Data Analysis and Experimental Design for Accelerated Life Testing with Heterogeneous Group Effects

abstract: In accelerated life tests (ALTs), complete randomization is hardly achievable because of economic and engineering constraints. Typical experimental protocols such as subsampling or random blocks in ALTs result in a grouped structure, which leads to correlated lifetime observations. In this dissertation, generalized linear mixed model (GLMM) approach is proposed to analyze ALT data and find the optimal ALT design with the consideration of heterogeneous group effects. Two types of ALTs are demonstrated for data analysis. First, constant-stress ALT (CSALT) data with Weibull failure time distribution is modeled by GLMM. The marginal likelihood of observations is approximated by the quadrature rule; and the maximum likelihood (ML) estimation method is applied in iterative fashion to estimate unknown parameters including the variance component of random effect. Secondly, step-stress ALT (SSALT) data with random group effects is analyzed in similar manner but with an assumption of exponentially distributed failure time in each stress step. Two parameter estimation methods, from the frequentist’s and Bayesian points of view, are applied; and they are compared with other traditional models through simulation study and real example of the heterogeneous SSALT data. The proposed random effect model shows superiority in terms of reducing bias and variance in the estimation of life-stress relationship. The GLMM approach is particularly useful for the optimal experimental design of ALT while taking the random group effects into account. In specific, planning ALTs under nested design structure with random test chamber effects are studied. A greedy two-phased approach shows that different test chamber assignments to stress conditions substantially impact on the estimation of unknown parameters. Then, the D-optimal test plan with two test chambers is constructed by applying the quasi-likelihood approach. Lastly, the optimal ALT planning is expanded for the case of multiple sources of random effects so that the crossed design structure is also considered, along with the nested structure.Dissertation/ThesisDoctoral Dissertation Industrial Engineering 201

Investigation of age-related protein changes in the human lens by quasi-elastic light scattering

The health and viability of cells and tissues in the human body depend on the functional integrity of proteins. A small number of long-lived proteins, including the crystallins in the lens of the eye, evade protein turnover, a typical cellular mechanism for repair and regeneration, and remain extant throughout life. The cumulative effect of post-translational modifications on the structure, function, and conformation of these long-lived proteins records the history of molecular aging in an individual. Along with absence of protein turnover, the optical accessibility, transparency, and age-related spatial order make the lens an ideal target for in vivo assessment of molecular aging. Accordingly, this doctoral thesis investigated the hypothesis that age-related perturbations that alter the protein environment in the human lens can be detected and monitored as a quantitative biomarker of molecular aging detectable by quasi-elastic light scattering (QLS). To test this hypothesis, QLS was applied in vitro and in vivo to study time-dependent changes in lens proteins. Water-soluble human lens protein extract was used in vitro as a model system that mimics the lens fiber cell cytoplasm. The effects of long-term incubation (nearly one year, proxy for aging), oxidative stress, ionizing radiation, metal-protein and pathogenic protein-protein interactions were investigated by QLS as a function of time. In vitro results were validated by protein gel electrophoresis and transmission electron microscopy. In vivo, age-dependent changes in lens proteins were assessed in healthy subjects across a broad age-range (5–61 years of age). Pathogenic protein aggregation in the lens was examined in vivo using Down syndrome (DS) subjects, a common chromosomal disease associated with an age-related Alzheimer’s disease (AD)-linked lens phenotype. Results obtained from the in vitro studies noted, for the first time, QLS detection of long-term supramolecular changes in a complex lens protein model system. Our FDA-approved QLS device was successful in assessing age-dependent lens protein changes in a clinical study at Boston Children’s Hospital (BCH). In two landmark studies conducted at BCH, we detected statistically significant AD-related lens protein changes in DS subjects aged 10–20 years, when compared with age-matched controls. These studies are the first clinical application of QLS in DS, and demonstrate protein changes in DS earlier than any previously reported studies. Due to the discrepancy in chronological and biological age and the lack of an objective index for the latter, we propose the application of QLS in the human lens as a quantitative biomarker of molecular aging

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 128, May 1974

This special bibliography lists 282 reports, articles, and other documents introduced into the NASA scientific and technical information system in April 1974

A study of chemically treated pericardia to manufacture the leaflets of percutaneous heart valves : biomechanical analyses and modelisation

Contexte: En raison de l'utilisation répandue des valvules cardiaques aortiques prothétiques, il est extrêmement important d'en étudier la biofonctionnalité, la biodurabilité et la biocompatibilité. Les valves mécaniques ont une excellente durabilité. Cependant, en raison des traitements anticoagulants, il existe des risques de thromboembolique et hémorragique. Les valves polymériques ont une faible résistance à la calcification et à la thrombose. À cet égard, les valves biologiques sont préférables. Plus récemment, les chirurgiens et les cardiologues ont développe à l'implantation de valves aortiques percutanées, plutôt qu’à la chirurgie ouverte pour traiter les patients âgés et fragiles. Cependant, la durabilité des bioprothèses soulève toujours des questions reliées au sertissage et l’expansion lors de l'implantation. Comme la performance des bioprothèses dépend de l'architecture et du comportement mécanique du tissu sélectionné, il est nécessaire de sélectionner le tissu le plus approprié pour fabriquer ces prothèses. Objectifs: Il s’agit d’identifier le tissu le plus approprié avec la plus longue durabilité pour fabriquer des valvules cardiaques en comparant les propriétés mécaniques et histologiques des péricardes équin, porcin et d’âne par rapport à celles du péricarde bovin et des feuillets de la valve aortique humaine. Hypothèse: La durabilité des valves cardiaques bioprothétiques est largement déterminée par les caractéristiques histologiques et mécaniques des tissus des feuillets. Par conséquent, la sélection du péricarde selon sa structure histologique et ses propriétés mécaniques permettra d’augmenter la durée de vie de ces prothèses. Méthodologie: 1. Étude des structures de collagène des tissus sélectionnés. 2. Étude des propriétés mécaniques des tissus et évaluation de leur durabilité avec différents tests mécaniques. 3. Extraction des propriétés hyperélastiques et viscoélastiques biaxiales à l'aide des modèles appropriés. 4. Application du modèles d'éléments finis est appliqué en utilisant les propriétés mécaniques extraites pour évaluer la déhiscence possible de la valve et le stress sous la charge physiologique. Résultats: Le péricarde d’âne et le péricarde équin ont démontré une architecture ondulée de faisceaux de collagène semblable à celle du péricarde bovin. L’architecture ondulée du péricarde peut convenir aux valves aortiques transcutanées car elles sont moins susceptibles d'être délaminées lors du sertissage. Selon des tests mécaniques, les pourcentages de relaxation des différents péricardes équin (16%), âne (28%) et bovin (21%) étaient supérieurs à ceux du péricarde porcin (11%) et similaires aux feuillets valvulaires aortiques humains natifs (21%). En particulier, le péricarde porcin a démontré un comportement plus rigide (module d'élasticité plus élevé), basé sur sa plus grande amplitude d'énergie de déformation et la pente moyenne des courbes contrainte-étirement. Ce tissu était également moins extensible que les deux autres péricardes et les feuillets humains, en raison de sa souche aréale inférieure. En général, les propriétés mécaniques du péricarde d’âne sont plus proches des feuillets valvulaires humains. De plus, le modèle âne n'a induit que des régions localisées à faible stress pendant les phases systolique et diastolique du cycle cardiaque. En outre, une diminution des contraintes mécaniques sur les feuillets bioprothétiques devrait contribuer à réduire la dégénérescence des tissus et augmenter la durabilité à long terme de la valve. Conclusion: D'après nos observations, les spécimens péricardiques se sont comportés comme des tissus anisotropes et non linéaires - bien caractérisés par des modèles constitutifs. Les résultats indiquent que le péricarde d'âne est mécaniquement et histologiquement plus approprié pour la fabrication de prothèses valvulaires cardiaques que le péricarde bovin. Les résultats de cette étude peuvent être utilisés dans la conception et la fabrication de valvules cardiaques bioprothétiques percutanéei.Background: Due to the widespread use of prosthetic aortic heart valves, investigating these prostheses in terms of biofunctionality, biodurability and biocompatibility is of considerable importance. Mechanical heart valves (MHVs) have excellent durability; however, due to the long-term use of anticoagulants, thromboembolism and hemorrhage remain a possibility. Polymeric valves have a low resistance to calcification and thromboembolism. In this respect, biological valves are preferred. In recent years, surgeons and cardiologists have also used transcatheter aortic valve implantation (TAVI) due to its superiority over the open-heart surgery to treat elderly and frail patients. However, the long-term durability of the commercially available bioprosthesesstill raises questions related to crimping and ballooning at the implantation. The function and performance of the bioprostheses depend on the collagen architecture and mechanical behaviors of the pericardial tissue. Therefore, it is necessary to select the most appropriate pericardia to manufacture these prostheses. Objectives: To identify the most appropriate tissue with a long durability to make bioprosthetic heart valves by analyzing the mechanical and histological properties of the equine, porcine, and donkey pericardia, with respect to those of the bovine pericardium and human aortic valve leaflets. Hypothesis: The long term durability of bioprosthetic heart valves is largely determined by the leaflet tissues. Consequently, selecting the pericardium based on its adequate mechanical property and histological structure will increase the lifetime of these prostheses. Methodologies: 1. Histological analysis was performed to investigate the collagen structures of the selected tissues. 2. Different mechanical tests (uniaxial tests, biaxial tests, and stress relaxation tests) were performed to determine the mechanical properties of the tissues and to evaluate their durability. 3. The biaxial hyperelastic and viscoelastic properties of the selected tissues were extracted using the appropriate models. 4. The finite element model was applied using the extracted mechanical properties to evaluate valve dehiscence and stress under physiological loadings. Results: The donkey and equine pericardia showed a wavy collagen bundle architecture similar to the bovine pericardium. The wavy pericardia may be suitable for the transcatheter aortic valves (TAVs) because they are less likely to be delaminated during crimping. According to the mechanical tests, the relaxation percentages of the equine (16%), donkey (28%), and bovine (21%) pericardia were greater than that of the porcine (11%) pericardium and similar to that of the native human aortic valve leaflets (21%). In particular, the porcine pericardium exhibited a stiffer behavior (higher elastic modulus), based on its greater strain energy magnitude and the average slope of stress-stretch curves. This tissue was also less distensible than the other two pericardia and the native leaflets, due to its lower areal strain. In general, among the pericardia analyzed, the mechanical properties of the donkey pericardium are closer to that of the native leaflets. Furthermore, the donkey model showed low stress regions during the systolic and diastolic phases of the cardiac cycle. Such decreased mechanical stress in the bioprosthetic leaflets should reduce tissue degeneration and increase the long-term durability of the valve. Conclusion: Based on the observations, the pericardial specimens behaved as anisotropic and nonlinear tissues, and their mechanical behaviors were very well characterized by the constitutive models. The results indicate that, compared to the bovine pericardium, the donkey pericardium is mechanically and histologically more appropriate to manufacture heart valve prostheses. Therefore, this study contributes to our understanding of the difference in animal pericardia with respect to human heart leaflets, which is very useful for the design and manufacture of the percutaneous bioprosthetic heart valves

Nondestructive Testing Methods and New Applications

Nondestructive testing enables scientists and engineers to evaluate the integrity of their structures and the properties of their materials or components non-intrusively, and in some instances in real-time fashion. Applying the Nondestructive techniques and modalities offers valuable savings and guarantees the quality of engineered systems and products. This technology can be employed through different modalities that include contact methods such as ultrasonic, eddy current, magnetic particles, and liquid penetrant, in addition to contact-less methods such as in thermography, radiography, and shearography. This book seeks to introduce some of the Nondestructive testing methods from its theoretical fundamentals to its specific applications. Additionally, the text contains several novel implementations of such techniques in different fields, including the assessment of civil structures (concrete) to its application in medicine

Fracture, Fatigue, and Structural Integrity of Metallic Materials and Components Undergoing Random or Variable Amplitude Loadings

Most metallic components and structures are subjected, in service, to random or variable amplitude loadings. There are many examples: vehicles subjected to loadings and vibrations caused by road irregularity and engine, structures exposed to wind, off-shore platforms undergoing wave-loadings, and so on. Just like constant amplitude loadings, random and variable amplitude loadings can make fatigue cracks initiate and propagate, even up to catastrophic failures. Engineers faced with the problem of estimating the structural integrity and the fatigue strength of metallic structures, or their propensity to fracture, usually make use of theoretical, numerical, or experimental approaches. This reprint collects a series of recent scientific contributions aimed at providing an up-to-date overview of approaches and case studies—theoretical, numerical or experimental—on several topics in the field of fracture, fatigue strength, and the structural integrity of metallic components subjected to random or variable amplitude loadings

Effect of adenosine A2A receptor gene transfer on nuclear factor-kappaB-regulated inflammatory responses in vascular endothelial cells

Inappropriate or prolonged inflammation contributes to the pathogenesis of many diseases including atherosclerosis, rheumatoid arthritis, sepsis, heart disease and cancer. It is widely accepted that the A2A adenosine receptor (A2aAR) is a critical non-redundant suppressor of inflammatory responses in vivo. Therefore understanding the mechanisms behind the suppression of inflammation would be beneficial in providing future drug targets for chronic inflammatory diseases. While the receptor is known to elevate intracellular cAMP levels, the molecular mechanisms underlying its inhibitory effects on defined pro-inflammatory signalling pathways remains obscure. We have demonstrated that adenovirus-mediated human A2aAR gene transfer into approximately 75% of virally-infected human umbilical vein endothelial cells (HUVECs) results in an expression level of 0.3-0.4 pmol/mg membrane protein as determined by 125I-ZM241385 antagonist radioligand binding studies. A2AAR-expression results in a constitutive suppression of TNFalpha-mediated induction of NFkB target genes such as cyclooxygenase-2 (COX-2) and the adhesion molecule E-selectin. To assess the functional significance of this phenomenon, the effects of A2aAR gene transfer in HUVECs on the accumulation of three important gene products known to be controlled at least in part by NFkB, namely COX-2, E-selectin and vascular cell adhesion molecule-1 (VCAM-1) was determined. Characterisation of TNFalpha-mediated COX-2 induction revealed that while sustained induction (24hr) was solely dependent on the activation of p38 MAP kinase, earlier time-points at which induction was first detectable (8hr) were also sensitive to inhibition of the NFkB pathway. At this time-point, A2aAR gene transfer alone was sufficient to reduce TNFalpha-mediated COX-2 induction compared with controls, whilst no effect of the A2aAR was detectable at 24hr. Surprisingly, addition of the A2AAR-selective agonist CGS21680 to A2aAR-expressing HUVECs actually reversed the effect observed with receptor expression alone. Time-course experiments in control cells using elevated concentrations of the adenylyl cyclase activator forskolin demonstrated that cAMP elevation was sufficient to promote the transient induction of COX-2 even in the absence of TNFalpha. However, in the presence of TNF?, exposure to different concentrations of forskolin exerted a biphasic effect, suppressing COX-2 induction at low concentrations while enhancing it at higher concentrations. These data suggest that the effects of A2aAR expression with or without agonist on TNFalpha-mediated COX-2 induction can be accounted for completely by changes in cAMP. (Abstract shortened by ProQuest.)

Cognitive Decay And Memory Recall During Long Duration Spaceflight

This dissertation aims to advance the efficacy of Long-Duration Space Flight (LDSF) pre-flight and in-flight training programs, acknowledging existing knowledge gaps in NASA\u27s methodologies. The research\u27s objective is to optimize the cognitive workload of LDSF crew members, enhance their neurocognitive functionality, and provide more meaningful work experiences, particularly for Mars missions.The study addresses identified shortcomings in current training and learning strategies and simulation-based training systems, focusing on areas requiring quantitative measures for astronaut proficiency and training effectiveness assessment. The project centers on understanding cognitive decay and memory loss under LDSF-related stressors, seeking to establish when such cognitive decline exceeds acceptable performance levels throughout mission phases. The research acknowledges the limitations of creating a near-orbit environment due to resource constraints and the need to develop engaging tasks for test subjects. Nevertheless, it underscores the potential impact on future space mission training and other high-risk professions. The study further explores astronaut training complexities, the challenges encountered in LDSF missions, and the cognitive processes involved in such demanding environments. The research employs various cognitive and memory testing events, integrating neuroimaging techniques to understand cognition\u27s neural mechanisms and memory. It also explores Rasmussen\u27s S-R-K behaviors and Brain Network Theory’s (BNT) potential for measuring forgetting, cognition, and predicting training needs. The multidisciplinary approach of the study reinforces the importance of integrating insights from cognitive psychology, behavior analysis, and brain connectivity research. Research experiments were conducted at the University of North Dakota\u27s Integrated Lunar Mars Analog Habitat (ILMAH), gathering data from selected subjects via cognitive neuroscience tools and Electroencephalography (EEG) recordings to evaluate neurocognitive performance. The data analysis aimed to assess brain network activations during mentally demanding activities and compare EEG power spectra across various frequencies, latencies, and scalp locations. Despite facing certain challenges, including inadequacies of the current adapter boards leading to analysis failure, the study provides crucial lessons for future research endeavors. It highlights the need for swift adaptation, continual process refinement, and innovative solutions, like the redesign of adapter boards for high radio frequency noise environments, for the collection of high-quality EEG data. In conclusion, while the research did not reveal statistically significant differences between the experimental and control groups, it furnished valuable insights and underscored the need to optimize astronaut performance, well-being, and mission success. The study contributes to the ongoing evolution of training methodologies, with implications for future space exploration endeavors