Automated synthesis and evaluation of potential new anti-microbial agents

A series of N1-benzylideneheteroarylcarboxamidrazones was prepared in an automated fashion, and tested against Mycobacterium fortuitum in a rapid screen for antimycobacterial activity. Many of the compounds from this series were also tested against Mycobacterium tuberculosis, and the usefulness as M.fortuitum as a rapid, initial screen for anti-tubercular activity evaluated. Various deletions were made to the N1-benzylideneheteroarylcarboxamidrazone structure in order to establish the minimum structural requirements for activity. The N1-benzylideneheteroarylcarbox-amidrazones were then subjected to molecular modelling studies and their activities against M.fortuitum and M.tuberculosis were analysed using quantitative structure-analysis relationship (QSAR) techniques in the computational package TSAR (Oxford Molecular Ltd.). A set of equations predictive of antimycobacterial activity was hereby obtained. The series of N1-benzylidenehetero-arylcarboxamidrazones was also tested against a multidrug-resistant strain of Staphylococcus aureus (MRSA), followed by a panel of Gram-positive and Gram-negative bacteria, if activity was observed for MRSA. A set of antimycobacterial N1-benzylideneheteroarylcarboxamidrazones was hereby discovered, the best of which had MICs against m. fortuitum in the range 4-8μgml-1 and displayed 94% inhibition of M.tuberculosis at a concentration of 6.25μgml-1. The antimycobacterial activity of these compounds appeared to be specific, since the same compounds were shown to be inactive against other classes of organisms. Compounds which were found to be sufficiently active in any screen were also tested for their toxicity against human mononuclear leucocytes. Polyethylene glycol (PEG) was used as a soluble polymeric support for the synthesis of some fatty acid derivatives, containing an isoxazoline group, which may inhibit mycolic acid synthesis in mycobacteria. Both the PEG-bound products and the cleaved, isolated products themselves were tested against M.fortuitum and some low levels of antimycobacterial activity were observed, which may serve as lead compounds for further studies.

Evaluation of the quality and promotion of open learning materials

In the UK, Open Learning has been used in industrial training for at least the last decade. Trainers and Open Learning practitioners have been concerned about the quality of the products and services being delivered. The argument put forward in this thesis is that there is ambiguity amongst industrialists over the meanings of `Open Learning' and `Quality in Open Learning'. For clarity, a new definition of Open Learning is proposed which challenges the traditional learner-centred approach favoured by educationalists. It introduces the concept that there are benefits afforded to the trainer/employer/teacher as well as to the learner. This enables a focussed view of what quality in Open Learning really means. Having discussed these issues, a new quantitative method of evaluating Open Learning is proposed. This is based upon an assessment of the degree of compliance with which products meet Parts 1 & 2 of the Open Learning Code of Practice. The vehicle for these research studies has been a commercial contract commissioned by the Training Agency for the Engineering Industry Training Board (EITB) to examine the quality of Open Learning products supplied to the engineering industry. A major part of this research has been the application of the evaluation technique to a range of 67 Open Learning products (in eight subject areas). The findings were that good quality products can be found right across the price range - so can average and poor quality ones. The study also shows quite convincingly that there are good quality products to be found at less than 50. Finally the majority (24 out of 34) of the good quality products were text based.

Which is the best solar thermal collection technology for electricity generation in north-west India? Evaluation of options using the analytical hierarchy process

This study of concentrating solar thermal power generation sets out to evaluate the main existing collection technologies using the framework of the Analytical Hierarchy Process (AHP). It encompasses parabolic troughs, heliostat fields, linear Fresnel reflectors, parabolic dishes, compound parabolic concentrators and linear Fresnel lenses. These technologies are compared based on technical, economic and environmental criteria. Within these three categories, numerous sub-criteria are identified; similarly sub-alternatives are considered for each technology. A literature review, thermodynamic calculations and an expert workshop have been used to arrive at quantitative and qualitative assessments. The methodology is applied principally to a case study in Gujarat in north-west India, though case studies based on the Sahara Desert, Southern Spain and California are included for comparison. A sensitivity analysis is carried out for Gujarat. The study concludes that the linear Fresnel lens with a secondary compound parabolic collector, or the parabolic dish reflector, is the preferred technology for north-west India.

Toward prediction of class II mouse major histocompatibility complex peptide binding affinity:in silico bioinformatic evaluation using partial least squares, a robust multivariate statistical technique

The accurate identification of T-cell epitopes remains a principal goal of bioinformatics within immunology. As the immunogenicity of peptide epitopes is dependent on their binding to major histocompatibility complex (MHC) molecules, the prediction of binding affinity is a prerequisite to the reliable prediction of epitopes. The iterative self-consistent (ISC) partial-least-squares (PLS)-based additive method is a recently developed bioinformatic approach for predicting class II peptide−MHC binding affinity. The ISC−PLS method overcomes many of the conceptual difficulties inherent in the prediction of class II peptide−MHC affinity, such as the binding of a mixed population of peptide lengths due to the open-ended class II binding site. The method has applications in both the accurate prediction of class II epitopes and the manipulation of affinity for heteroclitic and competitor peptides. The method is applied here to six class II mouse alleles (I-Ab, I-Ad, I-Ak, I-As, I-Ed, and I-Ek) and included peptides up to 25 amino acids in length. A series of regression equations highlighting the quantitative contributions of individual amino acids at each peptide position was established. The initial model for each allele exhibited only moderate predictivity. Once the set of selected peptide subsequences had converged, the final models exhibited a satisfactory predictive power. Convergence was reached between the 4th and 17th iterations, and the leave-one-out cross-validation statistical terms - q2, SEP, and NC - ranged between 0.732 and 0.925, 0.418 and 0.816, and 1 and 6, respectively. The non-cross-validated statistical terms r2 and SEE ranged between 0.98 and 0.995 and 0.089 and 0.180, respectively. The peptides used in this study are available from the AntiJen database (http://www.jenner.ac.uk/AntiJen). The PLS method is available commercially in the SYBYL molecular modeling software package. The resulting models, which can be used for accurate T-cell epitope prediction, will be made freely available online (http://www.jenner.ac.uk/MHCPred).

The use of computational QSAR analysis in the toxicological evaluation of a series of 2-pyridylcarboxamidrazone candidate anti-tuberculosis compounds

A series of N1-benzylidene pyridine-2-carboxamidrazone anti-tuberculosis compounds has been evaluated for their cytotoxicity using human mononuclear leucocytes (MNL) as target cells. All eight compounds were significantly more toxic than dimethyl sulphoxide control and isoniazid (INH) with the exception of a 4-methoxy-3-(2-phenylethyloxy) derivative, which was not significantly different in toxicity compared with INH. The most toxic agent was an ethoxy derivative, followed by 3-nitro, 4-methoxy, dimethylpropyl, 4-methylbenzyloxy, 3-methoxy-4-(-2-phenylethyloxy) and 4-benzyloxy in rank order. In comparison with the effect of selected carboxamidrazone agents on cells alone, the presence of either N-acetyl cysteine (NAC) or glutathione caused a significant reduction in the toxicity of INH, as well as on the 4-benzyloxy derivative, although both increased the toxicity of a 4-N,N-dimethylamino-1-naphthylidene and a 2-t-butylthio derivative. The derivatives from this and three previous studies were subjected to computational analysis in order to derive equations designed to establish quantitative structure activity relationships for these agents. Twenty-five compounds were thus resolved into two groups (1 and 2), which on analysis yielded equations with r2 values in the range 0.65-0.92. Group 1 shares a common mode of toxicity related to hydrophobicity, where cytotoxicity peaked at logP of 3.2, while Group 2 toxicity was strongly related to ionisation potential. The presence of thiols such as NAC and GSH both promoted and attenuated toxicity in selected compounds from Group 1, suggesting that secondary mechanisms of toxicity were operating. These studies will facilitate the design of future low toxicity high activity anti-tubercular carboxamidrazone agents. © 2003 Elsevier Science B.V. All rights reserved.

The Birmingham relationship continuity measure:the development and evaluation of a measure of the perceived continuity of spousal relationships in dementia

Background: Qualitative research has suggested that spousal carers of someone with dementia differ in terms of whether they perceive their relationship with that person as continuous with the premorbid relationship or as radically different, and that a perception of continuity may be associated with more person-centered care and the experience of fewer of the negative emotions associated with caring. The aim of the study was to develop and evaluate a quantitative measure of the extent to which spousal carers perceive the relationship to be continuous. Methods: An initial pool of 42 questionnaire items was generated on the basis of the qualitative research about relationship continuity. These were completed by 51 spousal carers and item analysis was used to reduce the pool to 23 items. The retained items, comprising five subscales, were then administered to a second sample of 84 spousal carers, and the questionnaire's reliability, discriminative power, and validity were evaluated. Results: The questionnaire showed good reliability: Cronbach's α for the full scale was 0.947, and test-retest reliability was 0.932. Ferguson's δ was 0.987, indicating good discriminative power. Evidence of construct validity was provided by predicted patterns of subscale correlations with the Closeness and Conflict Scale and the Marwit-Meuser Caregiver Grief Inventory. Conclusion: Initial psychometric evaluation of the measure was encouraging. The measure provides a quantitative means of investigating ideas from qualitative research about the role of relationship continuity in influencing how spousal carers provide care and how they react emotionally to their caring role. © 2012 International Psychogeriatric Association.

Visualisation of quality information for geospatial and remote sensing data:providing the GIS community with the decision support tools for geospatial dataset quality evaluation

The evaluation of geospatial data quality and trustworthiness presents a major challenge to geospatial data users when making a dataset selection decision. The research presented here therefore focused on defining and developing a GEO label – a decision support mechanism to assist data users in efficient and effective geospatial dataset selection on the basis of quality, trustworthiness and fitness for use. This thesis thus presents six phases of research and development conducted to: (a) identify the informational aspects upon which users rely when assessing geospatial dataset quality and trustworthiness; (2) elicit initial user views on the GEO label role in supporting dataset comparison and selection; (3) evaluate prototype label visualisations; (4) develop a Web service to support GEO label generation; (5) develop a prototype GEO label-based dataset discovery and intercomparison decision support tool; and (6) evaluate the prototype tool in a controlled human-subject study. The results of the studies revealed, and subsequently confirmed, eight geospatial data informational aspects that were considered important by users when evaluating geospatial dataset quality and trustworthiness, namely: producer information, producer comments, lineage information, compliance with standards, quantitative quality information, user feedback, expert reviews, and citations information. Following an iterative user-centred design (UCD) approach, it was established that the GEO label should visually summarise availability and allow interrogation of these key informational aspects. A Web service was developed to support generation of dynamic GEO label representations and integrated into a number of real-world GIS applications. The service was also utilised in the development of the GEO LINC tool – a GEO label-based dataset discovery and intercomparison decision support tool. The results of the final evaluation study indicated that (a) the GEO label effectively communicates the availability of dataset quality and trustworthiness information and (b) GEO LINC successfully facilitates ‘at a glance’ dataset intercomparison and fitness for purpose-based dataset selection.

In vivo biocompatibility evaluation of composite polymeric materials for use in a novel artificial heart valve

A novel trileaflet polymer valve is a composite design of a biostable polymer poly(styrene-isobutylene-styrene) (SIBS) with a reinforcement polyethylene terephthalate (PET) fabric. Surface roughness and hydrophilicity vary with fabrication methods and influence leaflet biocompatibility. The purpose of this study was to investigate the biocompatibility of this composite material using both small animal (nonfunctional mode) and large animal (functional mode) models. Composite samples were manufactured using dip coating and solvent casting with different coating thickness (251μm and 50μm). Sample's surface was characterized through qualitative SEM observation and quantitative surface roughness analysis. A novel rat abdominal aorta model was developed to test the composite samples in a similar pulsatile flow condition as its intended use. The sample's tissue response was characterized by histological examination. Among the samples tested, the 25μm solvent-cast sample exhibited the smoothest surface and best biocompatibility in terms of tissue capsulation thickness, and was chosen as the method for fabrication of the SIBS valve. Phosphocholine was used to create a hydrophilic surface on selected composite samples, which resulted in improved blood compatibility. Four SIBS valves (two with phosphocholine modification) were implanted into sheep. Echocardiography, blood chemistry, and system pathology were conducted to evaluate the valve's performance and biocompatibility. No adverse response was identified following implantation. The average survival time was 76 days, and one sheep with the phosphocholine modified valve passed the FDA minimum requirement of 140 days with approximately 20 million cycles of valve activity. The explanted valves were observed under the aid of a dissection microscope, and evaluated via histology, SEM and X-ray. Surface cracks and calcified tissue deposition were found on the leaflets. In conclusion, we demonstrated the applicability of using a new rat abdominal aorta model for biocompatibility assessment of polymeric materials. A smooth and complete coating surface is essential for the biocompatibility of PET/SIBS composite, and surface modification using phosphocholine improves blood compatibility. Extrinsic calcification was identified on the leaflets and was associated with regions of surface cracks.

A quantitative approach to the organizational design problem

The span of control is the most discussed single concept in classical and modern management theory. In specifying conditions for organizational effectiveness, the span of control has generally been regarded as a critical factor. Existing research work has focused mainly on qualitative methods to analyze this concept, for example heuristic rules based on experiences and/or intuition. This research takes a quantitative approach to this problem and formulates it as a binary integer model, which is used as a tool to study the organizational design issue. This model considers a range of requirements affecting management and supervision of a given set of jobs in a company. These decision variables include allocation of jobs to workers, considering complexity and compatibility of each job with respect to workers, and the requirement of management for planning, execution, training, and control activities in a hierarchical organization. The objective of the model is minimal operations cost, which is the sum of supervision costs at each level of the hierarchy, and the costs of workers assigned to jobs. The model is intended for application in the make-to-order industries as a design tool. It could also be applied to make-to-stock companies as an evaluation tool, to assess the optimality of their current organizational structure. Extensive experiments were conducted to validate the model, to study its behavior, and to evaluate the impact of changing parameters with practical problems. This research proposes a meta-heuristic approach to solving large-size problems, based on the concept of greedy algorithms and the Meta-RaPS algorithm. The proposed heuristic was evaluated with two measures of performance: solution quality and computational speed. The quality is assessed by comparing the obtained objective function value to the one achieved by the optimal solution. The computational efficiency is assessed by comparing the computer time used by the proposed heuristic to the time taken by a commercial software system. Test results show the proposed heuristic procedure generates good solutions in a time-efficient manner.

The effect of dual -language instruction on academic achievement as measured by the SAT: An evaluation of the "International Studies Program" of Miami -Dade County Public Schools

This study investigated the influence that receiving instruction in two languages, English and Spanish, had on the performance of students enrolled in the International Studies Program (delayed partial immersion model) of Miami Dade County Public Schools on a standardized test in English, the Stanford Achievement Test, eighth edition, for three of its sections, Reading Comprehension, Mathematics Computations, and Mathematics Applications.^ The performance of the selected IS program/Spanish section cohort of students (N = 55) on the SAT Reading Comprehension, Mathematics Computation, and Mathematics Application along four consecutive years was contrasted with that of a control group of comparable students selected within the same feeder pattern where the IS program is implemented (N = 21). The performance of the group was also compared to the cross-sectional achievement patterns of the school's corresponding feeder pattern, region, and district.^ The research model for the study was a variation of the "causal-comparative" or "ex post facto design" sometimes referred to as "prospective". After data were collected from MDCPS, t-tests were performed to compare IS-Spanish students SAT performance for grades 3 to 6 for years 1994 to 1997 to control group, feeder pattern, region and district norms for each year for Reading Comprehension, Mathematics Computation, and Mathematics Applications. Repeated measures ANOVA and Tukey's tests were calculated to compare the mean percentiles of the groups under study and the possible interactions of the different variables. All tests were performed at the 5% significance level.^ From the analyses of the tests it was deduced that the IS group performed significantly better than the control group for all the three measures along the four years. The IS group mean percentiles on the three measures were also significantly higher than those of the feeder pattern, region, and district. The null hypotheses were rejected and it was concluded that receiving instruction in two languages did not negatively affect the performance of IS program students on tests taken in English. It was also concluded that the particular design the IS program enhances the general performance of participant students on Standardized tests.^ The quantitative analyses were coupled with interviews from teachers and administrators of the IS program to gain additional insight about different aspects of the implementation of the program at each particular school. ^

The early development and pilot -testing of a case management intervention with victims of stalking: An evaluation study

This study evaluated the early development and pilot-testing of Project IMPACT, a case management intervention for victims of stalking. The Design and Development framework (Rothman & Thomas, 1994) was used as a guide for program development and evaluation. Nine research questions examined the processes and outcomes associated with program implementation. ^ The sample included all 36 clients who participated in Project IMPACT between February of 2000 and June of 2001, as well as the victim advocates who provided them with services. Quantitative and qualitative data were drawn from client case files, participant observation field notes and interview transcriptions. Quantitative data were entered into three databases where: (1) clients were the units of analysis (n = 36), (2) services were the units of analysis (n = 1146), and (3) goals were the units of analysis (n = 149). These data were analyzed using descriptive statistics, Pearson's Chi-square, Spearman's Rho, Phi, Cramer's V, Wilcoxon's Matched Pairs Signed-Ranked Test and McNemar's Test Statistic. Qualitative data were reduced via open, axial and selective coding methods. Grounded theory and case study frameworks were utilized to analyze these data. ^ Results showed that most clients noted an improved sense of well-being and safety, although residual symptoms of trauma remained for numerous individuals. Stalkers appeared to respond to criminal and civil justice-based interventions by reducing violent and threatening behaviors; however, covert behaviors continued. The study produced findings that provided preliminary support for the use of several intervention components including support services, psycho-education, safety planning, and boundary spanning. The psycho-education and safety planning in particular seemed to help clients cognitively reframe their perceptions of the stalking experience and gain a sense of increased safety and well-being. A 65% level of satisfactory goal achievement was observed overall, although goals involving justice-based organizations were associated with lower achievement. High service usage was related to low-income clients and those lacking in social support. Numerous inconsistencies in program implementation were found to be associated with the skills and experiences of victim advocates. Thus, recommendations were made to further refine, develop and evaluate the intervention. ^

An evaluation of an online peer support forum for university students with depressive symptoms

Background: Depression is the most common mental health problem among young people, particularly university students, with prevalence rates as high as 48% reported. This population however, is reluctant to seek professional help. Online interventions may be particularly appealing to students, with evidence suggesting that they use the Internet for mental health support. While there are many mental health resources on the Internet few focus specifically on the needs of young people and few have been evaluated. This research aimed to develop and pilot test an online peer support intervention for students experiencing depressive symptoms. Methods: A depression support Web site (www.losetheblues.ie) was designed specifically for 18-24. year old students. The study used a mixed method, involving quantitative descriptive, pre- and post-test and qualitative descriptive designs. Data were collected using the Centre for Epidemiological Studies Depression Scale (CES-D), a background questionnaire and online forum posts. Results: The sample consisted of 117 university students with self-reported depressive symptoms. Results from participants in the pre- and post-test element of the study, showed no statistical significance. The forum posts revealed that the participants' main difficulties were loneliness and perceived lack of socialization skills. The Web site provided a place for sharing, offering and receiving emotional and informational support. Conclusion: Developing health care interventions in an online environment presents unique challenges to the research process, however they have the potential to provide mental health care that is accessible and affordable.

‘Potentially inappropriate or specifically appropriate?’ Qualitative evaluation of general practitioners views on prescribing, polypharmacy and potentially inappropriate prescribing in older people

Background: Potentially inappropriate prescribing (PIP) is common in older people in primary care, as evidenced by a significant body of quantitative research. However, relatively few qualitative studies have investigated the phenomenon of PIP and its underlying processes from the perspective of general practitioners (GPs). The aim of this paper is to explore qualitatively, GP perspectives regarding prescribing and PIP in older primary care patients.

Method: Semi-structured qualitative interviews were conducted with GPs participating in a randomised controlled trial (RCT) of an intervention to decrease PIP in older patients (≥70 years) in Ireland. Interviews were conducted with GP participants (both intervention and control) from the OPTI-SCRIPT cluster RCT as part of the trial process evaluation between January and July 2013. Interviews were conducted by one interviewer and audio recorded. Interviews were transcribed verbatim and a thematic analysis was conducted.

Results: Seventeen semi-structured interviews were conducted (13 male; 4 female). Three main, inter-related themes emerged (complex prescribing environment, paternalistic doctor-patient relationship, and relevance of PIP concept). Patient complexity (e.g. polypharmacy, multimorbidity), as well as prescriber complexity (e.g. multiple prescribers, poor communication, restricted autonomy) were all identified as factors contributing to a complex prescribing environment where PIP could occur, as was a paternalistic-doctor patient relationship. The concept of PIP was perceived to be of variable usefulness to GPs and the criteria to measure it may be at odds with the complex processes of prescribing for this patient population.

Conclusions: Several inter-related factors contributing to the occurrence of PIP were identified, some of which may be amenable to intervention. Improvement strategies focused on improved management of polypharmacy and multimorbidity, and communication across primary and secondary care could result in substantial improvements in PIP.

A process evaluation of a cluster randomised trial to reduce potentially inappropriate prescribing in older people in primary care (OPTI-SCRIPT study)

Background
The OPTI-SCRIPT cluster randomised controlled trial (RCT) found that a three-phase multifaceted intervention including academic detailing with a pharmacist, GP-led medicines reviews, supported by web-based pharmaceutical treatment algorithms, and tailored patient information leaflets, was effective in reducing potentially inappropriate prescribing (PIP) in Irish primary care. We report a process evaluation exploring the implementation of the intervention, the experiences of those participating in the study and lessons for future implementation.

Methods
The OPTI-SCRIPT trial included 21 GP practices and 196 patients. The process evaluation used mixed methods. Quantitative data were collected from all GP practices and semi-structured interviews were conducted with GPs from intervention and control groups, and a purposive sample of patients from the intervention group. All interviews were transcribed verbatim and analysed using a thematic analysis.

Results
Despite receiving a standardised academic detailing session, intervention delivery varied among GP practices. Just over 70 % of practices completed medicines review as recommended with the patient present. Only single-handed practices conducted reviews without patients present, highlighting the influence of practice characteristics and resources on variation. Medications were more likely to be completely stopped or switched to another more appropriate medication when reviews were conducted with patients present. The patient information leaflets were not used by any of the intervention practices. Both GP (32 %) and patient (40 %) recruitment rates were modest. For those who did participate, overall, the experience was positively viewed, with GPs and patients referring to the value of medication reviews to improve prescribing and reduce unnecessary medications. Lack of time in busy GP practices and remuneration were identified as organisational barriers to future implementation.

Conclusions
The OPTI-SCRIPT intervention was positively viewed by both GPs and patients, both of whom valued the study’s objectives. Patient information leaflets were not a successful component of the intervention. Academic detailing and medication reviews are important components in changing PIP, and having patients present during the review process seems to be a more effective approach for decreasing PIP.

Experimental evaluation of the response of micro-channel plate detector to ions with 10s of MeV energies

The absolute calibration of a microchannel plate (MCP) assembly using a Thomson spectrometer for laser-driven ion beams is described. In order to obtain the response of the whole detection system to the particles’ impact, a slotted solid state nuclear track detector (CR-39) was installed in front of the MCP to record the ions simultaneously on both detectors. The response of the MCP (counts/particles) was measured for 5–58 MeV carbon ions and for protons in the energy range2–17.3 MeV. The response of the MCP detector is non-trivial when the stopping range of particles becomes larger than the thickness of the detector. Protons with energiesE>~ 10 MeV are energetic enough that they can pass through the MCP detector. Quantitative analysis of the pits formed in CR-39 and the signal generated in the MCP allowed to determine the MCP response to particles in this energy range. Moreover, a theoretical model allows to predict the response of MCP at even higher proton energies. This suggests that in this regime the MCP response is a slowly decreasing function of energy, consistently with the decrease of the deposited energy. These calibration data will enable particle spectra to be obtained in absolute terms over a broad energy range.