in routine diagnostics of hematological malignancies.

Over the last three decades, cytogenetic analysis of malignancies has become an integral part of disease evaluation and prediction of prognosis or responsiveness to therapy. In most diagnostic laboratories, conventional karyotyping, in conjunction with targeted fluorescence in situ hybridization analysis, is routinely performed to detect recurrent aberrations with prognostic implications. However, the genetic complexity of cancer cells requires a sensitive genome-wide analysis, enabling the detection of small genomic changes in a mixed cell population, as well as of regions of homozygosity. The advent of comprehensive high-resolution genomic tools, such as molecular karyotyping using comparative genomic hybridization or single-nucleotide polymorphism microarrays, has overcome many of the limitations of traditional cytogenetic techniques and has been used to study complex genomic lesions in, for example, leukemia. The clinical impact of the genomic copy-number and copy-neutral alterations identified by microarray technologies is growing rapidly and genome-wide array analysis is evolving into a diagnostic tool, to better identify high-risk patients and predict patients' outcomes from their genomic profiles. Here, we review the added clinical value of an array-based genome-wide screen in leukemia, and discuss the technical challenges and an interpretation workflow in applying arrays in the acquired cytogenetic diagnostic setting.

Diagnosis of invasive candidiasis in the ICU.

Invasive candidiasis ranges from 5 to 10 cases per 1,000 ICU admissions and represents 5% to 10% of all ICU-acquired infections, with an overall mortality comparable to that of severe sepsis/septic shock. A large majority of them are due to Candida albicans, but the proportion of strains with decreased sensitivity or resistance to fluconazole is increasingly reported. A high proportion of ICU patients become colonized, but only 5% to 30% of them develop an invasive infection. Progressive colonization and major abdominal surgery are common risk factors, but invasive candidiasis is difficult to predict and early diagnosis remains a major challenge. Indeed, blood cultures are positive in a minority of cases and often late in the course of infection. New nonculture-based laboratory techniques may contribute to early diagnosis and management of invasive candidiasis. Both serologic (mannan, antimannan, and betaglucan) and molecular (Candida-specific PCR in blood and serum) have been applied as serial screening procedures in high-risk patients. However, although reasonably sensitive and specific, these techniques are largely investigational and their clinical usefulness remains to be established. Identification of patients susceptible to benefit from empirical antifungal treatment remains challenging, but it is mandatory to avoid antifungal overuse in critically ill patients. Growing evidence suggests that monitoring the dynamic of Candida colonization in surgical patients and prediction rules based on combined risk factors may be used to identify ICU patients at high risk of invasive candidiasis susceptible to benefit from prophylaxis or preemptive antifungal treatment.

Use of Railroad Flat Cars for Low-Volume Road Bridges, August 1999

In an attempt to solve the bridge problem faced by many county engineers, this investigation focused on a low cost bridge alternative that consists of using railroad flatcars (RRFC) as the bridge superstructure. The intent of this study was to determine whether these types of bridges are structurally adequate and potentially feasible for use on low volume roads. A questionnaire was sent to the Bridge Committee members of the American Association of State Highway and Transportation Officials (AASHTO) to determine their use of RRFC bridges and to assess the pros and cons of these bridges based on others’ experiences. It was found that these types of bridges are widely used in many states with large rural populations and they are reported to be a viable bridge alternative due to their low cost, quick and easy installation, and low maintenance. A main focus of this investigation was to study an existing RRFC bridge that is located in Tama County, IA. This bridge was analyzed using computer modeling and field load testing. The dimensions of the major structural members of the flatcars in this bridge were measured and their properties calculated and used in an analytical grillage model. The analytical results were compared with those obtained in the field tests, which involved instrumenting the bridge and loading it with a fully loaded rear tandem-axle truck. Both sets of data (experimental and theoretical) show that the Tama County Bridge (TCB) experienced very low strains and deflections when loaded and the RRFCs appeared to be structurally adequate to serve as a bridge superstructure. A calculated load rating of the TCB agrees with this conclusion. Because many different types of flatcars exist, other flatcars were modeled and analyzed. It was very difficult to obtain the structural plans of RRFCs; thus, only two additional flatcars were analyzed. The results of these analyses also yielded very low strains and displacements. Taking into account the experiences of other states, the inspection of several RRFC bridges in Oklahoma, the field test and computer analysis of the TCB, and the computer analysis of two additional flatcars, RRFC bridges appear to provide a safe and feasible bridge alternative for low volume roads.

Structural assessment of single amino acid mutations: application to TP53 function.

Single amino acid substitution is the type of protein alteration most related to human diseases. Current studies seek primarily to distinguish neutral mutations from harmful ones. Very few methods offer an explanation of the final prediction result in terms of the probable structural or functional effect on the protein. In this study, we describe the use of three novel parameters to identify experimentally-verified critical residues of the TP53 protein (p53). The first two parameters make use of a surface clustering method to calculate the protein surface area of highly conserved regions or regions with high nonlocal atomic interaction energy (ANOLEA) score. These parameters help identify important functional regions on the surface of a protein. The last parameter involves the use of a new method for pseudobinding free-energy estimation to specifically probe the importance of residue side-chains to the stability of protein fold. A decision tree was designed to optimally combine these three parameters. The result was compared to the functional data stored in the International Agency for Research on Cancer (IARC) TP53 mutation database. The final prediction achieved a prediction accuracy of 70% and a Matthews correlation coefficient of 0.45. It also showed a high specificity of 91.8%. Mutations in the 85 correctly identified important residues represented 81.7% of the total mutations recorded in the database. In addition, the method was able to correctly assign a probable functional or structural role to the residues. Such information could be critical for the interpretation and prediction of the effect of missense mutations, as it not only provided the fundamental explanation of the observed effect, but also helped design the most appropriate laboratory experiment to verify the prediction results.

Fatigue Behavior of Air-Entrained Concrete, HR-183, 1977

When a material fails under a number of repeated loads, each smaller than the ultimate static strength, a fatigue failure is said to have taken place. Many studies have been made to characterize the fatigue behavior of various engineering materials. The results of some of these studies have proved invaluable in the evaluation and prediction of the fatigue strength of structural materials. Considerable time and effort has gone into the evaluation of the fatigue behavior of metals. These early studies were motivated by practical considerations: The first fatigue tests were performed on materials that had been observed to fail after repeated loading of a magnitude less than that required for failure under the application of a single load. Mine-hoist chains, railway axles, and steam engine parts were among the first structural components to be recognized as exhibiting fatigue behavior. Since concrete is usually subjected to static loading rather than cyclic loading, need for knowledge of the fatigue behavior of concrete has lagged behind that of metals. One notable exception to this, however, is in the area of highway and airfield pavement design. Due to the fact that the fatigue behavior of concrete must be understood in the design of pavements and reinforced concrete bridges, highway engineers have provided the motivation for concrete fatigue studies since the 1920's.

Fatigue Behavior of Air-Entrained Concrete: Phase II, HR-197, 1979

When a material fails under a number of repeated loads, each smaller than the ultimate static strength, a fatigue failure is said to have taken place. Many studies have been made to characterize the fatigue behavior of various engineering materials. The results of some of these studies have proved invaluable in the evaluation and prediction of the fatigue strength of structural materials. Considerable time and effort have gone into the evaluation of the fatigue behavior of metals. These early studies were motivated by practical considerations: the first fatigue tests were performed on materials that had been observed to fail after repeated loading of a magnitude less than that required for failure under the application of a single load. Mine-hoist chains (1829), railway axles (1852), and steam engine parts were among the first structural components to be recognized as exhibiting fatigue behavior. Since concrete is usually subjected to static loading rather than cyclic loading, need for knowledge of the fatigue behavior of concrete has lagged behind that of metals. One notable exception to this, however, is in the area of highway and airfield pavement design. Due to the fact that the fatigue behavior of concrete must be understood in the design of pavements and reinforced concrete bridges, highway engineers have provided the motivation for concrete fatigue studies since the 1920s.

An operator formulation of the multiscale finite-volume method with correction function

The multiscale finite-volume (MSFV) method has been derived to efficiently solve large problems with spatially varying coefficients. The fine-scale problem is subdivided into local problems that can be solved separately and are coupled by a global problem. This algorithm, in consequence, shares some characteristics with two-level domain decomposition (DD) methods. However, the MSFV algorithm is different in that it incorporates a flux reconstruction step, which delivers a fine-scale mass conservative flux field without the need for iterating. This is achieved by the use of two overlapping coarse grids. The recently introduced correction function allows for a consistent handling of source terms, which makes the MSFV method a flexible algorithm that is applicable to a wide spectrum of problems. It is demonstrated that the MSFV operator, used to compute an approximate pressure solution, can be equivalently constructed by writing the Schur complement with a tangential approximation of a single-cell overlapping grid and incorporation of appropriate coarse-scale mass-balance equations.

Differences in the evolutionary history of disease genes affected by dominant or recessive mutations

Background: Global analyses of human disease genes by computational methods have yielded important advances in the understanding of human diseases. Generally these studies have treated the group of disease genes uniformly, thus ignoring the type of disease-causing mutations (dominant or recessive). In this report we present a comprehensive study of the evolutionary history of autosomal disease genes separated by mode of inheritance.Results: We examine differences in protein and coding sequence conservation between dominant and recessive human disease genes. Our analysis shows that disease genes affected by dominant mutations are more conserved than those affected by recessive mutations. This could be a consequence of the fact that recessive mutations remain hidden from selection while heterozygous. Furthermore, we employ functional annotation analysis and investigations into disease severity to support this hypothesis. Conclusion: This study elucidates important differences between dominantly- and recessively-acting disease genes in terms of protein and DNA sequence conservation, paralogy and essentiality. We propose that the division of disease genes by mode of inheritance will enhance both understanding of the disease process and prediction of candidate disease genes in the future.

Smith Predictor Sliding Mode Closed-loop Glucose Controller in Type 1 Diabetes

Type 1 diabetic patients depend on external insulin delivery to keep their blood glucose within near-normal ranges. In this work, two robust closed-loop controllers for blood glucose regulation are developed to prevent the life-threatening hypoglycemia, as well as to avoid extended hyperglycemia. The proposed controllers are designed by using the sliding mode control technique in a Smith predictor structure. To improve meal disturbance rejection, a simple feedforward controller is added to inject meal-time insulin bolus. Simulations scenarios were used to test the controllers, and showed the controllers ability to maintain the glucose levels within the safe limits in the presence of errors in measurements, modeling and meal estimation

Are niche-based species distribution models transferable in space?

Aim To assess the geographical transferability of niche-based species distribution models fitted with two modelling techniques. Location Two distinct geographical study areas in Switzerland and Austria, in the subalpine and alpine belts. Methods Generalized linear and generalized additive models (GLM and GAM) with a binomial probability distribution and a logit link were fitted for 54 plant species, based on topoclimatic predictor variables. These models were then evaluated quantitatively and used for spatially explicit predictions within (internal evaluation and prediction) and between (external evaluation and prediction) the two regions. Comparisons of evaluations and spatial predictions between regions and models were conducted in order to test if species and methods meet the criteria of full transferability. By full transferability, we mean that: (1) the internal evaluation of models fitted in region A and B must be similar; (2) a model fitted in region A must at least retain a comparable external evaluation when projected into region B, and vice-versa; and (3) internal and external spatial predictions have to match within both regions. Results The measures of model fit are, on average, 24% higher for GAMs than for GLMs in both regions. However, the differences between internal and external evaluations (AUC coefficient) are also higher for GAMs than for GLMs (a difference of 30% for models fitted in Switzerland and 54% for models fitted in Austria). Transferability, as measured with the AUC evaluation, fails for 68% of the species in Switzerland and 55% in Austria for GLMs (respectively for 67% and 53% of the species for GAMs). For both GAMs and GLMs, the agreement between internal and external predictions is rather weak on average (Kulczynski's coefficient in the range 0.3-0.4), but varies widely among individual species. The dominant pattern is an asymmetrical transferability between the two study regions (a mean decrease of 20% for the AUC coefficient when the models are transferred from Switzerland and 13% when they are transferred from Austria). Main conclusions The large inter-specific variability observed among the 54 study species underlines the need to consider more than a few species to test properly the transferability of species distribution models. The pronounced asymmetry in transferability between the two study regions may be due to peculiarities of these regions, such as differences in the ranges of environmental predictors or the varied impact of land-use history, or to species-specific reasons like differential phenotypic plasticity, existence of ecotypes or varied dependence on biotic interactions that are not properly incorporated into niche-based models. The lower variation between internal and external evaluation of GLMs compared to GAMs further suggests that overfitting may reduce transferability. Overall, a limited geographical transferability calls for caution when projecting niche-based models for assessing the fate of species in future environments.