Adaptive strategy for the statistical analysis of connectomes.

We study an adaptive statistical approach to analyze brain networks represented by brain connection matrices of interregional connectivity (connectomes). Our approach is at a middle level between a global analysis and single connections analysis by considering subnetworks of the global brain network. These subnetworks represent either the inter-connectivity between two brain anatomical regions or by the intra-connectivity within the same brain anatomical region. An appropriate summary statistic, that characterizes a meaningful feature of the subnetwork, is evaluated. Based on this summary statistic, a statistical test is performed to derive the corresponding p-value. The reformulation of the problem in this way reduces the number of statistical tests in an orderly fashion based on our understanding of the problem. Considering the global testing problem, the p-values are corrected to control the rate of false discoveries. Finally, the procedure is followed by a local investigation within the significant subnetworks. We contrast this strategy with the one based on the individual measures in terms of power. We show that this strategy has a great potential, in particular in cases where the subnetworks are well defined and the summary statistics are properly chosen. As an application example, we compare structural brain connection matrices of two groups of subjects with a 22q11.2 deletion syndrome, distinguished by their IQ scores.

Global Nash convergence of Foster and Young's regret testing

We construct an uncoupled randomized strategy of repeated play such that, if every player follows such a strategy, then the joint mixed strategy profiles converge, almost surely, to a Nash equilibrium of the one-shot game. The procedure requires very little in terms of players' information about the game. In fact, players' actions are based only on their own past payoffs and, in a variant of the strategy, players need not even know that their payoffs are determined through other players' actions. The procedure works for general finite games and is based on appropriate modifications of a simple stochastic learningrule introduced by Foster and Young.

Testing mouse mammary tumor virus superantigen as adjuvant in cytotoxic T-lymphocyte responses against a melanoma tumor antigen.

Cytotoxic T cells represent a powerful strategy for antitumor treatment. Depending on the route of injection, an important role for CD4 T cell-mediated help was observed in the induction of this response. For this reason, we investigated whether induction of a CTL response to the HLA-A2-restricted immunodominant peptide melanoma antigen Melan-A was improved by using rVVs expressing the CTL-defined epitope alone or in combination with an SAg. In the latter case, the few infected dendritic cells simultaneously presented an SAg and an antigen, i.e., peptide. Here, we show that the anti-Melan-A response was efficiently induced but not significantly improved by coexpression of the SAg.

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.

Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing.

Influence of magnetic field strength and image registration strategy on voxel-based morphometry in a study of Alzheimer's disease.

Multi-centre data repositories like the Alzheimer's Disease Neuroimaging Initiative (ADNI) offer a unique research platform, but pose questions concerning comparability of results when using a range of imaging protocols and data processing algorithms. The variability is mainly due to the non-quantitative character of the widely used structural T1-weighted magnetic resonance (MR) images. Although the stability of the main effect of Alzheimer's disease (AD) on brain structure across platforms and field strength has been addressed in previous studies using multi-site MR images, there are only sparse empirically-based recommendations for processing and analysis of pooled multi-centre structural MR data acquired at different magnetic field strengths (MFS). Aiming to minimise potential systematic bias when using ADNI data we investigate the specific contributions of spatial registration strategies and the impact of MFS on voxel-based morphometry in AD. We perform a whole-brain analysis within the framework of Statistical Parametric Mapping, testing for main effects of various diffeomorphic spatial registration strategies, of MFS and their interaction with disease status. Beyond the confirmation of medial temporal lobe volume loss in AD, we detect a significant impact of spatial registration strategy on estimation of AD related atrophy. Additionally, we report a significant effect of MFS on the assessment of brain anatomy (i) in the cerebellum, (ii) the precentral gyrus and (iii) the thalamus bilaterally, showing no interaction with the disease status. We provide empirical evidence in support of pooling data in multi-centre VBM studies irrespective of disease status or MFS.

Observations on Software Testing Practice

This thesis investigates factors that affect software testing practice. The thesis consists of empirical studies, in which the affecting factors were analyzed and interpreted using quantitative and qualitative methods. First, the Delphi method was used to specify the scope of the thesis. Secondly, for the quantitative analysis 40industry experts from 30 organizational units (OUs) were interviewed. The survey method was used to explore factors that affect software testing practice. Conclusions were derived using correlation and regression analysis. Thirdly, from these 30 OUs, five were further selected for an in-depth case study. The data was collected through 41 semi-structured interviews. The affecting factors and their relationships were interpreted with qualitative analysis using grounded theory as the research method. The practice of software testing was analyzed from the process improvement and knowledge management viewpoints. The qualitative and quantitativeresults were triangulated to increase the validity of the thesis. Results suggested that testing ought to be adjusted according to the business orientation of the OU; the business orientation affects the testing organization and knowledge management strategy, and the business orientation andthe knowledge management strategy affect outsourcing. As a special case, the complex relationship between testing schedules and knowledge transfer is discussed. The results of this thesis can be used in improvingtesting processes and knowledge management in software testing.

Empirical study on the adoption, use and effects of cloud-based testing

Cloud computing is a practically relevant paradigm in computing today. Testing is one of the distinct areas where cloud computing can be applied. This study addressed the applicability of cloud computing for testing within organizational and strategic contexts. The study focused on issues related to the adoption, use and effects of cloudbased testing. The study applied empirical research methods. The data was collected through interviews with practitioners from 30 organizations and was analysed using the grounded theory method. The research process consisted of four phases. The first phase studied the definitions and perceptions related to cloud-based testing. The second phase observed cloud-based testing in real-life practice. The third phase analysed quality in the context of cloud application development. The fourth phase studied the applicability of cloud computing in the gaming industry. The results showed that cloud computing is relevant and applicable for testing and application development, as well as other areas, e.g., game development. The research identified the benefits, challenges, requirements and effects of cloud-based testing; and formulated a roadmap and strategy for adopting cloud-based testing. The study also explored quality issues in cloud application development. As a special case, the research included a study on applicability of cloud computing in game development. The results can be used by companies to enhance the processes for managing cloudbased testing, evaluating practical cloud-based testing work and assessing the appropriateness of cloud-based testing for specific testing needs.

New [18F]Tracers for Alzheimer's Disease Imaging. Labeling Synthesis And Biological Testing

Alzheimer’s disease (AD) is the most common form of dementia. Characteristic changes in an AD brain are the formation of β-amyloid protein (Aβ) plaques and neurofibrillary tangles, though other alterations in the brain have also been connected to AD. No cure is available for AD and it is one of the leading causes of death among the elderly in developed countries. Liposomes are biocompatible and biodegradable spherical phospholipid bilayer vesicles that can enclose various compounds. Several functional groups can be attached on the surface of liposomes in order to achieve long-circulating target-specific liposomes. Liposomes can be utilized as drug carriers and vehicles for imaging agents. Positron emission tomography (PET) is a non-invasive imaging method to study biological processes in living organisms. In this study using nucleophilic 18F-labeling synthesis, various synthesis approaches and leaving groups for novel PET imaging tracers have been developed to target AD pathology in the brain. The tracers were the thioflavin derivative [18F]flutemetamol, curcumin derivative [18F]treg-curcumin, and functionalized [18F]nanoliposomes, which all target Aβ in the AD brain. These tracers were evaluated using transgenic AD mouse models. In addition, 18F-labeling synthesis was developed for a tracer targeting the S1P3 receptor. The chosen 18F-fluorination strategy had an effect on the radiochemical yield and specific activity of the tracers. [18F]Treg-curcumin and functionalized [18F]nanoliposomes had low uptake in AD mouse brain, whereas [18F]flutemetamol exhibited the appropriate properties for preclinical Aβ-imaging. All of these tracers can be utilized in studies of the pathology and treatment of AD and related diseases.

A school-based cognitive behavior modification intervention strategy for learned helpless mentally retarded students

This study assessed the usefulness of a cognitive behavior modification (CBM) intervention package with mentally retarded students in overcoming learned helplessness and improving learning strategies. It also examined the feasibility of instructing teachers in the use of such a training program for a classroom setting. A modified single subject design across individuals was employed using two groups of three subjects. Three students from each of two segregated schools for the mentally retarded were selected using a teacher questionnaire and pupil checklist of the most learned helpless students enrolled there. Three additional learned helplessness assessments were conducted on each subject before and after the intervention in order to evaluate the usefulness of the program in alleviating learned helplessness. A classroom environment was created with the three students from each school engaged in three twenty minute work sessions a week with the experimenter and a tutor experimenter (TE) as instructors. Baseline measurements were established on seven targeted behaviors for each subject: task-relevant speech, task-irrelevant speech, speech denoting a positive evaluation of performance, speech denoting a negative evaluation of performance, proportion of time on task, non-verbal positive evaluation of performance and non-verbal negative evaluation of performance. The intervention package combined a variety of CBM techniques such as Meichenbaum's (1977) Stop, Look and Listen approach, role rehearsal and feedback. During the intervention each subject met with his TE twice a week for an individual half-hour session and one joint twenty minute session with all three students, the experimentor and one TE. Five weeks after the end of this experiment one follow up probe was conducted. All baseline, post-intervention and probe sessions were videotaped. The seven targeted behaviors were coded and comparisons of baseline, post intervention, and probe testing were presented in graph form. Results showed a reduction in learned helplessness in all subjects. Improvement was noted in each of the seven targeted behaviors for each of the six subjects. This study indicated that mentally retarded children can be taught to reduce learned helplessness with the aid of a CBM intervention package. It also showed that CBM is a viable approach in helping mentally retarded students acquire more effective learning strategies. Because the TEs (Tutor experimenters) had no trouble learning and implementing this program, it was considered feasible for teachers to use similar methods in the classroom.

Infant Attachment Security and the Timing of Puberty: Testing an Evolutionary Hypothesis

Life-history theories of the early programming of human reproductive strategy stipulate that early rearing experience, including that reflected in infant-parent attachment security, regulates psychological, behavioral, and reproductive development. We tested the hypothesis that infant attachment insecurity, compared with infant attachment security, at the age of 15 months predicts earlier pubertal maturation. Focusing on 373 White females enrolled in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development, we gathered data from annual physical exams from the ages of 9½ years to 15½ years and from self-reported age of menarche. Results revealed that individuals who had been insecure infants initiated and completed pubertal development earlier and had an earlier age of menarche compared with individuals who had been secure infants, even after accounting for age of menarche in the infants’ mothers. These results support a conditional-adaptational view of individual differences in attachment security and raise questions about the biological mechanisms responsible for the attachment effects we discerned.

Testing search strategies for systematic reviews in the Medline literature database through PubMed

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Microtensile Bond Strenh Between Indirect Composite Resin Inlays and Dentin: Effect of Cementation Strategy and Mechanical Aging

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Evaluation of a New Strategy for Control of Bovine Tuberculosis in Michigan White-Tailed Deer: Year 1 Progress Report

The State of Michigan is striving to eliminate bovine tuberculosis (Tb) infection among free-ranging white-tailed deer in the northeastern Lower Peninsula of the state. Aggressive reduction in the overall deer population abundance may help to further reduce TB prevalence, but this course of action is unacceptable to many hunters and landowners. Targeted culling of sick deer would likely be far more acceptable to these stakeholders, so in the winter of 2003 the Michigan Department of Natural Resources pilot-trialed a new strategy based on live-trapping and Tb-testing of wild deer. The field study was conducted in a township with relatively high TB prevalence within Deer Management Unit 452 in the northeastern Lower Peninsula. Over a 2-month trapping period, 119 individual deer were live-trapped, blood sampled, fitted with a radio-collar, and released. A total of 31 of these deer were subsequently classified as Tb-suspect by at least one of five blood tests employed (however there was a low level of agreement among tests). A delay in testing meant that only six of these suspect deer were culled by sharpshooters before pre-programmed release of their radio-collars, after which they could no longer be located. Mycobacterium bovis was cultured from one of these six suspect deer; the other five were negative on culture. All target deer were located to within shooting range with 1 – 2 days of effort, and all the radio-collars on the apparently-healthy deer dropped off after the intended 90-day interval, and were thereafter recovered for re-use. There was considerable support for this pilot project among hunters, farmers, state and federal agriculture agencies, the media and the general public, and so we recommend that further field trials be undertaken using this technique. The initial focus of these trials should be on improving the efficacy and reliability of the blood testing procedure.

Plasma Pro-B-Type Natriuretic Peptide Testing as a Screening Method for Hypertrophic Cardiomyopathy

Background: Clinical multistage risk assessment associated with electrocardiogram (ECG) and NT-proBNP may be a feasible strategy to screen hypertrophic cardiomyopathy (HCM). We investigated the effectiveness of a screening based on ECG and NT-proBNP in first-degree relatives of patients with HCM. Methods and Results: A total of 106 first-degree relatives were included. All individuals were evaluated by echocardiography, ECG, NT-proBNP, and molecular screening (available for 65 individuals). From the 106 individuals, 36 (34%) had diagnosis confirmed by echocardiography. Using echocardiography as the gold standard, ECG criteria had a sensitivity of 0.71, 0.42, and 0.52 for the Romhilt-Estes, Sokolow-Lyon, and Cornell criteria, respectively. Mean values of NT-ProBNP were higher in affected as compared with nonaffected relatives (26.1 vs. 1290.5, P < .001). The AUC of NT-proBNP was 0.98. Using a cutoff value of 70 pg/mL, we observed a sensitivity of 0.92 and specificity of 0.96. Using molecular genetics as the gold standard, ECG criteria had a sensitivity of 0.67, 0.37, and 0.42 for the Romhilt-Estes, Sokolow-Lyon, and Cornell criteria, respectively. Using a cutoff value of 70 pg/mL, we observed a sensitivity of 0.83 and specificity of 0.98. Conclusion: Values of NT-proBNP above 70 pg/mL can be used to effectively select high-risk first-degree relatives for HCM screening. (J Cardiac Fail 2012;18:564-568)

Using stress testing to guide primary prevention of coronary heart disease among intermediate-risk patients: a cost-effectiveness analysis

Noninvasive stress testing might guide the use of aspirin and statins for primary prevention of coronary heart disease, but it is unclear if such a strategy would be cost effective.