Researchers use the policy Delphi method to explore a complex topic with little historical context that requires expert opinion to fully understand underlying issues. The benefit of this research technique is the use of experts who have more timely information than can be gleamed from extant literature. Additionally, those experts place researchers in a specific moment, thus increasing the possibility of capturing change over time. One limitation of the policy Delphi is the difficulty in developing an accurate initial questionnaire to start the process. The purpose of this article is to identify benefits and limitations of this research method.

The aims of the present investigation are fourfold: (i) to review the range of non-invasive methods that may be used to diagnose acute cardiac allograft rejection; (ii) to review the use of the bioptome in sampling the donor heart endomyocardium; (iii) to review the light microscopic and histological grading of acute cardiac rejection; (iv) to characterise the mononuclear populations in endomyocardial biopsy samples and correlate the findings with the light microscopic appearances of the same biopsy specimens.

The great toe is the part of the foot that most often requires surgical intervention. The first metatarsophalangeal joint (FMTPJ) is the most prominent joint of the great toe. Primary causes of FMTPJ failure are rheumatoid arthritis, osteoarthrosis and joint degeneration secondary to deformities such as hallux valgus, hallux rigidus or the trauma of previous surgery. FMTPJ prostheses are used to restore a measure of motion, correct deformities and relieve pain. FMTPJ replacement is most often indicated for elderly and less active patients but is contra-indicated for young, rheumatoid and active patients. The most common types of FMTPJ prostheses are made from silicone elastomer. Although these have been in use since the 1960's, there are many problems associated with these and all other types of FMTPJ prostheses. For example, recent research has shown that silicone elastomer metatarsophalangeal arthroplasties may cause severe, chronic silicone granulomatous disease. Also, previous studies of the pressure distribution under normal feet, and pathological feet before and after surgery, can be used to show that FMTPJ prostheses fail to restore normal weight-bearing. In this regard, FMTPJ arthroplasties perform little better than amputation. The reasons for the poor biomechanical performance of FMTPJ arthroplasty are not well documented. Existing theoretical models of FMTPJ function cannot be used to explain why almost all surgery of the first ray causes weight bearing to transfer to the lateral side of the foot. A new hypothesis of FMTPJ function was therefore formulated. It is known that the motions of the FMTPJ are linked to motions of the other bones of the foot and ankle because the strong fibrous tissues of the plantar aponeurosis connect the hallux to the calcaneus. However, it is hypothesised that the particular orientation of the bones at the final stages of the stance phase is crucial to the weight-bearing functions of the FMTPJ. A specification for a new prosthesis was therefore developed in accordance with the biomechanical principles contained in the hypothesis. Various potential designs of prosthesis were investigated, but a ball-and-socket configuration was selected because it appeared to allow the motions necessary to restore normal loading in the foot. Three slightly different prototype ball-and-socket FMTPJ prostheses were designed and manufactured. These prototypes were inserted into cadavers; which allowed the range of motion of the prototype prostheses to be assessed in relation to the constraints imposed by the strong fibrous attachments in the foot. Some of the rudimentary surgical techniques and the instruments required to insert and align the prostheses were developed. The various design features that had been incorporated in the different prototypes were assessed in terms of their relevance to ultimate performance of the arthroplasty. In order to verify the biomechanical design principles, cadaveric FMTP joints were tested for range of motion before and after inserting the prostheses. The results were compared to the range of motions obtained from a dry bone specimen, and to the most successful FMTPJ design to date- a double-stem silicone elastomer prosthesis. Finally, the results from all the tests were compared and discussed in relation to the original hypothesis about the function of the great toe. The results obtained from the new prosthesis were sufficiently encouraging to be able to recommend that the prototype be manufactured for further clinical trials. The new prosthesis was found to simulate the conditions that are necessary to re-establish normal weight-bearing patterns in the foot; such as an elevated centre of rotation for the proximal end of the first metatarsal bone, tension in the plantar aponeurosis, mobile bones in the arch, and weight-bearing by the first metatarsal. Previous prostheses used in FMTPJ arthroplasty are believed to be inadequate in that they do not restore at least one of these conditions, which ultimately lead to implant failure. Within the limits of cadaver trials, the new design has demonstrated that it has the potential to succeed.

A project report submitted to the Faculty of Engineering, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Engineering. / The simulator uses the Monte Carlo technique to quickly and accurately estimate the reliability and availability of complex network systems, Non-exponential failure and repair distributions are included in the model, as is standby redundancy and K out of N active redundancy. The program is easy to use and will work on a large variety of computers and FORTRAN compilers. Some knowledge of FORTRAN is required to program the simulator for each reliability network, The simulator is limited to the analysis of network systems, i.e, those systems whose logic can be fully represented by a reliability block diagram. The applicability of the model was demonstrated by the analysis of numerous systems in the aerospace and industrial environments. Validation of the model was accomplished by comparing these results with analytically determined values, or those from AMIR and SPAR where an analytic solution was impossible. / Andrew Chakane 2018

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Amyloids are highly ordered cross-β sheet aggregates that are associated with many diseases such as Alzheimer‟s, type II diabetes and prion diseases. Recently a progress has been made in structure elucidation, environmental effects and thermodynamic properties of amyloid aggregates. However, detailed understanding of how mutation, packing polymorphism and small organic molecules influence amyloid structure and dynamics is still lacking. Atomistic modeling of these phenomena with molecular dynamics (MD) simulations holds a great promise to bridge this gap. This Thesis describes the results of MD simulations, which provide insight into the effects of mutation, packing polymorphism and molecular inhibitors on amyloid peptides aggregation. Chapter 1 discusses the structure of amyloid peptides, diseases associated with amyloid aggregation, mechanism of aggregation and strategies to treat amyloid diseases. Chapter 2 describes the basic principles of molecular dynamic simulation and methods of trajectory analysis used in the Thesis. Chapter 3 presents the results of the study of several all-atom molecular dynamics simulations with explicit solvent, starting from the crystalline fragments of two to ten monomers each. Three different hexapeptides and their analogs produced with single glycine replacement were investigated to study the structural stability, aggregation behavior and thermodynamics of the amyloid oligomers. Chapter 4 presents multiple molecular dynamics (MD) simulation of a pair polymorphic form of five short segments of amyloid peptide. Chapter 5 describes MD study of single-layer oligomers of the full-length insulin with a goal to identify the structural elements that are important for insulin amyloid stability, and to suggest single glycine mutants that may improve formulation. Chapter 6 presents the investigation of the mechanism of the interaction of polyphenols molecules with the protofibrils formed by an amyloidogenic hexapeptide fragment (VQIVYK) of Tau peptide by molecular dynamics iii simulations in explicit solvent. We analyzed the trajectories of the large (7×4) aggregate with and without the polyphenols. Our MD simulations for both the short and full length amyloids revealed adding strands enhances the internal stability of wildtype aggregates. The degree of structural similarity between the oligomers in simulation and the fibril models constructed based on experimental data may explain why adding oligomers shortens the experimentally observed nucleation lag phase of amyloid aggregation. The MM-PBSA free energy calculation revealed nonpolar components of the free energy is more favorable while electrostatic solvation is unfavorable for the sheet to sheet interaction. This explains the acceleration of aggregation by adding nonpolar co-solvents (methanol, trifluoroethanol, and hexafluoroisopropanol). Free energy decomposition shows residues situated at the interface were found to make favorable contribution to the peptide -peptide association. The results from the simulations might provide both the valuable insight for amyloid aggregation as well as assist in inhibitor design efforts. First, the simulation of the single glycine mutants at the steric zipper of the short segments of various pathological peptides indicates the intersheet steric zipper is important for amyloid stability. Mutation of the side chains at the dry steric zipper disrupts the sheet to sheet packing, making the aggregation unstable. Thus, designing new peptidomimetic inhibitors able to prevent the fibril formation based on the steric zipper motif of the oligomers, similar to the ones examined in this study may become a viable therapeutic strategy. The various steric zipper microcrystal structures of short amyloid segments could be used as a template to design aggregation inhibitor that can block growth of the aggregates. Modification of the steric zipper structure (structure based design) with a single amino acid changes, shuffling the sequences, N- methylation of peptide amide bonds to suppress hydrogen iv bonding ability of NH groups or replacement with D amino acid sequence that interact with the parent steric zipper could be used in computational search for the new inhibitors. Second, the polyphenols were found to interact with performed oligomer through hydrogen bonding and induce conformational change creating an altered aggregate. The conformational change disrupts the intermolecular amyloid contact remodeling the amyloid aggregate. The recently reported microcrystal structure of short segments of amyloid peptides with small organic molecules could serve as a pharamcophore for virtual screening of aggregation inhibitor using combined docking and MD simulation with possible enhancement of lead enrichment. Finally, our MD simulation of short segments of amyloids with steric zipper polymorphism showed the stability depends on both sequence and packing arrangements. The hydrophilic polar GNNQQNY and NNQNTF with interface containing large polar and/or aromatic side chains (Q/N) are more stable than steric zipper interfaces made of small or hydrophobic residues (SSTNVG, VQIVYK, and MVGGVV). The larger sheet to sheet interface of the dry steric zipper through polar Q/N rich side chains was found to holds the sheets together better than non Q/N rich short amyloid segments. The packing polymorphism could influence the structure based design of aggregation inhibitor and a combination of different aggregation inhibitors might be required to bind to various morphologic forms of the amyloid peptides.

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The flow of traffic at an intersection is often controlled by a traffic signal. This research report models a T-intersection with a disjoint network for each direction of traffic flow, eastbound, westbound and southbound. The traffic signal is modeled with a fourth network. Three types of signal control (pretimed, semi-actuated and full-actuated) are modeled to examine the effect of each type on the average delay time and average length of queues for each lane of traffic queue at the intersection. The computer models presented in the report use SLAM computer language to simulate the traffic signal and vehicle flow.

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