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A probabilistic approach to assess the stability of flood embankments : the case study of the Adige river embankment
Get PDFThis thesis was previously held under moratorium from 13 June 2019 until 13 June 2024.Flood embankments are a key asset in flood defence systems; assessing their
probability of failure is therefore important for the evaluation of flood hazard. Flood
embankments, however, can reach lengths of thousands of kilometres. Probability of
failure assessments are complex and expensive, which limits their applicability on
such a large scale. This challenge highlights the need to develop both a simple
probabilistic approach that does not require excessive time or computational effort,
and an affordable method for the deterministic hydro-mechanical characterisation of
flood embankments that can easily be extended to long segments.
This thesis addresses these challenges by first focusing on the development of an
accessible probabilistic method that accounts for uncertainties in the soil properties
and hydrological loading. This approach benefits from the simple First Order Second
Moment method while addressing its main limitation, namely the assumed
probability distribution of the Factor of Safety. The approach is successfully
validated against its ability to capture the annual probability of failure of a segment
of the Adige River embankment that experienced instability of the landside slope.
The hydro-mechanical model of the embankment is characterised via site
investigation and laboratory tests. In particular, the hydraulic model is characterised
via inverse analysis of water flow in the saturated and unsaturated zones based on
field monitoring data. However, this approach may be difficult to extend to long
segments of the embankment, given the challenge to monitor water flow on a large
scale. In order to address this issue, the use of Electrical Resistivity Tomography
(ERT) for monitoring of water flow is investigated. Results show that ERT can be a
valuable tool to quantify water content if a field-specific relationship between water
content and ERT-measured resistivity is calibrated.
4
The case study of the Adige River embankment is further analysed to investigate the
factors governing the water flow and stability of the embankment. Comparison of the
water flow regime between two sections, located within and outside the failure
segment, highlights the critical role played by the hydraulic response of the material
on the landside outside the footprint of the embankment. This key finding can
support the decision-making process when planning site investigation aimed to the
stability assessment of flood embankments.
These outcomes combine to provide a flexible approach for the probabilistic stability
analysis of flood embankments that can be easily adapted and applied to different
contexts with limited levels of investment of time and resource. This approach may
be developed into a suitable tool for the routine hazard assessment of the stability of
flood embankments.Flood embankments are a key asset in flood defence systems; assessing their
probability of failure is therefore important for the evaluation of flood hazard. Flood
embankments, however, can reach lengths of thousands of kilometres. Probability of
failure assessments are complex and expensive, which limits their applicability on
such a large scale. This challenge highlights the need to develop both a simple
probabilistic approach that does not require excessive time or computational effort,
and an affordable method for the deterministic hydro-mechanical characterisation of
flood embankments that can easily be extended to long segments.
This thesis addresses these challenges by first focusing on the development of an
accessible probabilistic method that accounts for uncertainties in the soil properties
and hydrological loading. This approach benefits from the simple First Order Second
Moment method while addressing its main limitation, namely the assumed
probability distribution of the Factor of Safety. The approach is successfully
validated against its ability to capture the annual probability of failure of a segment
of the Adige River embankment that experienced instability of the landside slope.
The hydro-mechanical model of the embankment is characterised via site
investigation and laboratory tests. In particular, the hydraulic model is characterised
via inverse analysis of water flow in the saturated and unsaturated zones based on
field monitoring data. However, this approach may be difficult to extend to long
segments of the embankment, given the challenge to monitor water flow on a large
scale. In order to address this issue, the use of Electrical Resistivity Tomography
(ERT) for monitoring of water flow is investigated. Results show that ERT can be a
valuable tool to quantify water content if a field-specific relationship between water
content and ERT-measured resistivity is calibrated.
4
The case study of the Adige River embankment is further analysed to investigate the
factors governing the water flow and stability of the embankment. Comparison of the
water flow regime between two sections, located within and outside the failure
segment, highlights the critical role played by the hydraulic response of the material
on the landside outside the footprint of the embankment. This key finding can
support the decision-making process when planning site investigation aimed to the
stability assessment of flood embankments.
These outcomes combine to provide a flexible approach for the probabilistic stability
analysis of flood embankments that can be easily adapted and applied to different
contexts with limited levels of investment of time and resource. This approach may
be developed into a suitable tool for the routine hazard assessment of the stability of
flood embankments
Design and evaluation of ophthalmic formulations in an unlicensed medicines manufacturing unit
Get PDFPreviously held under moratorium from 3rd October 2018 until 3rd October 2022.Bespoke unlicensed medicines manufactured as ‘specials’ often have qualityattributes that are minimally qualified with little formal assessment of thebenefits and risks associated with their clinical use. Mitomycin C is acytotoxic antibiotic used as an unlicensed ophthalmic medicine in ocularsurgery and the treatment of ocular malignancies. Amphotericin B is anantimycotic agent used in ophthalmology to treat eye fungal infections. Bothcompounds have limited aqueous stability which restricts its clinical usage.For this reason, the development of innovative ophthalmic formulations withsuperior stability was pursued.As part of the design, drug stability of the formulations was determinedusing a validated HPLC method with samples tested periodically. Also,characterisation of the pharmaceutical products was carried out as part of theevaluation.The novel mitomycin C formulation represents a substantial improvement inshelf life of at least 16 months at 4°C compared to 6 weeks shelf life of theexisting clinical formulation. A toxicological evaluation of the novelmitomycin C eye drops showed that this formulation had a comparableprofile to the aqueous mitomycin C solution.On the other hand amphotericin B products were also developed as eyedrops, in situ and ready to use gel formulation. The instability and thepossible drug-excipient interaction of the in-situ gel formulation make thisoption unfit for purpose. In terms of the other 2 products, either the eyedrops or the ready to use gel stored at 4°C have superior stability than theformulation currently manufactured at the Pharmacy Production Unit withinNHS in GG&C. Although the characterization of the eye drops showed betterresults and the manufacturing process is easier, the ophthalmic gelformulation could imply a better acceptance by patients.These findings will reduce manufacturing costs and extend patient accessimproving the treatment of ocular pathologies. In vivo research to evaluatethe ocular bioavailability of the novel ophthalmic formulations would bedesirable.Bespoke unlicensed medicines manufactured as ‘specials’ often have qualityattributes that are minimally qualified with little formal assessment of thebenefits and risks associated with their clinical use. Mitomycin C is acytotoxic antibiotic used as an unlicensed ophthalmic medicine in ocularsurgery and the treatment of ocular malignancies. Amphotericin B is anantimycotic agent used in ophthalmology to treat eye fungal infections. Bothcompounds have limited aqueous stability which restricts its clinical usage.For this reason, the development of innovative ophthalmic formulations withsuperior stability was pursued.As part of the design, drug stability of the formulations was determinedusing a validated HPLC method with samples tested periodically. Also,characterisation of the pharmaceutical products was carried out as part of theevaluation.The novel mitomycin C formulation represents a substantial improvement inshelf life of at least 16 months at 4°C compared to 6 weeks shelf life of theexisting clinical formulation. A toxicological evaluation of the novelmitomycin C eye drops showed that this formulation had a comparableprofile to the aqueous mitomycin C solution.On the other hand amphotericin B products were also developed as eyedrops, in situ and ready to use gel formulation. The instability and thepossible drug-excipient interaction of the in-situ gel formulation make thisoption unfit for purpose. In terms of the other 2 products, either the eyedrops or the ready to use gel stored at 4°C have superior stability than theformulation currently manufactured at the Pharmacy Production Unit withinNHS in GG&C. Although the characterization of the eye drops showed betterresults and the manufacturing process is easier, the ophthalmic gelformulation could imply a better acceptance by patients.These findings will reduce manufacturing costs and extend patient accessimproving the treatment of ocular pathologies. In vivo research to evaluatethe ocular bioavailability of the novel ophthalmic formulations would bedesirable
Evaluating the effectiveness of carbapenem and piperacillin-tazobactam prescribing guidelines and implementation strategies on multi-drug resistant gram-negative bacteria within NHS Scotland
Get PDFBackground: Antimicrobial resistance is one of the most challenging aspects of healthcare worldwide. In 2013 the Scottish Antimicrobial Prescribing Group (SAPG) produced guidance to promote better use of carbapenems and piperacillin-tazobactam as a measure to reduce emergence of Multi-Drug Resistant Gram Negative Bacteria (MDRGNB). The effectiveness of implementation of this national guidance and its impact on the utilisation of these agents in local clinical practice was unknown.;Objectives: To evaluate how SAPG guidance against MDRGNB had been adopted and implemented across NHS Scotland health boards, assess how this translated into clinical practice, and investigate clinicians' views and behaviours about prescribing carbapenems and alternative agents.;Methods: The current research was divided into three parts; online survey, national point prevalence surveillance, and semi-structured interviews. Part one: Local implementation of SAPG MDRGNB guidance was assessed from local AMT committee's responses using an online survey. Part two: A bespoke national point prevalence survey was used to evaluate prescribing of meropenem and piperacillin-tazobactam in clinical practice. Part three: Clinicians' experience of using carbapenems and alternatives was examined through semi-structured interviews within four health boards.;Results: Part one: all 15 health boards responded to the survey. There were greater local restrictions for carbapenems than for piperacillin-tazobactam. Meropenem was the most common used carbapenem. Laboratory result suppression was inconsistent between health boards and carbapenem-sparing antimicrobials were not widely available. Part two: 13 health boards were included and a total of 12,478 inpatients in 38 hospitals were surveyed. Adherence to local guidelines was good for meropenem but lower for piperacillin-tazobactam. Indication for use was well documented but review/stop dates were poorly documented for both antimicrobials.;Part three: 28 interviews were conducted. Decisions to prescribe a carbapenem were influenced by local guidelines and specialist team's advice. Many clinicians lacked confidence to de-escalate treatment. Use of both antimicrobials decreased during the course of the programme.;Conclusions: A multifaceted quality improvement programme was used to gather intelligence, promote behaviour change, and focus interventions on the use of carbapenems and piperacillin-tazobactam. Use of these antimicrobials decreased during the programme, a trend not seen elsewhere in Europe. The programme identified variation in practice and guidance adaptation between health boards, and different approaches had been adopted to encounter MDRGNB. The importance of local guidelines and support of specialised teams were highly influential and much appreciated between participants. The programme could be generalised to other antimicrobials in future.Background: Antimicrobial resistance is one of the most challenging aspects of healthcare worldwide. In 2013 the Scottish Antimicrobial Prescribing Group (SAPG) produced guidance to promote better use of carbapenems and piperacillin-tazobactam as a measure to reduce emergence of Multi-Drug Resistant Gram Negative Bacteria (MDRGNB). The effectiveness of implementation of this national guidance and its impact on the utilisation of these agents in local clinical practice was unknown.;Objectives: To evaluate how SAPG guidance against MDRGNB had been adopted and implemented across NHS Scotland health boards, assess how this translated into clinical practice, and investigate clinicians' views and behaviours about prescribing carbapenems and alternative agents.;Methods: The current research was divided into three parts; online survey, national point prevalence surveillance, and semi-structured interviews. Part one: Local implementation of SAPG MDRGNB guidance was assessed from local AMT committee's responses using an online survey. Part two: A bespoke national point prevalence survey was used to evaluate prescribing of meropenem and piperacillin-tazobactam in clinical practice. Part three: Clinicians' experience of using carbapenems and alternatives was examined through semi-structured interviews within four health boards.;Results: Part one: all 15 health boards responded to the survey. There were greater local restrictions for carbapenems than for piperacillin-tazobactam. Meropenem was the most common used carbapenem. Laboratory result suppression was inconsistent between health boards and carbapenem-sparing antimicrobials were not widely available. Part two: 13 health boards were included and a total of 12,478 inpatients in 38 hospitals were surveyed. Adherence to local guidelines was good for meropenem but lower for piperacillin-tazobactam. Indication for use was well documented but review/stop dates were poorly documented for both antimicrobials.;Part three: 28 interviews were conducted. Decisions to prescribe a carbapenem were influenced by local guidelines and specialist team's advice. Many clinicians lacked confidence to de-escalate treatment. Use of both antimicrobials decreased during the course of the programme.;Conclusions: A multifaceted quality improvement programme was used to gather intelligence, promote behaviour change, and focus interventions on the use of carbapenems and piperacillin-tazobactam. Use of these antimicrobials decreased during the programme, a trend not seen elsewhere in Europe. The programme identified variation in practice and guidance adaptation between health boards, and different approaches had been adopted to encounter MDRGNB. The importance of local guidelines and support of specialised teams were highly influential and much appreciated between participants. The programme could be generalised to other antimicrobials in future
Synthesis and biological evaluation of selective inhibitory kappa B kinase-alpha (IKKa) inhibitors for the treatment of prostate and pancreatic cancer
No full textA framework for developing a prognostic model using partial discharge data from electrical trees
Get PDFInsulation breakdown is a key failure mode of high voltage (HV) equipment, with progressive faults such as electrical treeing leading to potentially catastrophic failure. Electrical treeing proceeds from defects in solid insulation, and cables are particularly affected. Research has shown that diagnosis of the fault can be achieved based on partial discharge (PD) analysis. Nonetheless, after diagnosis of a defect, engineers need to know how long they have to take action. This requires prognosis of remaining insulation life. The progression of a defect is far less well understood than diagnosis, making prognosis a key challenge requiring new approaches to defect modelling. The practical deployment of prognostics for cable monitoring is not currently feasible, due to the lack of understanding of degradation mechanisms and limited data relating defect inception to plant failure. However, this thesis advances the academic state of the art, with an eye towards practical deployment in the future. The expected beneficiaries of this work are therefore researchers in the field of HV condition monitoring in general, and electrical treeing within cables in particular. This research work develops a prognostic model of insulation failure due to the electrical treeing phenomenon by utilising the associated PD data from previous experiment. Both phase-resolved and pulse sequence approaches were employed for PD features extraction. The performance of the PD features as prognostic parameters were evaluated using three metrics, monotonicity, prognosability and trendability. The analysis revealed that features from pulse sequence approach are better than phase-resolved approach in terms of monotonicity and prognosability. The key contributions to knowledge of this work are three-fold: the selection of the most appropriate prognostic parameter for PD in electrical trees, through thorough analysis of the behaviour of a number of candidate parameters; a prognostic modelling approach for this parameter based on curve-fitting; and a generalised framework for prognostic modelling using data-driven techniques.Insulation breakdown is a key failure mode of high voltage (HV) equipment, with progressive faults such as electrical treeing leading to potentially catastrophic failure. Electrical treeing proceeds from defects in solid insulation, and cables are particularly affected. Research has shown that diagnosis of the fault can be achieved based on partial discharge (PD) analysis. Nonetheless, after diagnosis of a defect, engineers need to know how long they have to take action. This requires prognosis of remaining insulation life. The progression of a defect is far less well understood than diagnosis, making prognosis a key challenge requiring new approaches to defect modelling. The practical deployment of prognostics for cable monitoring is not currently feasible, due to the lack of understanding of degradation mechanisms and limited data relating defect inception to plant failure. However, this thesis advances the academic state of the art, with an eye towards practical deployment in the future. The expected beneficiaries of this work are therefore researchers in the field of HV condition monitoring in general, and electrical treeing within cables in particular. This research work develops a prognostic model of insulation failure due to the electrical treeing phenomenon by utilising the associated PD data from previous experiment. Both phase-resolved and pulse sequence approaches were employed for PD features extraction. The performance of the PD features as prognostic parameters were evaluated using three metrics, monotonicity, prognosability and trendability. The analysis revealed that features from pulse sequence approach are better than phase-resolved approach in terms of monotonicity and prognosability. The key contributions to knowledge of this work are three-fold: the selection of the most appropriate prognostic parameter for PD in electrical trees, through thorough analysis of the behaviour of a number of candidate parameters; a prognostic modelling approach for this parameter based on curve-fitting; and a generalised framework for prognostic modelling using data-driven techniques
The application of SOA for dispersion management of 2D-WH/TS codesin incoherent OCDMA system
Get PDFIn high data rate optical fibre communication networks, dispersion phenomenon plays a pivotal role. It is important to investigate the dispersion effects in a multi-wavelength picosecond optical code division multiple access (OCDMA) system. This research is focused on the analysis of the effects of fibre dispersion on the OCDMA autocorrelation; and how these effects can be resolved in a tuneable way so that the originally recovered OCDMA autocorrelation function at the decoder receiver can be revived without further manual adjustment of fibre (SMF-28) cable lengths.;The environmental effects and the subsequent mitigation process are also investigated further in this research. The chirp in OCDMA is examined experimentally and analytically in an initiative to find the more in-depth understanding of finely tuneable chromatic dispersion (CD) compensation technique in a coarsely compensated link by using semiconductor optical amplifier (SOA). A practical investigation was carried over a partially CD compensated 17 km bidirectional testbed between the University of Strathclyde and the University of Glasgow to perform the fine-tuning of CD adjustment using SOA.;A 19.5 km SMF-28 fibre spool was also used in an environmental chamber to investigate the temperature induced dispersion effects and subsequent mitigation. The tuneable dispersion compensation measures are vital to ensure the high data rate optical communication using an all-optical approach in future data network end-points where the advantages of ultra-high speed optical communication bandwidth are at present disrupted due to opto-electronic conversions commonly known as 'electronic bottlenecks'.In high data rate optical fibre communication networks, dispersion phenomenon plays a pivotal role. It is important to investigate the dispersion effects in a multi-wavelength picosecond optical code division multiple access (OCDMA) system. This research is focused on the analysis of the effects of fibre dispersion on the OCDMA autocorrelation; and how these effects can be resolved in a tuneable way so that the originally recovered OCDMA autocorrelation function at the decoder receiver can be revived without further manual adjustment of fibre (SMF-28) cable lengths.;The environmental effects and the subsequent mitigation process are also investigated further in this research. The chirp in OCDMA is examined experimentally and analytically in an initiative to find the more in-depth understanding of finely tuneable chromatic dispersion (CD) compensation technique in a coarsely compensated link by using semiconductor optical amplifier (SOA). A practical investigation was carried over a partially CD compensated 17 km bidirectional testbed between the University of Strathclyde and the University of Glasgow to perform the fine-tuning of CD adjustment using SOA.;A 19.5 km SMF-28 fibre spool was also used in an environmental chamber to investigate the temperature induced dispersion effects and subsequent mitigation. The tuneable dispersion compensation measures are vital to ensure the high data rate optical communication using an all-optical approach in future data network end-points where the advantages of ultra-high speed optical communication bandwidth are at present disrupted due to opto-electronic conversions commonly known as 'electronic bottlenecks'
Alkali metal alumiate chemistry : advances in hydroelementation catalysis
Get PDFApplying main group compounds, especially aluminium hydride complexes, as catalysts for hydroelementation reactions is gaining momentum. This project develops the application of heterobimetallic lithium aluminates to the catalytic regime. Five lithium aluminates of general formula (HMDS)₂Al(H)₂Li(donor)x, 1 - 6, were prepared and characterised by X-ray crystallography and multinuclear NMR spectroscopy. Subsequently, 1 - 6 were applied as catalysts for hydroboration of aldehydes and ketones. An alkali metal effect was observed upon changing the donor at lithium, indicating that lithium plays a role in catalysis. A catalytic cycle is proposed whereby the carbonyl substrate is initially hydroaluminated; then the boronic ester product forms, with regeneration of the lithium aluminium hydride complex. A postulated intermediate, (HMDS)₂Al(μ-OCH₂Ph)₂Li(THF)₂, 8, was isolated and characterised. A comparative study between charged bimetallic lithium aluminate complexes and neutral monometallic aluminium counterparts was undertaken. Lithium aluminates were generally observed to exhibit superior catalytic reactivity for hydroboration of aldehydes,ketones, imines and alkynes. A novel catalyst initiation pathway was uncovered for precatalyst iBu₂Al(TMP) via β-hydride transfer from iso-butyl ligands, generating the characterised aluminium benzyloxide complex, [(TMP){Ph₂(H)CO}Al{μ-OC(H)Ph₂}]₂, 15.The reactivity of aluminium compounds towards boranes was examined, to try to uncover potential aluminium catalyst decomposition pathways. Novel structures were crystallographically characterised resulting from cleavage of a B - O bond in pinacolborane resulting in a new aluminium complex. Less active catalytically than the parent aluminium complex, this represents a possible catalyst decomposition product.Finally, the concept of lithium aluminate hydroelementation catalysis was extended to hydrophosphination, representing the first reported example of aluminium catalysed hydrophosphination of alkynes, alkenes and carbodiimides. The active catalyst, lithiumaluminium phosphide, iBu₃AlPPh₂Li(THF)₃, 22, was successfully isolated. Analysis of the reaction mechanism by kinetic studies shows that this reaction is inhibited by excessphosphine. Moreover, postulated intermediates were identified via stoichiometric reactions,and their reactivity probed, further supporting the mechanism proposed.Applying main group compounds, especially aluminium hydride complexes, as catalysts for hydroelementation reactions is gaining momentum. This project develops the application of heterobimetallic lithium aluminates to the catalytic regime. Five lithium aluminates of general formula (HMDS)₂Al(H)₂Li(donor)x, 1 - 6, were prepared and characterised by X-ray crystallography and multinuclear NMR spectroscopy. Subsequently, 1 - 6 were applied as catalysts for hydroboration of aldehydes and ketones. An alkali metal effect was observed upon changing the donor at lithium, indicating that lithium plays a role in catalysis. A catalytic cycle is proposed whereby the carbonyl substrate is initially hydroaluminated; then the boronic ester product forms, with regeneration of the lithium aluminium hydride complex. A postulated intermediate, (HMDS)₂Al(μ-OCH₂Ph)₂Li(THF)₂, 8, was isolated and characterised. A comparative study between charged bimetallic lithium aluminate complexes and neutral monometallic aluminium counterparts was undertaken. Lithium aluminates were generally observed to exhibit superior catalytic reactivity for hydroboration of aldehydes,ketones, imines and alkynes. A novel catalyst initiation pathway was uncovered for precatalyst iBu₂Al(TMP) via β-hydride transfer from iso-butyl ligands, generating the characterised aluminium benzyloxide complex, [(TMP){Ph₂(H)CO}Al{μ-OC(H)Ph₂}]₂, 15.The reactivity of aluminium compounds towards boranes was examined, to try to uncover potential aluminium catalyst decomposition pathways. Novel structures were crystallographically characterised resulting from cleavage of a B - O bond in pinacolborane resulting in a new aluminium complex. Less active catalytically than the parent aluminium complex, this represents a possible catalyst decomposition product.Finally, the concept of lithium aluminate hydroelementation catalysis was extended to hydrophosphination, representing the first reported example of aluminium catalysed hydrophosphination of alkynes, alkenes and carbodiimides. The active catalyst, lithiumaluminium phosphide, iBu₃AlPPh₂Li(THF)₃, 22, was successfully isolated. Analysis of the reaction mechanism by kinetic studies shows that this reaction is inhibited by excessphosphine. Moreover, postulated intermediates were identified via stoichiometric reactions,and their reactivity probed, further supporting the mechanism proposed
Digital Forensics CS414 exam papers
No full textNo papers available.PAST EXAM PAPERS ARE NO LONGER BEING ADDED TO STAX. PLEASE VISIT SUPRIMO TO ACCESS AN UP-TO-DATE COLLECTION OF PAST EXAM PAPERS: https://suprimo.lib.strath.ac.uk
Nudging contracting firms rivals within municipal road projects in Saudi Arabia to bid competitively
Get PDFSeveral preventive measures have been proposed to tackle bid-rigging practices in public procurement, which are based on reducing opportunities for such illicit arrangements. Maximising the number of market players is one of the most prevalent measures suggested in previous studies. However, there has been little empirical examination of strategies to ensure this increase, particularly in the Saudi Arabian public procurement context. Accordingly, this research aims to develop an institutional framework which will be adopted by relevant stakeholders to reduce risk of bid-rigging by targeting an increase in the number of potential bidders.;Accordingly, the research consisted of two main stage, each of them with two data collection steps. The exploratory stage began by investigating the nature of local contractors' engagement in bidding. More than 500 sets of minutes were studied, recording the opening of sealed bids in five major municipalities over a five-year period. Based on a proposed framework developed according to four market screening tools (market concentration, members number, participation rate, and prices volatility), the scarcity of contractors' participation in these tenders was demonstrated, especially the contractors in lower classifications. It was found that a few contractors suspiciously monopolised these contracts.;Integratively, the key factors that local contractors believed were contributing to their failure to engage in this market were identified through a desk study, which included reviewing literature concerning the rationale for contractors' participation in the same context and reviewing barriers to delivering public construction projects in Saudi Arabia associated with the tendering phase. Consequently, the attributes which might encourage decision-makers in contracting firms to bid were proposed, and were subsequently examined in the second stage.;The second stage adopted a sequential explanatory mixed method approach. First, a 5-point Likert questionnaires were distributed to local contractors in order to examine the influence of each attribute on their desire to participate in bidding. The majority of contractors agreed on the potential influence of these attributes on future participation, although there were slight differences in influence assessment by contractors according to their classification or success in previous bids. The three most influenced attributes were: accurate and detailed terms and technical specifications, technical advice to tackle bidders' problems in electronic bidding, publishing the contractors' classification criteria and their weighting scores.;Then, standardised open-ended interviews were conducted with both contractors and relevant government authorities, to assess current performance level of these attributes. The customer satisfaction was employed when interviewing contractors, while the self-assessment was the base of the government authorities' interviews. A different level of performance of the relevant stakeholders in these attributes has recorded, which supported prioritising the proposed institutional framework.;Therefore, an Importance-Performance Analysis grid, with a zero gap diagonal line, was adopted. Interestingly, most of these attributes have a performance gap, and consequently, need the concentration of the relevant stakeholders' efforts. This research provides a useful reference for other public construction authorities in similar contexts to adopt requisite managerial actions achieving the same aim, yet further investigation on rivals' assessments of importance and performance are needed to reprioritize those actions.Several preventive measures have been proposed to tackle bid-rigging practices in public procurement, which are based on reducing opportunities for such illicit arrangements. Maximising the number of market players is one of the most prevalent measures suggested in previous studies. However, there has been little empirical examination of strategies to ensure this increase, particularly in the Saudi Arabian public procurement context. Accordingly, this research aims to develop an institutional framework which will be adopted by relevant stakeholders to reduce risk of bid-rigging by targeting an increase in the number of potential bidders.;Accordingly, the research consisted of two main stage, each of them with two data collection steps. The exploratory stage began by investigating the nature of local contractors' engagement in bidding. More than 500 sets of minutes were studied, recording the opening of sealed bids in five major municipalities over a five-year period. Based on a proposed framework developed according to four market screening tools (market concentration, members number, participation rate, and prices volatility), the scarcity of contractors' participation in these tenders was demonstrated, especially the contractors in lower classifications. It was found that a few contractors suspiciously monopolised these contracts.;Integratively, the key factors that local contractors believed were contributing to their failure to engage in this market were identified through a desk study, which included reviewing literature concerning the rationale for contractors' participation in the same context and reviewing barriers to delivering public construction projects in Saudi Arabia associated with the tendering phase. Consequently, the attributes which might encourage decision-makers in contracting firms to bid were proposed, and were subsequently examined in the second stage.;The second stage adopted a sequential explanatory mixed method approach. First, a 5-point Likert questionnaires were distributed to local contractors in order to examine the influence of each attribute on their desire to participate in bidding. The majority of contractors agreed on the potential influence of these attributes on future participation, although there were slight differences in influence assessment by contractors according to their classification or success in previous bids. The three most influenced attributes were: accurate and detailed terms and technical specifications, technical advice to tackle bidders' problems in electronic bidding, publishing the contractors' classification criteria and their weighting scores.;Then, standardised open-ended interviews were conducted with both contractors and relevant government authorities, to assess current performance level of these attributes. The customer satisfaction was employed when interviewing contractors, while the self-assessment was the base of the government authorities' interviews. A different level of performance of the relevant stakeholders in these attributes has recorded, which supported prioritising the proposed institutional framework.;Therefore, an Importance-Performance Analysis grid, with a zero gap diagonal line, was adopted. Interestingly, most of these attributes have a performance gap, and consequently, need the concentration of the relevant stakeholders' efforts. This research provides a useful reference for other public construction authorities in similar contexts to adopt requisite managerial actions achieving the same aim, yet further investigation on rivals' assessments of importance and performance are needed to reprioritize those actions
In vitro and in silico profiling to assist pharmaceutical development
Get PDFDuring the pharmaceutical development process of a new drug it is necessary to fully elucidate the physico-chemical properties of the molecule in order to find the appropriate formulation. For drugs intended to be administered orally water-solubility is a an essential requirement. The development of high-throughput screening and combinatorial chemistry gave a rapid access to a lot of potential drug candidates but as a consequence led to new challenges. On one hand there is an increasing number of molecules with poor water solubility which can be addressed with adequate in vitro testing. On the other hand studies demonstrated that poor pharmacokinetic behaviour was responsible for the majority of drug candidate failures. Therefore the challenge is to be able to keep up with the rate of production to study the in vivo behaviour of so many drugs more rapidly and efficiently. The emergence of physiologically based pharmacokinetic modelling provides a potential solution by making use of the physico-chemical information along with the human physiology to simulate the clinical performance.;In this work an experimental approach is presented to study the in vitro solubility of poorly soluble drugs. A new biorelevant medium simulating the fasted and fed intestinal states was developed to examine the feasibility of merging the individual fasted and fed studies into one single experiment. The purpose was to forecast the parameters influencing solubility and anticipate the solubility behaviour such as potential significant food effects. Results showed that acidic drugs were greatly driven by pH and oleate while for neutral and basic drugs a combination of three factors (pH, bile salt and sodium oleate) and their interactions were dominant. Solubility testing in biorelevant media has been accepted as a reliable predictive tool of in vivo solubility. The prediction of better estimates of in vivo behaviour allowed BCS class II drugs to be reconsidered provided that an adequate formulation is designed. This is applied in the recent developability classification system (DCS). This classification incorporates an estimate of the fasted intestinal solubility along with the dose/solubility ratio of the drug and allows a better understanding of the factors limiting oral absorption. This classification adds a distinction between dissolution-rate limited drugs and solubility-limited drugs which provides a very useful tool for formulators in the early stage of development. This approach is presented in this work on a set of BCS class II drugs and the consequences on the drug formulation strategy is discussed.;The integration of computational techniques in drug development is getting more and more attention with the immense progress in computational power and the pressure to improve the efficiency and reduce the overall cost of the development process. In this work the use of computer models was employed in two aspects. First, the performance of two simulations software was compared in the ability to predict the solubility of poorly soluble drugs in a fasted or fed biorelevant medium. Secondly a physiologically based pharmacokinetic (PBPK) modelling method was utilised to simulate the pharmacokinetic profiles of the same drugs. Interestingly both models produced satisfactory results for the solubility prediction of acidic drug and in the fed state however the solubility prediction of the neutral drug and in the fasted state showed some limitations. This outcome highlighted the need for improvement of in silico models for solubility prediction in particularly with the development of more sophisticated models for the integration of the multiple components present in the human intestinal fluid. Nonetheless, the successful PBPK prediction of the plasma concentration profiles confirmed the interest of this approach to be a useful tool in the drug development process. In addition the results demonstrated that for two drugs variable input of solubility had a significant influence on the in vivo plasma concentrations. Finally a PBPK approach in a special population is presented in this work. It was used to model the pharmacokinetic behaviour of a cancer molecule in patients. The objective was to reproduce the phase I dose escalation study. Due to the sparse in vitro data and the poor solubility and permeability profile of the drug, the model development was very challenging and could not be fully validated. In fact the main obstacle of the model was the suboptimal formulation and the absorption of the drug in the intestinal tract. The performance of the software to successfully predict this drug could be challenged by another PBPK software for comparison. However given the physico-chemical properties of this drug its behaviour is very likely to be drug related. This case study emphasised the difficulty of developing poorly soluble drugs.During the pharmaceutical development process of a new drug it is necessary to fully elucidate the physico-chemical properties of the molecule in order to find the appropriate formulation. For drugs intended to be administered orally water-solubility is a an essential requirement. The development of high-throughput screening and combinatorial chemistry gave a rapid access to a lot of potential drug candidates but as a consequence led to new challenges. On one hand there is an increasing number of molecules with poor water solubility which can be addressed with adequate in vitro testing. On the other hand studies demonstrated that poor pharmacokinetic behaviour was responsible for the majority of drug candidate failures. Therefore the challenge is to be able to keep up with the rate of production to study the in vivo behaviour of so many drugs more rapidly and efficiently. The emergence of physiologically based pharmacokinetic modelling provides a potential solution by making use of the physico-chemical information along with the human physiology to simulate the clinical performance.;In this work an experimental approach is presented to study the in vitro solubility of poorly soluble drugs. A new biorelevant medium simulating the fasted and fed intestinal states was developed to examine the feasibility of merging the individual fasted and fed studies into one single experiment. The purpose was to forecast the parameters influencing solubility and anticipate the solubility behaviour such as potential significant food effects. Results showed that acidic drugs were greatly driven by pH and oleate while for neutral and basic drugs a combination of three factors (pH, bile salt and sodium oleate) and their interactions were dominant. Solubility testing in biorelevant media has been accepted as a reliable predictive tool of in vivo solubility. The prediction of better estimates of in vivo behaviour allowed BCS class II drugs to be reconsidered provided that an adequate formulation is designed. This is applied in the recent developability classification system (DCS). This classification incorporates an estimate of the fasted intestinal solubility along with the dose/solubility ratio of the drug and allows a better understanding of the factors limiting oral absorption. This classification adds a distinction between dissolution-rate limited drugs and solubility-limited drugs which provides a very useful tool for formulators in the early stage of development. This approach is presented in this work on a set of BCS class II drugs and the consequences on the drug formulation strategy is discussed.;The integration of computational techniques in drug development is getting more and more attention with the immense progress in computational power and the pressure to improve the efficiency and reduce the overall cost of the development process. In this work the use of computer models was employed in two aspects. First, the performance of two simulations software was compared in the ability to predict the solubility of poorly soluble drugs in a fasted or fed biorelevant medium. Secondly a physiologically based pharmacokinetic (PBPK) modelling method was utilised to simulate the pharmacokinetic profiles of the same drugs. Interestingly both models produced satisfactory results for the solubility prediction of acidic drug and in the fed state however the solubility prediction of the neutral drug and in the fasted state showed some limitations. This outcome highlighted the need for improvement of in silico models for solubility prediction in particularly with the development of more sophisticated models for the integration of the multiple components present in the human intestinal fluid. Nonetheless, the successful PBPK prediction of the plasma concentration profiles confirmed the interest of this approach to be a useful tool in the drug development process. In addition the results demonstrated that for two drugs variable input of solubility had a significant influence on the in vivo plasma concentrations. Finally a PBPK approach in a special population is presented in this work. It was used to model the pharmacokinetic behaviour of a cancer molecule in patients. The objective was to reproduce the phase I dose escalation study. Due to the sparse in vitro data and the poor solubility and permeability profile of the drug, the model development was very challenging and could not be fully validated. In fact the main obstacle of the model was the suboptimal formulation and the absorption of the drug in the intestinal tract. The performance of the software to successfully predict this drug could be challenged by another PBPK software for comparison. However given the physico-chemical properties of this drug its behaviour is very likely to be drug related. This case study emphasised the difficulty of developing poorly soluble drugs
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