In this work we discuss the design and implementation of a computer program to simulate the wear on knee implants over a standardized gait cycle. The contact problems during the gait cycle are formulated using linear elasticity with a linear non-penetration condition. Archard's wear law is used to estimate long-term wear. The algebraic problem after discretization is solved using the Truncated Nonsmooth Newton Multigrid (TNNMG) algorithm. The linear correction step of the algorithm leads to indefinite systems in our application for which we describe a novel heuristic damping algorithm. Our problem sizes allow using a direct solver for these systems and with some modifications we are able to reuse the Cholesky factorization of the system matrix over multiple iterations of the TNNMG algorithm. For our application we are able to significantly improve over the performance of IPopt, a state-of-the-art solver using penalty-based methods. The program is then used for in-silico simulations of wear of two different total knee implant models for which in-vitro results are also available. Both wear volume and spatial distribution of wear that are computed compare well with the experimental results.

Purpose. Road transportation is one of the major sources of GHG emissions today. Technological improvements in fuel consumption, as well as the electrification of vehicles can reduce emissions from road transportation. This study aims to investigate the optimal time for vehicle replacement in Sweden for an ICEV to minimise GHG emissions. While many LCA studies compare the total emissions from ICEVs with BEVs and conduct a break-even analysis, little focus is dedicated to the implications of the results. Previous studies did not estimate the time of vehicle replacement at which GHG emissions are minimised. To represent the Swedish vehicle fleet, the optimal replacement time is estimated for a Volvo V70 (petrol, 2011 model), when replacing it with a Volvo V60 (petrol, 2020 model) (Scenario 1), correspondingly when replacing with a Polestar 2 (battery-electric, 2020 model) (Scenario 2). Methods. For the estimation of lifetime emissions resulting from the three vehicle models, a Life Cycle Analysis was conducted. The functional unit investigated was 200.000 km driven with the V70, the V60 and Polestar 2, assuming that the vehicles were operated in Sweden. The emission values are then used to model the vehicle replacement in each scenario and the results are analysed. Findings. The LCA study showed that the V70 emits 64,08 tCO2eq. over its total lifespan, the V60 46,48 tCO2eq., and the Polestar 2 29,05 tCO2eq. The study showed that there is not one optimal replacement time, but the optimal time for vehicle replacement, from a carbon emission point of view, is inherently linked to the total driven mileage and number of cars owned. However, the trend shows that the time of replacement in Scenario 1 should be close to the End-of-Life of the V70. For Scenario 2 it is beneficial to replace the V70 immediately.

Osteoarthritis (OA) of the knee, a musculoskeletal disease characterized by degenerations in multiple joint tissues including the articular cartilage and subchondral bone, is a major clinical challenge worldwide that currently has no cure. Traumatic knee injuries such as anterior cruciate ligament (ACL) tear predispose subjects to early onset of post-traumatic OA (PTOA), necessitating the development of effective disease modifying therapies as total knee replacement surgeries have a limited lifetime. Significant knowledge gap remains in the pathogenesis of OA, while recent evidence suggests the important role of subchondral bone microstructure and mechanics in OA development. Subchondral bone is composed of the subchondral bone plate, a thin layer of cortical lamella, and the subchondral trabecular bone, composed of individual plate-like and rod-like trabeculae. These trabecular plates and rods determine the microstructure and mechanics of trabecular bone entirely and can be quantitatively analyzed using individual trabecula segmentation (ITS). Recent application of ITS showed that changes in the plate-and-rod microstructure of subchondral trabecular bone precede cartilage damage and are implicated to play a role in disease pathogenesis. Studies presented in this thesis aim to provide a deeper understanding of subchondral bone in knee OA scientifically and clinically, which may ultimately be used to improve diagnosis, prevention and treatment of this prevalent and disabling disease. In the first study, we comprehensively quantified microstructural and tissue biomechanical properties of the subchondral bone and articular cartilage in human knee specimens with advanced OA and control knees without OA. We found reduced tissue modulus in trabecular plates and rods in regions with moderate OA, where cartilage is still intact, that persisted in severe OA regions, where cartilage is severely damaged. These observations suggest that tissue biomechanical changes in the subchondral trabecular bone may precede cartilage damage in OA development. Furthermore, we found strong correlations between structural and mechanical parameters of the cartilage and subchondral bone in CT knees, suggesting cross-talk at the tissue level. This coupling persisted in moderate OA regions but disappeared in severe OA regions, suggesting that loss of tissue crosstalk may be an additional indicator of disease progression. In the second study, we quantified subchondral bone microstructural changes after ACL tear in vivo in human subjects using the second-generation high resolution peripheral quantitative computed tomography (HR-pQCT). We examined short-term longitudinal changes during the acute phase (~18 days to ~141 days) after injury, as well as long-term adaptations (~5 years post injury) in the injured knee relative to the contralateral knee in a cross-sectional cohort. We found subchondral bone loss within 1 month from injury that primarily targeted trabecular rods, especially at the distal femur. We also found increased spatial heterogeneity in subchondral trabecular microstructure within the injured knees compared to the contralateral knees in the long-term after injury. These findings indicate that ACL tear results in both short-term and long-term microstructural adaptations in the subchondral bone. ITS based on HR-pQCT knee scans may be a valuable tool to monitor disease progression in vivo. Finally, we quantified subchondral bone microstructural changes after ACL-transection in a canine model of PTOA and investigated the effects of bisphosphonate and NSAID treatment on subchondral bone changes and OA progression. Studies were conducted in skeletally-mature and juvenile animals to investigate the effect of injury age. We found that subchondral bone adaptations after surgery and treatment effects depended on skeletal maturity of animals. In mature animals, changes in the microstructure of trabecular plates and rods occurred 1-month post-op and persisted until 8-months post-op. Bisphosphonate treatment attenuated these microstructural changes and cartilage degeneration while NSAID treatment did not. In juvenile animals that have not reached skeletal maturity, transient changes in trabecular plate and rod microstructure occurred at 3-months post-op but disappeared by 9-months post-op. Neither bisphosphonate nor NSAID treatment attenuated bone microstructural changes or cartilage damages. These findings suggest that age and skeletal maturity at time of injury may need to be considered as additional factors in studying PTOA progression and developing preventative treatments. Taken together, these studies highlight the importance of microstructural and tissue biomechanical changes of subchondral bone in the development of OA. In vivo quantification of subchondral bone using advanced imaging modalities enable longitudinal monitoring of disease progression. Therapeutic agents targeting subchondral bone changes after traumatic injury may be effective preventative strategies for PTOA.

Analysis of spontaneous adverse drug reactions reporting hormonal contraception and hormone replacement therapy Author: Vendula Ryndová Supervisor: PharmDr. Kateřina Malá, Ph.D. Consultant: PharmDr. Eva Zimčíková, Ph.D. Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Introduction: Hormonal contraception (HC) is the most widely used method to prevent pregnancy worldwide. In addition to pregnancy planning and other non-contraceptional benefits, it also has certain risks. Hormone replacement therapy (HRT) is used primarily for treatment of estrogen deficiency in postmenopausal women. HRT is associated with a number of risks, in particularly for women 60+ of age. Analysis of spontaneous adverse drug reactions (ADRs) reporting contribute to detection of potential risks associated with pharmacotherapy, thereby increases the safety of the drugs. Aim: The aim of this thesis was to analyse spontaneous ADRs reports of HC and HRT registered in the Czech Central Database of ADRs of the State Institute for Drug Control (SÚKL). Methods: Retrospective analysis of the spontaneous ADRs reports of HC and HRT registered in the database of SÚKL from 10/2004 to 6/2017. Mainly, method of receiving the report, reporting person, patient information, seriousness, and...

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<p>Type 1 Diabetes Mellitus (T1D), a chronic disease affecting over 1.5 million Americans, is characterized by the autoimmune destruction of insulin-producing β-cells within pancreatic islets. Islet/β-cell replacement therapies, where replenishable β-cell sources are implanted within protective microenvironments, have the potential to provide a long-term solution for individuals with T1D by restoring glucose-sensitive, insulin release and overall glycemic control. However, most conventional encapsulation materials elicit an immune reaction, known as a foreign body response (FBR), which compromises β-cell health and function. In this dissertation, we designed and evaluated various formulations of a polymerizable collagen, namely type I oligomeric collagen (Oligomer), as encapsulation materials for minimally invasive, subcutaneous delivery of replacement β-cells. Preclinical validation in chemically-induced diabetic mice demonstrated rapid (within 24 hours) reversal of diabetes for beyond 90 days with no signs of rejection or FBR after subcutaneous delivery of both allogeneic and xenogeneic (rat) islets. To further define this uncommon mechanism of protection, the tissue response to Oligomer, in comparison to commercial synthetic and collagen-based materials, was evaluated following subcutaneous implantation within rats, a well-established biocompatibility model. Histological and transcriptomics analyses were used to define the immune response at both cellular and molecular levels. Interestingly, Oligomer showed minimal and transient activation of innate immune cells similar to the sham surgical control, with no evidence of foreign body giant cell formation, inflammatory-mediated bioresorption, or fibrosis. Overall, this work evaluates preclinical efficacy and demonstrates mechanistic understanding of immune tolerance for Oligomer materials for β-cell replacement therapy and other regenerative medicine applications.</p>

Overwhelming evidence throughout the literature has shown that bus overhead and maintenance (O&M) costs increase as buses age. This has implications toward a fleet manager's decision of when one should buy, use, or sell buses to minimize total fleet costs. Unfortunately, there are uncertain market conditions associated with bus fleets that cloud the manager's ability to make appropriate decisions. Using integer programming (IP), O&M trends and changing market conditions are integrated into a model to better analyze bus fleets. Due to recent budget constraints of transit agencies, needs for a bus fleet replacement model have arisen. King County in Washington State has supplied cost aggregated data of their New Flyer (NF) and NF hybrid buses. These data have been analyzed to create statistical relationships based on rising O&M costs per mile with age, which are then integrated with the IP model to determine the impact of changing diesel prices, potential carbon dioxide (CO2) emissions costs, uncertain maintenance costs, and bus purchase cost subsidies. The goal is to aid fleet managers to determine the costs of early or delayed suboptimal bus replacement timing and the impacts of market variability on fleet costs and optimal replacement timing. The optimal replacement age for NF and NF hybrid buses based on King County data and current fuel prices of $3.99/gal are 16.7 and 18.3 years, respectively. It has been consistently observed that greater expense is incurred when buses are replaced earlier rather than later from optimal. To minimize total CO2 emissions (including operation and construction emissions), buses should be replaced slightly before the optimal replacement time without considering CO2 emissions. High diesel prices and CO2 emissions had little or no effect, on when buses should be replaced. However, higher maintenance costs reduced the optimal replacement time by almost two years. Although NF hybrid buses have been found to have no economic advantage over conventional buses, this finding may be a consequence of the different costs associated to the different routes operated by hybrid and conventional buses. Due to the lack of detailed King County's route level historical data, a study of the economic competitiveness of NF hybrids against conventional buses is outside the scope of this thesis. If buses are used less with age, the optimal replacement age is reduced. The optimal replacement age also dropped significantly when the Federal Transit Agency's procurement assistance is applied into the model. The procurement assistance can be up to 80% of the capital costs and can be considered a purchase subsidy from the transit agency viewpoint. If purchase subsidies decrease bus purchase prices by 1%, the optimal replacement age drops approximately 1.5%. When the bus purchase price is reduced by 80%, the optimal bus replacement age is less than 12 years, the FTA's minimum replacement age.

In endoprosthesis surgery there are typically a high percentage of implant defects, these can lead to failure of the whole prosthesis. One type of total hip replacement function loss is acetabular cup loosening from the pelvic bone. This disertation examines manufacture perturbations as one of the possible reasons for this kind of failure. Both dimension and geometry manufacturing perturbations of ceramic head and polyethylen cup were analyzed. We find that perturbations in the variables analysed here affect considered values of contact pressure and frictional moment. Furthermore, contact pressure and frictional moment are quantities affecting replacement success and durability. From obtained results it can be recommended to fit head and cup with a clearance of between 0 mm and 0.05 mm. It can not be recommend using interference type of fit because of strong deterioration of the contact conditions. Roundness perturbation of ceramic head should not exceed 0.025 mm.

This thesis compares foundation methods for buildings on low-strength, limited-depth soil. The study focuses on soil replacement and piling, specifically concrete and steel piles. The studyaims to answer the key questions about the possibility to use short piles on limited depth, cost-efficiency, and environmental impact of these methods. Geotechnical and structural calculations are used to assess the loads on the piles and evaluate their strength. WIN-statik Frame Analysis helps analyze deformations, moments, and stresses. The foundation transfers vertical loads to three piles, generating horizontal loads at the pile tops. However, the challenge lies in short piles in clay, which experience low earth pressure and may rotate due to bad stabilization. The analysis reveals that concrete piles are unable to transfer loads to solid rock effectively. Without fixed anchorage points, they are prone to rotation due to insufficient stiffness and lateral earth pressure. In contrast, steel piles are preferred because they can be drilled into the rock, providing fixed anchorage at the clay-rock transition and enabling them to withstand loads transferred through the foundation. Soil replacement is considered as an alternative method but proves economically expensive, approximately three times more than piling with steel piles. From an environmental standpoint, piling contributes only slightly more carbon dioxide emissions, about 0.4 tons, compared to soil replacement. Considering the significant cost advantage and minor environmental impact difference between soil replacement and piling, piling with steel piles is recommended as the optimal foundation method. Concrete piles are dismissed due to their instability. This choice ensures stability, cost-efficiency, and reduced environmental impact for buildings on low-strength, shallow-depth soil.

The utilization of renewable sources as alternatives for petroleum and natural gas products has immense commercial, health and global warming significance. D-Isosorbide (2) is a bifunctional, polar, chiral and rigid molecule, which is produced from renewable sources. Synthesis of new polymers containing 2 is of interest for polymers and in drug delivery. The aim of the present work is to synthesize various polymers (homo- and copolymers) containing 2 via the olefin metathesis routes, ring-opening metathesis polymerization (ROMP) and acyclic-diene metathesis polymerization (ADMET). N-Phenyl-7-oxanorbornene-dicarboximide, and norbornene functionalized onto 2 were used as the monomers for ROMP. These monomers were polymerized using Grubbs’ catalysts to generate a series of homo-, co-, block and cross-linked-polymers. These polymers were characterized using GPC, NMR, and IR. In addition, ADMET polymerization of a terminal diolefinunctionalized D-isosorbide (2) was also conducted to produce ADMET polymers.