ITSM ProcessGuide – a longitudinal and multi-method field study for real-world DSR artifact evaluation

Process guidance supports users to increase their process model understanding, process execution effectiveness as well as efficiency, and process compliance performance. This paper presents a research in progress encompassing our ongoing DSR project on Process Guidance Systems and a field evaluation of the resulting artifact in cooperation with a company. Building on three theory-grounded design principles, a Process Guidance System artifact for the company’s IT service ticketing process is developed, deployed and used. Fol-lowing a multi-method approach, we plan to evaluate the artifact in a longitudinal field study. Thereby, we will not only gather self-reported but also real usage data. This article describes the development of the artifact and discusses an innovative evaluation approach.

Design, synthesis and evaluation of novel ellipticine derivatives and analogues as anti-cancer agents

This thesis describes work carried out on the synthesis of novel 5- and 11-substituted ellipticines and derivatives of the ellipticine analogues, isoellipticine and deazaellipticine, followed by investigation of their potential as anti-cancer agents. Preparation of the key 5- and 11-substituted ellipticine targets involved the development of regiospecific, sequential alkylation reactions with alkenyllithium and Grignard reagents. Investigation of these novel reactions resulted in a new route towards 5-substituted ellipticines via Grignard reaction with vinylmagnesium bromide. These novel 5-vinylellipticine derivatives were further functionalised in an ozonolysis reaction, followed by oxidation to give a range of novel 5-substituted ellipticines. Less success was encountered in the 11-substituted ellipticine series, however preparation of these derivatives using a previously published route was accomplished, and the resulting 11-formylellipticine was further derivatised to give a panel of novel 9- and 11-substituted ellipticines, incorporating amide, carboxylate, imine and amine functionality. The successful route towards 5-substituted ellipticines was applied to the preparation of a range of novel 11-substituted isoellipticines and 6-substituted deazaellipticines, the first time substantial synthesis has been undertaken with these analogues. In addition to this, the first preparation of isoellipticinium salts is described, and a panel of novel isoellipticinium, 7 formylisoellipticinium and 7-hydroxyisoellipticinium salts were synthesised in good yields. Biological evaluation of a panel of 43 novel ellipticine, isoellipticine and deazaellipticine derivatives was accomplished with a topoisomerase II decatenation assay and submission to the NCI 60-cell line screen. Four novel isoellipticine topoisomerase II inhibitors were identified from the decatenation assay, with strong activity at 10 μM. In addition to this, NCI screening identified five highly cytotoxic ellipticine and isoellipticine compounds with remarkable selectivity profiles for different cancer types. These novel lead compounds represent new templates for further research and synthesis.

Design and evaluation of novel microencapsulation technologies to enhance delivery of Ciclosporin

Drug delivery systems influence the various processes of release, absorption, distribution and elimination of drug. Conventional delivery methods administer drug through the mouth, the skin, transmucosal areas, inhalation or injection. However, one of the current challenges is the lack of effective and targeted oral drug administration. Development of sophisticated strategies, such as micro- and nanotechnology that can integrate the design and synthesis of drug delivery systems in a one-step, scalable process is fundamental in advancing the limitations of conventional processing techniques. Thus, the objective of this thesis is to evaluate novel microencapsulation technologies in the production of size-specific and target-specific drug-loaded particles. The first part of this thesis describes the utility of PDMS and silicon microfluidic flow focusing devices (MFFDs) to produce PLGA-based microparticles. The formation of uniform droplets was dependent on the surface of PDMS remaining hydrophilic. However, the durability of PDMS was limited to no more than 1 hour before wetting of the microchannel walls with dichloromethane and subsequent swelling occurred. Critically, silicon MFFDs revealed very good solvent compatibility and was sufficiently robust to withstand elevated fluid flow rates. Silicon MFFDs facilitated experiments to run over days with continuous use and re-use of the device with a narrower microparticle size distribution, relative to conventional production techniques. The second part of this thesis demonstrates an alternative microencapsulation technology, SmPill® minispheres, to target CsA delivery to the colon. Characterisation of CsA release in vitro and in vivo was performed. By modulating the ethylcellulose:pectin coating thickness, release of CsA in-vivo was more effectively controlled compared to current commercial CsA formulations and demonstrated a linear in-vitro in-vivo relationship. Coated minispheres were shown to limit CsA release in the upper small intestine and enhance localised CsA delivery to the colon.

Hardware design of cryptographic accelerators

With the rapid growth of the Internet and digital communications, the volume of sensitive electronic transactions being transferred and stored over and on insecure media has increased dramatically in recent years. The growing demand for cryptographic systems to secure this data, across a multitude of platforms, ranging from large servers to small mobile devices and smart cards, has necessitated research into low cost, flexible and secure solutions. As constraints on architectures such as area, speed and power become key factors in choosing a cryptosystem, methods for speeding up the development and evaluation process are necessary. This thesis investigates flexible hardware architectures for the main components of a cryptographic system. Dedicated hardware accelerators can provide significant performance improvements when compared to implementations on general purpose processors. Each of the designs proposed are analysed in terms of speed, area, power, energy and efficiency. Field Programmable Gate Arrays (FPGAs) are chosen as the development platform due to their fast development time and reconfigurable nature. Firstly, a reconfigurable architecture for performing elliptic curve point scalar multiplication on an FPGA is presented. Elliptic curve cryptography is one such method to secure data, offering similar security levels to traditional systems, such as RSA, but with smaller key sizes, translating into lower memory and bandwidth requirements. The architecture is implemented using different underlying algorithms and coordinates for dedicated Double-and-Add algorithms, twisted Edwards algorithms and SPA secure algorithms, and its power consumption and energy on an FPGA measured. Hardware implementation results for these new algorithms are compared against their software counterparts and the best choices for minimum area-time and area-energy circuits are then identified and examined for larger key and field sizes. Secondly, implementation methods for another component of a cryptographic system, namely hash functions, developed in the recently concluded SHA-3 hash competition are presented. Various designs from the three rounds of the NIST run competition are implemented on FPGA along with an interface to allow fair comparison of the different hash functions when operating in a standardised and constrained environment. Different methods of implementation for the designs and their subsequent performance is examined in terms of throughput, area and energy costs using various constraint metrics. Comparing many different implementation methods and algorithms is nontrivial. Another aim of this thesis is the development of generic interfaces used both to reduce implementation and test time and also to enable fair baseline comparisons of different algorithms when operating in a standardised and constrained environment. Finally, a hardware-software co-design cryptographic architecture is presented. This architecture is capable of supporting multiple types of cryptographic algorithms and is described through an application for performing public key cryptography, namely the Elliptic Curve Digital Signature Algorithm (ECDSA). This architecture makes use of the elliptic curve architecture and the hash functions described previously. These components, along with a random number generator, provide hardware acceleration for a Microblaze based cryptographic system. The trade-off in terms of performance for flexibility is discussed using dedicated software, and hardware-software co-design implementations of the elliptic curve point scalar multiplication block. Results are then presented in terms of the overall cryptographic system.

Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics

This thesis details the design and implementation of novel chemical routes towards a series of highly propitious 7-azaindolyl derivatives of the indolocarbazole (ICZ) and bisindolylmaleimide (BIM) families, with subsequent evaluation for use as cancer chemotherapeutic agents. A robust synthetic strategy was devised to allow the introduction of a 7-azaindolyl moiety into our molecular template. This approach allowed access to a wide range of β-keto ester and β-keto nitrile intermediates. Critical analysis identified F-ring modulation as a major theme towards the advancement of ICZ and BIM derivatives in drug therapy. Thus, the employment of cyclocondensation methodology furnished a number of novel aminopyrazole, isoxazolone, pyrazolone and pyrimidinone analogues, considerably widening the scope of the prevalent maleimide functionality. Photochemical cyclisation provided for the first reported aza ICZ containing a six-membered F-ring. Another method towards achieving the aza ICZ core involved use of a Perkin-type condensation approach, with chemical elaboration of the headgroup instigated post-aromatisation. Subsequent use of a modified Lossen rearrangement allowed access to further analogues containing a six-membered F-ring. Extensive screening of the novel aza ICZ and BIM derivatives was carried out against the NCI-60 cancer cell array, with nine prospective candidates selected for continued biological evaluation. From these assays, a number of compounds were shown to inhibit cancer cell growth at concentrations of below 10 nM. Indeed, the most active aza ICZ tested is currently under assessment by the Biological Evaluation Committee of the NCI due to excellent antiproliferative activity demonstrated across the panel of cell lines, with a mean GI50 of 34 nM, a mean total growth inhibition (TGI) of 4.6 μM and a mean cytotoxicity (LC50) of 63.1 μM. Correlation to known topoisomerase I (topo I) inhibitors was revealed by COMPARE analysis, and subsequent topo I-mediated DNA cleavage assays showed inhibitory activity below 1 μM for several derivatives.

Self-neglect: development and evaluation of a self-neglect (SN-37) measurement instrument

Aim: To develop and evaluate the psychometric properties of an instrument for the measurement of self-neglect (SN).Conceptual Framework: An elder self-neglect (ESN) conceptual framework guided the literature review and scale development. The framework has two key dimensions physical/psycho-social and environmental and seven sub dimensions which are representative of the factors that can contribute to intentional and unintentional SN. Methods: A descriptive cross-sectional design was adopted to achieve the research aim. The study was conducted in two phases. Phase 1 involved the development of the questionnaire content and structure. Phase 2 focused on establishing the psychometric properties of the instrument. Content validity was established by a panel of 8 experts and piloted with 9 health and social care professionals. The instrument was subsequently posted with a stamped addressed envelope to 566 health and social care professionals who met specific eligibility criteria across the four HSE areas. A total of 341 questionnaires were returned, a response rate of 60% and 305 (50%) completed responses were included in exploratory factor analysis (EFA). Item and factor analyses were performed to elicit the instruments underlying factor structure and establish preliminary construct validity. Findings: Item and factor analyses resulted in a logically coherent, 37 items, five factor solution, explaining 55.6% of the cumulative variance. The factors were labelled: ‘Environment’, ‘Social Networks’, ‘Emotional and Behavioural Liability’, ‘Health Avoidance’ and ‘Self-Determinism’. The factor loadings were >0.40 for all items on each of the five subscales. Preliminary construct validity was supported by findings. Conclusion: The main outcome of this research is a 37 item Self-Neglect (SN-37) measurement instrument that was developed by EFA and underpinned by an ESN conceptual framework. Preliminary psychometric evaluation of the instrument is promising. Future work should be directed at establishing the construct and criterion related validity of the instrument.

Development and psychometric evaluation of the spirituality instrument (SpI-27) in a sample of people with chronic illness

Background: Spirituality is fundamental to all human beings, existing within a person, and developing until death. This research sought to operationalise spirituality in a sample of individuals with chronic illness. A review of the conceptual literature identified three dimensions of spirituality: connectedness, transcendence, and meaning in life. A review of the empirical literature identified one instrument that measures the three dimensions together. Yet, recent appraisals of this instrument highlighted issues with item formulation and limited evidence of reliability and validity. Aim: The aim of this research was to develop a theoretically-grounded instrument to measure spirituality – the Spirituality Instrument-27 (SpI-27). A secondary aim was to psychometrically evaluate this instrument in a sample of individuals with chronic illness (n=249). Methods: A two-phase design was adopted. Phase one consisted of the development of the SpI-27 based on item generation from a concept analysis, a literature review, and an instrument appraisal. The second phase established the psychometric properties of the instrument and included: a qualitative descriptive design to establish content validity; a pilot study to evaluate the mode of administration; and a descriptive correlational design to assess the instrument’s reliability and validity. Data were analysed using SPSS (Version 18). Results: Results of exploratory factor analysis concluded a final five-factor solution with 27 items. These five factors were labelled: Connectedness with Others, Self-Transcendence, Self-Cognisance, Conservationism, and Connectedness with a Higher Power. Cronbach’s alpha coefficients ranged from 0.823 to 0.911 for the five factors, and 0.904 for the overall scale, indicating high internal consistency. Paired-sample t-tests, intra-class correlations, and weighted kappa values supported the temporal stability of the instrument over 2 weeks. A significant positive correlation was found between the SpI-27 and the Spirituality Index of Well-Being, providing evidence for convergent validity. Conclusion: This research addresses a call for a theoretically-grounded instrument to measure spirituality.

Synthesis and evaluation of novel quinolines and quinazolinediones as potential anti-cancer agents

This thesis outlines the design and effectuation of novel chemical routes towards a nascent class of functionalised quinoline-5,8-diones and the expansion of a series of contemporary quinazolinediones towards an innovative family of pyridinoquinazolinetetrone derivatives. This fragment based approach is envisaged to lead to advancements in the three scaffolds, expanding the SAR pool of both quinolines and quinazolinediones with subsequent evaluation of chemotherapeutic potential as well as furnishing a new class of tricycle for biological investigation. Development of novel quinoline-5,8-diones is provided for by expanding on existing methodology. Using a variety of nucleophiles on a critical intermediate, a broad range of novel compounds was afforded allowing chemotherapeutic potential to be assessed, while also serving as intermediates for accomplishing novel pyridinoquinazolinetetrone congeners. In order to incorporate functionality into our quinazolinedione template, an efficient synthetic strategy was constructed which provided a robust route to effectuate a highly derivatised pyrimidinedione ring. As derivatisation of this template is unreported our chief priority was to synthesise a range of diverse quinazolinediones. The application of annulation methodology using functionalised precursors provided a library of N-3 derivatised quinazolinedione analogues. These, along with their N-1 functionalised derivatives provide a wide scope from which to construct a series of pyridinoquinazolinetetrone derivatives while also serving as a unique class of molecules whose biological potential is uncharted. Although the actualisation of the pyridinoquinazolinetetrone was ultimately unsuccessful, our work has led to the development of novel quinoline-5,8-diones which were found to possess excellent anti-cancer activity when assessed by the NCI screen. Of the quinazolinediones synthesised eight compounds were accepted for screening by the NCI. Results from the single-dose tests however indicated that these compounds possessed little cytotoxic activity at 10 μM. The development of this novel template in conjunction with the highly active quinolinediones serves as an excellent rostrum for future synthetic endeavours.