Monitoring inflammation and airway remodeling by FMT in a chronic asthma model

Asthma is a multifactorial disease for which a variety of mouse models have been developed. A major drawback of these models is represented by the transient nature of the airway pathology peaking 24 to 72 hours after challenge and resolving in 1 to 2 weeks. The objective of this study is to characterize the temporal evolution of pulmonary inflammation and remodeling in a recently described mouse model of chronic asthma (8 week treatment with 3 allergens relevant for the human pathology: Dust mite, Ragweed, and Aspergillus; DRA). We studied the DRA model taking advantage of fluorescence molecular tomography (FMT) imaging using near-infrared probes to non-invasively evaluate lung inflammation and airway remodeling. At 4, 6, 8 or 11 weeks, cathepsin- and metalloproteinase-dependent fluorescence was evaluated in vivo. A subgroup of animals, after 4 weeks of DRA, was treated with Budesonide (100 µg/kg intranasally) daily for 4 weeks. Cathepsin-dependent fluorescence in DRA-sensitized mice resulted significantly increased at 6 and 8 weeks, and was markedly inhibited by budesonide. This fluorescent signal well correlated with ex vivo analysis such as bronchoalveolar lavage eosinophils and alveolar cell infiltration. Metalloproteinase-dependent fluorescence was significantly increased at 8 and 11 weeks, nicely correlated with collagen deposition, as evaluated histologically by Masson’s Trichrome staining, and airway epithelium hypertrophy, and was also partly inhibited by budesonide. In conclusion, FMT proved suitable for longitudinal study to evaluate asthma progression, both in terms of inflammatory cell infiltration and airway remodeling, allowing the determination of treatment efficacy in a chronic asthma model in mice.

Genetics and competing strategies in a threshold model for mail processing

Multi-agent algorithms inspired by the division of labour in social insects are applied to a problem of distributed mail retrieval in which agents must visit mail producing cities and choose between mail types under certain constraints.The efficiency (i.e. the average amount of mail retrieved per time step), and the flexibility (i.e. the capability of the agents to react to changes in the environment) are investigated both in static and dynamic environments. New rules for mail selection and specialisation are introduced and are shown to exhibit improved efficiency and flexibility compared to existing ones. We employ a genetic algorithm which allows the various rules to evolve and compete. Apart from obtaining optimised parameters for the various rules for any environment, we also observe extinction and speciation. From a more theoretical point of view, in order to avoid finite size effects, most results are obtained for large population sizes. However, we do analyse the influence of population size on the performance. Furthermore, we critically analyse the causes of efficiency loss, derive the exact dynamics of the model in the large system limit under certain conditions, derive theoretical upper bounds for the efficiency, and compare these with the experimental results.

DEA-R:ratio-based comparative efficiency model, its mathematical relation to DEA and its use in applications

We propose a new mathematical model for efficiency analysis, which combines DEA methodology with an old idea-Ratio Analysis. Our model, called DEA-R, treats all possible ratios "output/input" as outputs within the standard DEA model. Although DEA and DEA-R generate different summary measures for efficiency, the two measures are comparable. Our mathematical and empirical comparisons establish the validity of DEA-R model in its own right. The key advantage of DEA-R over DEA is that it allows effective integration of the model with experts' opinions via flexible restrictive conditions on individual "output/input" pairs. © 2007 Springer Science+Business Media, LLC.

Do β-amyloid (Aβ) deposits in patients with Alzheimer's disease and Down's syndrome grow according to the log-normal model?

The size frequency distributions of diffuse, primitive and classic β- amyloid (Aβ) deposits were studied in single sections of cortical tissue from patients with Alzheimer's disease (AD) and Down's syndrome (DS) and compared with those predicted by the log-normal model. In a sample of brain regions, these size distributions were compared with those obtained by serial reconstruction through the tissue and the data used to adjust the size distributions obtained in single sections. The adjusted size distributions of the diffuse, primitive and classic deposits deviated significantly from a log-normal model in AD and DS, the greatest deviations from the model being observed in AD. More Aβ deposits were observed close to the mean and fewer in the larger size classes than predicted by the model. Hence, the growth of Aβ deposits in AD and DS does not strictly follow the log-normal model, deposits growing to within a more restricted size range than predicted. However, Aβ deposits grow to a larger size in DS compared with AD which may reflect differences in the mechanism of Aβ formation.

Managing uncertainty in complex stochastic models: design and emulation of a Rabies model

In this paper we present a novel method for emulating a stochastic, or random output, computer model and show its application to a complex rabies model. The method is evaluated both in terms of accuracy and computational efficiency on synthetic data and the rabies model. We address the issue of experimental design and provide empirical evidence on the effectiveness of utilizing replicate model evaluations compared to a space-filling design. We employ the Mahalanobis error measure to validate the heteroscedastic Gaussian process based emulator predictions for both the mean and (co)variance. The emulator allows efficient screening to identify important model inputs and better understanding of the complex behaviour of the rabies model.

A critique of a model for an academic staff activity database developed to aid a department in strategic and operational decision making

This paper discusses the use of a Model developed by Aston Business School to record the work load of its academic staff. By developing a database to register annual activity in all areas of teaching, administration and research the School has created a flexible tool which can be used for facilitating both day-to-day managerial and longer term strategic decisions. This paper gives a brief outline of the Model and discusses the factors which were taken into account when setting it up. Particular attention is paid to the uses made of the Model and the problems encountered in developing it. The paper concludes with an appraisal of the Model’s impact and of additional developments which are currently being considered. Aston Business School has had a Load Model in some form for many years. The Model has, however, been refined over the past five years, so that it has developed into a form which can be used for a far greater number of purposes within the School. The Model is coordinated by a small group of academic and administrative staff, chaired by the Head of the School. This group is responsible for the annual cycle of collecting and inputting data, validating returns, carrying out analyses of the raw data, and presenting the mater ial to different sections of the School. The authors of this paper are members of this steer ing group.

Secure routing and trust computation in multihop infrastructureless networks

Today's wireless networks rely mostly on infrastructural support for their operation. With the concept of ubiquitous computing growing more popular, research on infrastructureless networks have been rapidly growing. However, such types of networks face serious security challenges when deployed. This dissertation focuses on designing a secure routing solution and trust modeling for these infrastructureless networks. ^ The dissertation presents a trusted routing protocol that is capable of finding a secure end-to-end route in the presence of malicious nodes acting either independently or in collusion, The solution protects the network from active internal attacks, known to be the most severe types of attacks in an ad hoc application. Route discovery is based on trust levels of the nodes, which need to be dynamically computed to reflect the malicious behavior in the network. As such, we have developed a trust computational model in conjunction with the secure routing protocol that analyzes the different malicious behavior and quantifies them in the model itself. Our work is the first step towards protecting an ad hoc network from colluding internal attack. To demonstrate the feasibility of the approach, extensive simulation has been carried out to evaluate the protocol efficiency and scalability with both network size and mobility. ^ This research has laid the foundation for developing a variety of techniques that will permit people to justifiably trust the use of ad hoc networks to perform critical functions, as well as to process sensitive information without depending on any infrastructural support and hence will enhance the use of ad hoc applications in both military and civilian domains. ^

Children's perceptions of marital conflict, parent -child relations and anxiety in children: A proposed systemic model

This study tested a systemic model in which internalizing behaviors in a clinically-referred sample of children are predicted by children's perceptions of marital conflict in the context of three additional, well-researched, familial variables: parent-child relations, mother's emotional functioning, and children's perception of social support. After finding preliminary support for the model, its generalizability was tested in a combined sample of the clinically-referred group and a community-based group of elementary school children. ^ The clinical group consisted of 31 participants from a specialty clinic for children's anxiety disorders: 15 boys and 16 girls, aged 6 to 16, from both intact and divorced homes. Children's reports and mothers' reports of children's internalizing behaviors were submitted to separate analyses. Mothers' reports of children's internalizing behaviors were predicted only by mothers' emotional functioning. As hypothesized by the model, children's own reports of their internalizing behaviors were predicted significantly by children's perceptions of marital conflict. Parent-child relations, children's perception of social support, and one interaction term, children's perception of marital conflict x children's perception of parental rejection, contributed to the regression solution, while mother's emotional functioning failed to meet entry criterion. ^ The combined sample added 37 community-based children, 18 boys and 19 girls, aged 6 to 11, creating a total of 68 subjects. The model was replicated on the combined sample. ^ Findings of the study suggest child perceptions of marital conflict have a strong direct effect on child internalizing behaviors, accounting for 28% of the variance between marital conflict and child outcome in the clinical sample and 42% in the combined sample. In the past only about 10% of the variance in children's internalizing behaviors was explained by marital conflict. Importance implications are made for optimal assessment and specific treatment strategies for children and families experiencing marital conflict, especially for those at risk for anxiety disorders. ^

Quality of life and application of the transtheoretical model to diabetes self -management behaviors in older adults with type 2 diabetes

One in five adults 65 years and older has diabetes. Coping with diabetes is a lifelong task, and much of the responsibility for managing the disease falls upon the individual. Reports of non-adherence to recommended treatments are high. Understanding the additive impact of diabetes on quality of life issues is important. The purpose of this study was to investigate the quality of life and diabetes self-management behaviors in ethnically diverse older adults with type 2 diabetes. The SF-12v2 was used to measure physical and mental health quality of life. Scores were compared to general, age sub-groups, and diabetes-specific norms. The Transtheoretical Model (TTM) was applied to assess perceived versus actual behavior for three diabetes self-management tasks: dietary management, medication management, and blood glucose self-monitoring. Dietary intake and hemoglobin A1c values were measured as outcome variables. Utilizing a cross-sectional research design, participants were recruited from Elderly Nutrition Program congregate meal sites (n = 148, mean age 75). ^ Results showed that mean scores of the SF-12v2 were significantly lower in the study sample than the general norms for physical health (p < .001), mental health (p < .01), age sub-group norms (p < .05), and diabetes-specific norms for physical health (p < .001). A multiple regression analysis found that adherence to an exercise plan was significantly associated with better physical health (p < .001). Transtheoretical Model multiple regression analyses explained 68% of the variance for % Kcal from fat, 41% for fiber, 70% for % Kcal from carbohydrate, and 7% for hemoglobin A 1c values. Significant associations were found between TTM stage of change and dietary fiber intake (p < .01). Other significant associations related to diet included gender (p < .01), ethnicity (p < .05), employment (p < .05), type of insurance (p < .05), adherence to an exercise plan (p < .05), number of doctor visits/year ( p < .01), and physical health (p < .05). Significant associations were found between hemoglobin A1c values and age ( p < .05), being non-Hispanic Black (p < .01), income (p < .01), and eye problems (p < .05). ^ The study highlights the importance of the beneficial effects of exercise on quality of life issues. Furthermore, application of the Transtheoretical Model in conjunction with an assessment of dietary intake may be valuable in helping individuals make lifestyle changes. ^

Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder.

Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including "axon guidance" and "regulation of actin cytoskeleton." In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.

Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial

BACKGROUND: In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223.

METHODS: We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16.

FINDINGS: Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months-NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA).

INTERPRETATION: Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials.

FUNDING: Pharmaceutical Division of Bayer.

Parental involvement in sport: psychometric development and empirical test of a theoretical model

The purposes of the present multistudy were to develop and provide initial construct validity for measures based on the model of parental involvement in sport (Study 1) and examine structural relationships among the constructs of the model (Study 2). In Study 1 (nparents = 342, nathletes = 223), a confirmatory factor analysis was used to verify the psychometric properties of the measures. Content and construct validity were evaluated, as well individual and composite reliability. Multi-group analysis with two independent samples provided evidence of factorial invariance. In Study 2 (nparents = 754, nathletes = 438), structural equation modeling analysis supported the hypothesised model in which athletes’ perceptions of parents’ behaviours mediated the relationship between parents’ reported behaviours and the athletes’ psychological variables conducive to their achievement in sport. The findings provide support for the parental involvement in sport model and demonstrate the role of perceptions of parents’ behaviours on young athletes’ cognitions in sport.

Multi-body simulation of a canine hind limb: model development, experimental validation and calculation of ground reaction forces

Background: Among other causes the long-term result of hip prostheses in dogs is determined by aseptic loosening. A prevention of prosthesis complications can be achieved by an optimization of the tribological system which finally results in improved implant duration. In this context a computerized model for the calculation of hip joint loadings during different motions would be of benefit. In a first step in the development of such an inverse dynamic multi-body simulation (MBS-) model we here present the setup of a canine hind limb model applicable for the calculation of ground reaction forces. Methods: The anatomical geometries of the MBS-model have been established using computer tomography- (CT-) and magnetic resonance imaging- (MRI-) data. The CT-data were collected from the pelvis, femora, tibiae and pads of a mixed-breed adult dog. Geometric information about 22 muscles of the pelvic extremity of 4 mixed-breed adult dogs was determined using MRI. Kinematic and kinetic data obtained by motion analysis of a clinically healthy dog during a gait cycle (1 m/s) on an instrumented treadmill were used to drive the model in the multi-body simulation. Results and Discussion: As a result the vertical ground reaction forces (z-direction) calculated by the MBS-system show a maximum deviation of 1.75%BW for the left and 4.65%BW for the right hind limb from the treadmill measurements. The calculated peak ground reaction forces in z- and y-direction were found to be comparable to the treadmill measurements, whereas the curve characteristics of the forces in y-direction were not in complete alignment. Conclusion: In conclusion, it could be demonstrated that the developed MBS-model is suitable for simulating ground reaction forces of dogs during walking. In forthcoming investigations the model will be developed further for the calculation of forces and moments acting on the hip joint during different movements, which can be of help in context with the in silico development and testing of hip prostheses.

Probing doubly charged Higgs bosons in e(+)e(-) colliders at the ILC and the CLIC in a 3-3-1 model

The SU(3)(L) circle times U(1)(N) electroweak model predicts new Higgs bosons beyond the one of the standard model. In this work we investigate the signature and production of doubly charged Higgs bosons in the e(+)e(-) International Linear Collider and in the CERN Linear Collider. We compute the branching ratios for the doubly charged gauge bosons of the model.

Biomechanical and morphological adaptations in women during pregnancy and the postpartum period in walking

A gravidez é uma fase especial da vida, com diversas alterações nos sistemas hormonais, anatómicos, e na composição corporal da mulher. No entanto, não é claro que alterações biomecânicas tridimensionais ocorrerem. Através do acompanhamento da mulher na gravidez e pós-parto, os objetivos da presente tese foram: 1) determinar os parâmetros temporais e espaciais do ciclo da marcha; 2) descrever a cinemática angular do membro inferior; 3) calcular os momentos e potências articulares do tornozelo, joelho e coxofemoral, utilizando o cálculo por dinâmica inversa; 4) descrever as magnitudes dos picos dos momentos e potências articulares dos membros inferiores; 5) identificar possíveis diferenças entre as fases de recolha relativamente aos parâmetros biomecânicos; 6) descrever longitudinalmente a composição corporal as alterações morfológicas; 7) analisar a influência das alterações antropométricas na cinética articular. Os resultados mostram que as mulheres mantêm os parâmetros temporais e espaciais da marcha. A cinemática angular do membro inferior tem o mesmo padrão, no entanto, a magnitude de alguns picos, especialmente na bacia e coxofemoral durante a fase terminal do apoio, pré-balanço e de balanço, apresentam alterações significativas. A coxofemoral é a articulação com mais alterações na cinética articular, com um aumento da carga interna associada aos momentos articulares da coxofemoral no plano transversal. No entanto, diversos momentos e potências articulares revelam uma diminuição significativa para o final da gravidez e/ou um aumento entre alguns trimestres da gravidez e o pós-parto. Como esperado, a maioria das variáveis associadas à composição corporal e às dimensões corporais tem um aumento significativo durante a gravidez e uma diminuição no pós-parto. Os modelos desenvolvidos para prever a carga interna aplicada ao membro inferior da grávida através de variáveis antropométricas, incluem quatro modelos com variáveis associadas à quantidade de gordura, quatro modelos com variáveis associadas à massa corporal global, três modelos que incluem a massa livre de gordura, e um modelo que inclui a forma do tronco. Os altos valores do R2 ajustado, mostram que as alterações na composição corporal e morfologia, determinam em grande parte a cinética articular da mulher nesta fase particular da vida.