Combinatorial approach to multi-substituted 1,4-Benzodiazepines as novel non-peptide CCK-antagonists

For the drug discovery process, a library of 168 multisubstituted 1,4-benzodiazepines were prepared by a 5-step solid phase combinatorial approach. Substituents were varied in the 3,5, 7 and 8-position on the benzodiazepine scaffold. The combinatorial library was evaluated in a CCK radiolabelled binding assay and CCKA (alimentary) and CCKB (brain) selective lead structures were discovered. The template of CCKA selective 1,4-benzodiazepin-2-ones bearing the tryptophan moiety was chemically modified by selective alkylation and acylation reactions. These studies provided a series of Asperlicin naturally analogues. The fully optimised Asperlicin related compound possessed a similar CCKA activity as the natural occuring compound. 3-Alkylated 1,4-benzodiazepines with selectivity towards the CCKB receptor subtype were optimised on A) the lipophilic side chain and B) the 2-aminophenyl-ketone moiety, together with some stereochemical changes. A C3 unit in the 3-position of 1,4-benzodiazepines possessed a CCKB activity within the nanomolar range. Further SAR optimisation on the N1-position by selective alkylation resulted in an improved CCKB binding with potentially decreased activity on the GABAA/benzodiazepine receptor complex. The in vivo studies revealed two N1-alkylated compounds containing unsaturated alkyl groups with anxiolytic properties. Alternative chemical approaches have been developed, including a route that is suitable for scale up of the desired target molecule in order to provide sufficient quantities for further in vivo evaluation.

An evaluation of Home Office extended interviews for police personnel

In this thesis the validity of an Assessment Centre (called 'Extended Interview') operated on behalf of the British police is investigated. This Assessment Centre (AC) is used to select from amongst internal candidates (serving policemen and policewomen) and external candidates (graduates) for places on an accelerated promotion scheme. The literature is reviewed with respect to history, content, structure, reliability, validity, efficiency and usefulness of ACs, and to contextual issues surrounding AC use. The history of, background to and content of police Extended Interviews (Els) is described, and research issues are identified. Internal validation involved regression of overall EI grades on measures from component tests, exercises, interviews and peer nominations. Four samples numbering 126, 73, 86 and 109 were used in this part of the research. External validation involved regression of three types of criteria - training grades, rank attained, and supervisory ratings - on all EI measures. Follow-up periods for job criteria ranged from 7 to 19 years. Three samples, numbering 223, 157 and 86, were used in this part of the research. In subsidiary investigations, supervisory ratings were factor analysed and criteria intercorrelated. For two of the samples involved in the external validition, clinical/judgemental prediction was compared with mechanical (unit-weighted composite) prediction. Main conclusions are that: (1) EI selection decisions were valid, but only for a job performance criterion; relatively low validity overall was interpreted principally in terms of the questionable job relatedness of the EI procedure; (2) Els as a whole had more validity than was reflected in final EI decisions; (3) assessors' use of information was not optimum, tending to over-emphasize subjectively derived information particularly from interviews; and (4) mechanical prediction was superior to clinical/judgemental prediction for five major criteria.

The derivation and application of risk tolerability criteria

This research involves a study of the questions, "what is considered safe", how are safety levels defined or decided, and according to whom. Tolerable or acceptable risk questions raise various issues: about values and assumptions inherent in such levels; about decision-making frameworks at the highest level of policy making as well as on the individual level; and about the suitability and competency of decision-makers to decide and to communicate their decisions. The wide-ranging topics covering philosophical and practical concerns examined in the literature review reveal the multi-disciplined scope of this research. To support this theoretical study empirical research was undertaken at the European Space Research and Technology Centre (ESTEC) of the European Space Agency (ESA). ESTEC is a large, multi-nationality, high technology organisation which presented an ideal case study for exploring how decisions are made with respect to safety from a personal as well as organisational aspect. A qualitative methodology was employed to gather, analyse and report the findings of this research. Significant findings reveal how experts perceive risks and the prevalence of informal decision-making processes partly due to the inadequacy of formal methods for deciding risk tolerability. In the field of occupational health and safety, this research has highlighted the importance and need for criteria to decide whether a risk is great enough to warrant attention in setting standards and priorities for risk control and resources. From a wider perspective and with the recognition that risk is an inherent part of life, the establishment of tolerability risk levels can be viewed as cornerstones indicating our progress, expectations and values, of life and work, in an increasingly litigious, knowledgeable and global society.

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.

Whole life performance bid evaluation in the Korean public sector

Korea has increasingly adopted design-build for public construction projects in the last few years. There is a much greater awareness of the need to change a system based on ‘Value for Money’ which is high on the government's agenda. A whole life performance bid evaluation model is proposed to aid decision makers in the selection of a design-builder. This is based on the integration of a framework using an analytic hierarchy process as the bid awarding system is being changed from one based on lowest price, to one based on best value over the life-cycle. Key criteria like whole life cost, service life planning and design quality are important through the key stages of evaluation process. The model uses a systematic and holistic approach which enables a public sector to make better decisions in design-builder selection, which will deliver whole life benefits, based on long term cost-effectiveness and whole life.

Evaluation of options for energy recovery from municipal solid waste in India using the hierarchical analytical network process

In this paper a Hierarchical Analytical Network Process (HANP) model is demonstrated for evaluating alternative technologies for generating electricity from MSW in India. The technological alternatives and evaluation criteria for the HANP study are characterised by reviewing the literature and consulting experts in the field of waste management. Technologies reviewed in the context of India include landfill, anaerobic digestion, incineration, pelletisation and gasification. To investigate the sensitivity of the result, we examine variations in expert opinions and carry out an Analytical Hierarchy Process (AHP) analysis for comparison. We find that anaerobic digestion is the preferred technology for generating electricity from MSW in India. Gasification is indicated as the preferred technology in an AHP model due to the exclusion of criteria dependencies and in an HANP analysis when placing a high priority on net output and retention time. We conclude that HANP successfully provides a structured framework for recommending which technologies to pursue in India, and the adoption of such tools is critical at a time when key investments in infrastructure are being made. Therefore the presented methodology is thought to have a wider potential for investors, policy makers, researchers and plant developers in India and elsewhere. © 2013 Elsevier Ltd. All rights reserved.

A framework for performance evaluation of employment offices:a case of Tunisia

This paper proposes a new framework for evaluating the performance of employment offices based on non-parametric technique of data envelopment analysis. This framework is explained using the assessment of technical efficiency of 82 employment offices in Tunisia which are under the direction of the National Agency for Employment and Independent Work. We further investigated the exogenous factors that may explain part of the variation in efficiency scores using a bootstrapping approach in period January 2006 to December 2008. Given the specialisation of employment offices, we used the proposed approach for the efficiency evaluation of graduate employment offices and multi-services employment offices, separately.

Merging and ranking answers in the semantic web:the wisdom of crowds

In this paper we propose algorithms for combining and ranking answers from distributed heterogeneous data sources in the context of a multi-ontology Question Answering task. Our proposal includes a merging algorithm that aggregates, combines and filters ontology-based search results and three different ranking algorithms that sort the final answers according to different criteria such as popularity, confidence and semantic interpretation of results. An experimental evaluation on a large scale corpus indicates improvements in the quality of the search results with respect to a scenario where the merging and ranking algorithms were not applied. These collective methods for merging and ranking allow to answer questions that are distributed across ontologies, while at the same time, they can filter irrelevant answers, fuse similar answers together, and elicit the most accurate answer(s) to a question.

Evaluation of hemifield sector analysis protocol in multifocal visual evoked potential (MFVEP) objective perimetry for the diagnosis and early detection of glaucomatous field defects

Visual field assessment is a core component of glaucoma diagnosis and monitoring, and the Standard Automated Perimetry (SAP) test is considered up until this moment, the gold standard of visual field assessment. Although SAP is a subjective assessment and has many pitfalls, it is being constantly used in the diagnosis of visual field loss in glaucoma. Multifocal visual evoked potential (mfVEP) is a newly introduced method used for visual field assessment objectively. Several analysis protocols have been tested to identify early visual field losses in glaucoma patients using the mfVEP technique, some were successful in detection of field defects, which were comparable to the standard SAP visual field assessment, and others were not very informative and needed more adjustment and research work. In this study, we implemented a novel analysis approach and evaluated its validity and whether it could be used effectively for early detection of visual field defects in glaucoma. OBJECTIVES: The purpose of this study is to examine the effectiveness of a new analysis method in the Multi-Focal Visual Evoked Potential (mfVEP) when it is used for the objective assessment of the visual field in glaucoma patients, compared to the gold standard technique. METHODS: 3 groups were tested in this study; normal controls (38 eyes), glaucoma patients (36 eyes) and glaucoma suspect patients (38 eyes). All subjects had a two standard Humphrey visual field HFA test 24-2 and a single mfVEP test undertaken in one session. Analysis of the mfVEP results was done using the new analysis protocol; the Hemifield Sector Analysis HSA protocol. Analysis of the HFA was done using the standard grading system. RESULTS: Analysis of mfVEP results showed that there was a statistically significant difference between the 3 groups in the mean signal to noise ratio SNR (ANOVA p<0.001 with a 95% CI). The difference between superior and inferior hemispheres in all subjects were all statistically significant in the glaucoma patient group 11/11 sectors (t-test p<0.001), partially significant 5/11 (t-test p<0.01) and no statistical difference between most sectors in normal group (only 1/11 was significant) (t-test p<0.9). sensitivity and specificity of the HAS protocol in detecting glaucoma was 97% and 86% respectively, while for glaucoma suspect were 89% and 79%. DISCUSSION: The results showed that the new analysis protocol was able to confirm already existing field defects detected by standard HFA, was able to differentiate between the 3 study groups with a clear distinction between normal and patients with suspected glaucoma; however the distinction between normal and glaucoma patients was especially clear and significant. CONCLUSION: The new HSA protocol used in the mfVEP testing can be used to detect glaucomatous visual field defects in both glaucoma and glaucoma suspect patient. Using this protocol can provide information about focal visual field differences across the horizontal midline, which can be utilized to differentiate between glaucoma and normal subjects. Sensitivity and specificity of the mfVEP test showed very promising results and correlated with other anatomical changes in glaucoma field loss.

Accounting for derivatives:an evaluation of reporting practice by UK banks

In 1998 the Accounting Standards Board (ASB) published FRS 13, ‘Derivatives and other Financial Instruments: Disclosures’. This laid down the requirements for disclosures of an entity’s policies, objectives and strategies in using financial instruments, their impact on its risk, performance and financial condition, and details of how risks are managed. FRS 13 became effective in March 1999, and this paper uses the 1999 annual reports of UK banks to evaluate the usefulness of disclosures from a user’s perspective. Usefulness is measured in terms of the criteria of materiality, relevance, reliability, comparability and understandability as defined in the ASB’s Statement of Principles (ASB, 1999). Our findings suggest that the narrative disclosures are generic in nature, the numerical data incomplete and not always comparable, and that it is difficult for the user to combine both narrative and numerical information in order to assess the banks’ risk profile. Our overall conclusion is therefore that current UK financial reporting practices are of limited help to users wishing to assess the scale of an institution’s financial risk exposure.

A new three phase method (SDP method) for the multi-objective vehicle routing problem with simultaneous delvery and pickup (VRPSDP)

Transportation service operators are witnessing a growing demand for bi-directional movement of goods. Given this, the following thesis considers an extension to the vehicle routing problem (VRP) known as the delivery and pickup transportation problem (DPP), where delivery and pickup demands may occupy the same route. The problem is formulated here as the vehicle routing problem with simultaneous delivery and pickup (VRPSDP), which requires the concurrent service of the demands at the customer location. This formulation provides the greatest opportunity for cost savings for both the service provider and recipient. The aims of this research are to propose a new theoretical design to solve the multi-objective VRPSDP, provide software support for the suggested design and validate the method through a set of experiments. A new real-life based multi-objective VRPSDP is studied here, which requires the minimisation of the often conflicting objectives: operated vehicle fleet size, total routing distance and the maximum variation between route distances (workload variation). The former two objectives are commonly encountered in the domain and the latter is introduced here because it is essential for real-life routing problems. The VRPSDP is defined as a hard combinatorial optimisation problem, therefore an approximation method, Simultaneous Delivery and Pickup method (SDPmethod) is proposed to solve it. The SDPmethod consists of three phases. The first phase constructs a set of diverse partial solutions, where one is expected to form part of the near-optimal solution. The second phase determines assignment possibilities for each sub-problem. The third phase solves the sub-problems using a parallel genetic algorithm. The suggested genetic algorithm is improved by the introduction of a set of tools: genetic operator switching mechanism via diversity thresholds, accuracy analysis tool and a new fitness evaluation mechanism. This three phase method is proposed to address the shortcoming that exists in the domain, where an initial solution is built only then to be completely dismantled and redesigned in the optimisation phase. In addition, a new routing heuristic, RouteAlg, is proposed to solve the VRPSDP sub-problem, the travelling salesman problem with simultaneous delivery and pickup (TSPSDP). The experimental studies are conducted using the well known benchmark Salhi and Nagy (1999) test problems, where the SDPmethod and RouteAlg solutions are compared with the prominent works in the VRPSDP domain. The SDPmethod has demonstrated to be an effective method for solving the multi-objective VRPSDP and the RouteAlg for the TSPSDP.

Evaluation of vulnerability factors for cyclones : the case of Patuakhali, Bangladesh

Tropical cyclones are considered as the most severe natural disasters in Bangladesh; they cause extensive damage, create losses in the country׳s economy, and affect social settings. The impact of natural disasters has been further intensified due to various vulnerability factors within the Bangladeshi community such as low income; shortages of food; lack of assets such as land and permanent housing; dense population, illiteracy. This study evaluates the vulnerability factors for cyclones in the community based in the Patuakhali region of south western Bangladesh. The bottom-up research approach was adopted for the study, whereby the local community was consulted for their viewpoints by using focus group interviews and semi-structured interviews. Different community groups and social categories including both men and women, from different age groups and livelihoods, participated in the study. The study revealed how the community׳s vulnerability to cyclones has been further aggravated by socio-economic factors such as social status, political influences and economic conditions. The majority of the community in Patuakhali has been “knowingly” vulnerable to cyclone disaster as a result of the lack of alternatives especially in terms of their livelihood patterns. The vulnerability of women, due to their lack of authority, domestic work, and fear of exposure within the society was also highlighted. The study revealed how vulnerability factors are interlinked with each other making them further difficult to manage. This calls for multi-faceted disaster risk reduction strategies that targets vulnerability factors deriving from different origins and root causes.

Evaluation of vulnerability factors for cyclones:the case of Patuakhali, Bangladesh

Tropical cyclones are considered as the most severe natural disasters in Bangladesh; they cause extensive damage, create losses in the country[U+05F3]s economy, and affect social settings. The impact of natural disasters has been further intensified due to various vulnerability factors within the Bangladeshi community such as low income; shortages of food; lack of assets such as land and permanent housing; dense population, illiteracy. This study evaluates the vulnerability factors for cyclones in the community based in the Patuakhali region of south western Bangladesh. The bottom-up research approach was adopted for the study, whereby the local community was consulted for their viewpoints by using focus group interviews and semi-structured interviews. Different community groups and social categories including both men and women, from different age groups and livelihoods, participated in the study. The study revealed how the community[U+05F3]s vulnerability to cyclones has been further aggravated by socio-economic factors such as social status, political influences and economic conditions. The majority of the community in Patuakhali has been "knowingly" vulnerable to cyclone disaster as a result of the lack of alternatives especially in terms of their livelihood patterns. The vulnerability of women, due to their lack of authority, domestic work, and fear of exposure within the society was also highlighted. The study revealed how vulnerability factors are interlinked with each other making them further difficult to manage. This calls for multi-faceted disaster risk reduction strategies that targets vulnerability factors deriving from different origins and root causes. © 2014 Elsevier Ltd.

Multicriteria Evaluation and Optimization of Hierarchical Systems

It is shown that any multicriteria problem can be represented by a hierarchical system. Separate properties of the object are evaluated at the lower level of the system, using a criteria vector, and a composition mechanism is used to evaluate the object as a whole at the upper level. The paper proposes a method to solve complex multicriteria problems of evaluation and optimization. It is based on nested scalar convolutions of vector- valued criteria and allows simple structural and parametrical synthesis of multicriteria hierarchical systems.

Complex skills and academic writing:a review of evidence about the types of learning required to meet core assessment criteria

Assessment criteria are increasingly incorporated into teaching, making it important to clarify the pedagogic status of the qualities to which they refer. We reviewed theory and evidence about the extent to which four core criteria for student writing-critical thinking, use of language, structuring, and argument-refer to the outcomes of three types of learning: generic skills learning, a deep approach to learning, and complex learning. The analysis showed that all four of the core criteria describe to some extent properties of text resulting from using skills, but none qualify fully as descriptions of the outcomes of applying generic skills. Most also describe certain aspects of the outcomes of taking a deep approach to learning. Critical thinking and argument correspond most closely to the outcomes of complex learning. At lower levels of performance, use of language and structuring describe the outcomes of applying transferable skills. At higher levels of performance, they describe the outcomes of taking a deep approach to learning. We propose that the type of learning required to meet the core criteria is most usefully and accurately conceptualized as the learning of complex skills, and that this provides a conceptual framework for maximizing the benefits of using assessment criteria as part of teaching. © 2006 Taylor & Francis.