Approaches and Strategy for Cancer Research and Surveillance Data: Integration, Information Pipeline, Data Models, and Informatics Opportunities

Thesis (Ph.D.)--University of Washington, 2016-04

Effects of nitrogen supply on xylem cytokinin delivery, transpiration and leaf expansion of pea genotypes differing in xylem-cytokinin concentration

The rms2 and rms4 pea ( Pisum sativum L.) branching mutants have higher and lower xylem-cytokinin concentration, respectively, relative to wild type (WT) plants. These genotypes were grown at two levels of nitrogen (N) supply for 18 - 20 d to determine whether or not xylem-cytokinin concentration (X-CK) or delivery altered the transpiration and leaf growth responses to N deprivation. Xylem sap was collected by pressurising de-topped root systems. As sap-flow rate increased, X-CK declined in WT and rms2, but did not change in rms4. When grown at 5.0 mM N, X-CKs of rms2 and rms4 were 36% higher and 6-fold lower, respectively, than WT at sap-flow rates equivalent to whole-plant transpiration. Photoperiod cytokinin (CK) delivery rates ( the product of transpiration and X-CK) decreased more than 6-fold in rms4. Growth of plants at 0.5 mM N had negligible (< 10%) effects on transpiration rates expressed on a leaf area basis in WT and rms4, but decreased transpiration rates of rms2. The low-N treatment decreased leaf expansion by 20 - 25% and expanding leaflet N concentration by 15%. These changes were similar in all genotypes. At sap-flow rates equivalent to whole-plant transpiration, the low N treatment decreased X-CK in rms2 but had no discernible effect in WT and rms4. Since the low N treatment decreased transpiration of all genotypes, photoperiod CK delivery rates also decreased in all genotypes. The similar leaf growth response of all genotypes to N deprivation despite differences in both absolute and relative X-CKs and deliveries suggests that shoot N status is more important in regulating leaf expansion than xylem-supplied cytokinins. The decreased X-CK and transpiration rate of rms2 following N deprivation suggests that changes in xylem-supplied CKs may modify water use.

Top teams and strategy in a UK university

This paper reports on the results of an in-depth study of how a top management team (TMT) puts strategy into practice in a UK university. A study of the top team in Warwick University was conducted to analyse how strategy was formulated and implemented. The results suggest that a combination of two broad theoretical lenses provide useful analytical insight. These are strategy as practice and strategy as process. The main elements of this university’s strategy result from an interplay of localized routines and patterns of action within an organizational context, which both produces and is a product of such actions. The TMT itself was found to be clearly identifiable and stable in composition. The team exhibited identifiable patterns of strategic thinking and acting. However, the role of organizational structure was also found to be a key influence on the actions and processes of the TMT with strong central control tendencies in the team being counterbalanced by devolved operational control to individual departments. The data also reveal inter-relationships between organizational structures and the TMT in four key areas: direction-setting, monitoring and control, the allocation of resources, and processes of interaction. The overall conclusion is that to understand how strategy is practised, analysis needs to focus on how patterns of action are associated with the characteristics of both the team and the wider organization. The nature and characteristics of these patterns can be related to how strategy is put into practice.

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Introduction: improving manufacturing performance through technology diffusion, implementation and management

The role of technology management in achieving improved manufacturing performance has been receiving increased attention as enterprises are becoming more exposed to competition from around the world. In the modern market for manufactured goods the demand is now for more product variety, better quality, shorter delivery and greater flexibility, while the financial and environmental cost of resources has become an urgent concern to manufacturing managers. This issue of the International Journal of Technology Management addresses the question of how the diffusion, implementation and management of technology can improve the performance of manufacturing industries. The authors come from a large number of different countries and their contributions cover a wide range of topics within this general theme. Some papers are conceptual, others report on research carried out in a range of different industries including steel production, iron founding, electronics, robotics, machinery, precision engineering, metal working and motor manufacture. In some cases they describe situations in specific countries. Several are based on presentations made at the UK Operations Management Association's Sixth International Conference held at Aston University at which the conference theme was 'Achieving Competitive Edge: Getting Ahead Through Technology and People'. The first two papers deal with questions of advanced manufacturing technology implementation and management. Firstly Beatty describes a three year longitudinal field study carried out in ten Canadian manufacturing companies using CADICAM and CIM systems. Her findings relate to speed of implementation, choice of system type, the role of individuals in implementation, organization and job design. This is followed by a paper by Bessant in which he argues that a more a strategic approach should be taken towards the management of technology in the 1990s and beyond. Also considered in this paper are the capabilities necessary in order to deploy advanced manufacturing technology as a strategic resource and the way such capabilities might be developed within the firm. These two papers, which deal largely with the implementation of hardware, are supplemented by Samson and Sohal's contribution in which they argue that a much wider perspective should be adopted based on a new approach to manufacturing strategy formulation. Technology transfer is the topic of the following two papers. Pohlen again takes the case of advanced manufacturing technology and reports on his research which considers the factors contributing to successful realisation of AMT transfer. The paper by Lee then provides a more detailed account of technology transfer in the foundry industry. Using a case study based on a firm which has implemented a number of transferred innovations a model is illustrated in which the 'performance gap' can be identified and closed. The diffusion of technology is addressed in the next two papers. In the first of these, by Lowe and Sim, the managerial technologies of 'Just in Time' and 'Manufacturing Resource Planning' (or MRP 11) are examined. A study is described from which a number of factors are found to influence the adoption process including, rate of diffusion and size. Dahlin then considers the case of a specific item of hardware technology, the industrial robot. Her paper reviews the history of robot diffusion since the early 1960s and then tries to predict how the industry will develop in the future. The following two papers deal with the future of manufacturing in a more general sense. The future implementation of advanced manufacturing technology is the subject explored by de Haan and Peters who describe the results of their Dutch Delphi forecasting study conducted among a panel of experts including scientists, consultants, users and suppliers of AMT. Busby and Fan then consider a type of organisational model, 'the extended manufacturing enterprise', which would represent a distinct alternative pure market-led and command structures by exploiting the shared knowledge of suppliers and customers. The three country-based papers consider some strategic issues relating manufacturing technology. In a paper based on investigations conducted in China He, Liff and Steward report their findings from strategy analyses carried out in the steel and watch industries with a view to assessing technology needs and organizational change requirements. This is followed by Tang and Nam's paper which examines the case of machinery industry in Korea and its emerging importance as a key sector in the Korean economy. In his paper which focuses on Venezuela, Ernst then considers the particular problem of how this country can address the problem of falling oil revenues. He sees manufacturing as being an important contributor to Venezuela's future economy and proposes a means whereby government and private enterprise can co-operate in development of the manufacturing sector. The last six papers all deal with specific topics relating to the management manufacturing. Firstly Youssef looks at the question of manufacturing flexibility, introducing and testing a conceptual model that relates computer based technologies flexibility. Dangerfield's paper which follows is based on research conducted in the steel industry. He considers the question of scale and proposes a modelling approach determining the plant configuration necessary to meet market demand. Engstrom presents the results of a detailed investigation into the need for reorganising material flow where group assembly of products has been adopted. Sherwood, Guerrier and Dale then report the findings of a study into the effectiveness of Quality Circle implementation. Stillwagon and Burns, consider how manufacturing competitiveness can be improved individual firms by describing how the application of 'human performance engineering' can be used to motivate individual performance as well as to integrate organizational goals. Finally Sohal, Lewis and Samson describe, using a case study example, how just-in-time control can be applied within the context of computer numerically controlled flexible machining lines. The papers in this issue of the International Journal of Technology Management cover a wide range of topics relating to the general question of improving manufacturing performance through the dissemination, implementation and management of technology. Although they differ markedly in content and approach, they have the collective aim addressing the concepts, principles and practices which provide a better understanding the technology of manufacturing and assist in achieving and maintaining a competitive edge.

Gene delivery using cationic liposomes

The development of cationic liposomes for gene delivery has been ongoing for almost 20 years; however, despite extensive efforts to develop a successful therapeutic agent, there has been limited progress towards generating an effective pharmaceutical product. Since the introduction of N-(1-[2,3-dioley-loxy]propyl)-N,N,N-trimethylammonium chloride, an immense number of different cationic lipids have been synthesised and used to formulate cationic liposome - DNA complexes. Structural modification of the cationic lipids and the addition of components within the delivery system that can facilitate the fusion, cellular uptake and targeting of liposome - DNA complexes have all been used in a bid to enhance their transfection efficiency. Unfortunately, the overall impact of these improvements is still nominal, with the vast majority of clinical trials (∼ 85%) continuing to rely on more potent viral delivery of DNA despite their associated toxicity issues. Key characteristics of the most effective cationic liposomes for the delivery of plasmid DNA (from a consensus of the literature) is identified here and the problems of converting these attributes into an effective pharmaceutical product are outlined. © 2006 Informa UK Ltd.

Increased potential of a cationic liposome-based delivery system:enhancing stability and sustained immunological activity in pre-clinical development

The combination of dimethyl dioctadecyl ammonium bromide (DDA) and the synthetic cord factor trehalose dibehenate (TDB) with Ag85B-ESAT-6 (H1 fusion protein) has been found to promote strong protective immune responses against Mycobacterium tuberculosis. The development of a vaccine formulation that is able to facilitate the requirements of sterility, stability and generation of a vaccine product with acceptable composition, shelf-life and safety profile may necessitate selected alterations in vaccine formulation. This study describes the implementation of a sterilisation protocol and the use of selected lyoprotective agents in order to fulfil these requirements. Concomitantly, close analysis of any alteration in physico-chemical characteristics and parameters of immunogenicity have been examined for this promising DDA liposome-based tuberculosis vaccine. The study addresses the extensive guidelines on parameters for non-clinical assessment, suitable for liposomal vaccines and other vaccine delivery systems issued by the World Health Organisation (WHO) and the European Medicines Agency (EMEA). Physical and chemical stability was observed following alteration in formulations to include novel cryoprotectants and radiation sterilisation. Immunogenicity was maintained following these alterations and even improved by modification with lysine as the cryoprotective agent for sterilised formulations. Taken together, these results outline the successful alteration to a liposomal vaccine, representing improved formulations by rational modification, whilst maintaining biological activity.

Strategy making process, its content and context in small professional football clubs

This thesis examines the phenomenon of strategy. Making as practised by small professional football clubs. The study was undertaken because football clubs were perceived to have problems with strategy-making and because it was believed that the specific circumstances of football clubs could be outside the range of views covered by conventional views of strategy-making. The characteristics of the club environment are its uncertainty and unpredictability, simultaneous competition and co--operation, strong regulations, and a not-for-profit orientation. Small clubs in particular face a constant struggle for financial viability and survival, due in part to split business and playing objectives. The study was designed to establish the extent and nature of the difficulties clubs experience with a view to preparing the way for creating practical guidance on ways to overcome them. Clearly, in order to survive in the long term, small professional football clubs require very effective strategic decisions. This study has addressed this issue by inquiring into the nature of strategy making for these organisations with the objective to establish the general direction in which the football clubs in question should be moving. As a result, the main research question to guide this investigation was determined as: Why do small professional football clubs have difficulties making strategies. The investigation was based on an analysis the concept of strategy and its elements, the strategic vision and objectives, the process by which strategic action comes about, the strategic action itself, and the context within which this action occurs. Data has been collected, analysed and interpreted in relation to each of these elements. Together with a wide variety of published material, 20 small football clubs have been sampled and personal interviews were conducted with board members of those clubs. The findings indicate that small football clubs do indeed experience considerable difficulties in making strategies, the reasons for which lie both in the characteristics of their competitive environment and their approaches to strategy-making. The competitive environment is characterised by a cartel-like structure with a high degree of regulation, high levels of uncertainty, little control over the core product or the production process, short-term business cycles and a close geographical link between a club with its local market. The management of clubs is characterised by the need to balance conflicting sporting and business objectives. Formal planning techniques are of little use in the small football club context as decision-making processes have a strong political character and the development of novel strategies is hindered by a strong conservative, industry paradigm and a lack of financial and managerial resources. It is concluded that there is no simple advice to be given to clubs, as they must re-examine the relationship between their playing and business objectives to create a unified and workable approach.

A comparative and longitudinal analysis of the evolving relationship between the environment and the strategy, structure and performance of selected organisations in the British carpet industry 1959-1986:a firms in sector perspective of organisational adaptation

Orthodox contingency theory links effective organisational performance to compatible relationships between the environment and organisation strategy and structure and assumes that organisations have the capacity to adapt as the environment changes. Recent contributions to the literature on organisation theory claim that the key to effective performance is effective adaptation which in turn requires the simultaneous reconciliation of efficiency and innovation which is afforded by an unique environment-organisation configuration. The literature on organisation theory recognises the continuing confusion caused by the fragmented and often conflicting results from cross-sectional studies. Although the case is made for longitudinal studies which comprehensively describe the evolving relationship between the environment and the organisation there is little to suggest how such studies should be executed in practice. Typically the choice is between the approaches of the historicised case study and statistical analysis of large populations which examine the relationship between environment and organisation strategy and/or structure and ignore the product-process relationship. This study combines the historicised case study and the multi-variable and ordinal scale approach of statistical analysis to construct an analytical framework which tracks and exposes the environment-organisation-performance relationship over time. The framework examines changes in the environment, strategy and structure and uniquely includes an assessment of the organisation's product-process relationship and its contribution to organisational efficiency and innovation. The analytical framework is applied to examine the evolving environment-organisation relationship of two organisations in the same industry over the same twenty-five year period to provide a sector perspective of organisational adaptation. The findings demonstrate the significance of the environment-organisation configuration to the scope and frequency of adaptation and suggest that the level of sector homogeneity may be linked to the level of product-process standardisation.

CNS delivery of antisense oligodeoxynucleotides using biodegradable microspheres

Antisense oligodeoxynucleotides can selectively inhibit gene expression provided they are delivered to their target site successfully for a sufficient duration. Biodegradable microspheres have previously been developed for the potential systemic delivery of antisense oligodeoxynucleotides and offer an excellent strategy for central administration of antisense oligodeoxynucleotides, providing a sustained-release delivery system. Biodegradable microspheres were formulated to entrap antisense oligodeoxynucleotides for stereotaxic implantation into site-specific regions of the rat brain.Release profiles of antisense oligodeoxynucleotides from biodegradable microspheres over 56 days that were triphasic were observed with high molecular weight polymers. Antisense oligodeoxynucleotides loaded into microspheres (1-10μm) had a five-fold increase in cellular association with glial and neuronal cells compared to the naked molecule, which was partially due to a greater cellular accumulation as observed by a slower efflux profile. In vivo distribution studies of antisense oligodeoxynucleotides demonstrated that the use of microspheres provided a sustained-release over more than 2 days compared to 12 hours of the naked molecule. Efficacy of antisense oligodeoxynucleotides was demonstrated during locomotor activity investigations, which significantly reduced cocaine-induced locomotor activity, where no efficacy was demonstrated with microspheres, possibly attributed to antisense loading and measurements being taken during a lag phase of antisense oligodeoxynucleotide release. Biodegradable microspheres can be delivered site-specifically into the brain and provide sustained-release of antisense oligodeoxynucleotides, offering the potential of in vivo efficacy in these reagents in the brain.

Development and formulation of wax-based transdermal drug delivery systems

Topical and transdermal formulations are promising platforms for the delivery of drugs. A unit dose topical or transdermal drug delivery system that optimises the solubility of drugs within the vehicle provides a novel dosage form for efficacious delivery that also offers a simple manufacture technique is desirable. This study used Witepsol® H15 wax as a abase for the delivery system. One aspect of this project involved determination of the solubility of ibuprofen, flurbiprofen and naproxen in the was using microscopy, Higuchi release kinetics, HyperDSC and mathematical modelling techniques. Correlations between the results obtained via these techniques were noted with additional merits such as provision of valuable information on drug release kinetics and possible interactions between the drug and excipients. A second aspect of this project involved the incorporation of additional excipients: Tween 20 (T), Carbopol®971 (C) and menthol (M) to the wax formulation. On in vitro permeation through porcine skin, the preferred formulations were: ibuprofen (5% w/w) within Witepsol®H15 + 1% w/w T; flurbiprofen (10% w/w) within Witepsol®H15 + 1% w/w T; naproxen (5% w/w) within Witepsol®H15 + 1% w/w T + 1% C and sodium diclofenac (10% w/w) within Witepsol®H15 + 1% w/w T + 1% w/w T + 1% w/w C + 5% w/w M. Unit dose transdermal tablets containing ibuprofen and diclofenac were produced with improved flux compared to marketed products; Voltarol Emugel® demonstrated flux of 1.68x10-3 cm/h compared to 123 x 10-3 cm/h for the optimised product as detailed above; Ibugel Forte® demonstrated a permeation coefficient value of 7.65 x 10-3 cm/h compared to 8.69 x 10-3 cm/h for the optimised product as described above.

Formulation and characterisation of an effective particulate delivery vehicle for the novel sub-unit vaccine antigen, Ag85B-ESAT-6

This research focused on the formation of particulate delivery systems for the sub-unit fusion protein, Ag85B-ESAT-6, a promising tuberculosis (TB) vaccine candidate. Initial work concentrated on formulating and characterising, both physico-chemically and immunologically, cationic liposomes based on the potent adjuvant dimethyl dioctadecyl ammonium (DDA). These studies demonstrated that addition of the immunomodulatory trehalose dibehenate (TDB) enhanced the physical stability of the system whilst also adding further adjuvanticity. Indeed, this formulation was effective in stimulating both a cell mediated and humoural immune response. In order to investigate an alternative to the DDA-TDB system, microspheres based on poly(DL-lactide-co-glycolide) (PLGA) incorporating the adjuvants DDA and TDB, either alone or in combination, were first optimised in terms of physico-chemical characteristics, followed by immunological analysis. The formulation incorporating PLGA and DDA emerged as the lead candidate, with promising protection data against TB. Subsequent optimisation of the lead microsphere formulation investigated the effect of several variables involved in the formulation process on physico-chemical and immunological characteristics of the particles produced. Further, freeze-drying studies were carried out with both sugar-based and amino acid-based cryoprotectants, in order to formulate a stable freexe-dried product. Finally, environmental scanning electron microscopy (ESEM) was investigated as a potential alternative to conventional SEM for the morphological investigation of microsphere formulations. Results revealed that the DDA-TDB liposome system proved to be the most immunologically efficient delivery vehicle studied, with high levels of antibody and cytokine production, particularly gamma-interferon (IFN-ϒ), considered the key cytokine marker for anti-mycobacterial immunity. Of the microsphere systems investigated, PLGA in combination with DDA showed the most promise, with an ability to initiate a broad spectrum of cytokine production, as well as antigen specific spleen cell proliferation comparable to that of the DDA-TDB formulation.

Oral delivery strategies for the controlled release of cimetidine

It is advantageous to develop controlled release dosage forms utilising site-specific delivery or gastric retention for those drugs with frequent or high dosing regimes. Cimetidine is a potent and selective H2 -reception antagonist used in the treatment of various gastrointestinal disorders and localisation in the upper gastrointestinal tract could significantly improve the drug absorption. Three strategies were undertaken to prepare controlled release systems for the delivery of cimetidine to the GI tract. Firstly, increasing the contact time of the dosage form with the mucus layer which coats the gastrointestinal tract, may lead to increased gastric residence times. Mucoadhesive microspheres, by forming a gel-like structure in contact with the mucus, should prolong the contact between the delivery system and the mucus layer, and should have the potential for releasing the drug in sustained and controlled manner. Gelatin microspheres were prepared, optimised and characterised for their physicochemical properties. Crosslinking concentration, particle size and cimetidine loading influenced drug release profiles. Particle size was influenced by surfactant concentration and stirring speed. Mucoadheisve polymers such as alginates, chitosans, carbopols and polycarbophil were incorporated into the microspheres using different strategies. The mucoadhesion of the microspheres was determined using in vitro surface adsorption and ex vivo rat intestine models. The surface-modification strategy resulted in highest levels of microsphere adhesion, with chitosan, carbopols and polycarbophil as the most successful candidates for improvement of adhesion, with over 70% of the microspheres retained ex vivo. Specific targeting agent UEA I lectin was conjugated to the surface of gelatin microspheres, which enhanced the adhesion of the microspheres. Alginate raft systems containing antacids have been used extensively in the treatment of gastro-oesophageal disease and protection of the oesophageal mucosa from acid reflux by forming a viscous raft layer on the surface of the stomach content, and could be an effective delivery system for controlled release of cimetidine.

Novel bioadhesive formulations for mucosal and parenteral delivery of vaccines

In this work we have established the efficient mucosal delivery of vaccines using absorption enhancers and chitosan. In addition, the use of chitosan was shown to enhance the action of other known adjuvants, such as CTB or Quil-A. Collectively, the results presented herein indicate that chitosan has excellent potential as a mucosal adjuvant. We have evaluated a number of absorption enhancers for their adjuvant activity in vivo. Polyornithine was shown to engender high scrum immune reasons to nasally delivered antigens, with higher molecular weight polyornithine facilitating the best results. We have demonstrated for the first time that vitamin E TPGS can act as mucosal adjuvant. Deoxycholic acid, cyclodextrins and acylcarnitines were also identified as effective mucosal adjuvants and showed enhanced immune responses to nasally delivered TT, DT and Yersinia pestis V and F1 antigens. Previously, none of these agents, common in their action as absorption enhancing agents, have been shown to have immunopotentiating activity for mucosal immunisation. We have successfully developed novel surface modified microspheres using chitosan as an emulsion stabiliser during the preparation of PLA microspheres. It was found that immune responses could be substantially increased, effectively exploiting the immunopenetrating characteristics of both chitosan and PLA microspheres in the same delivery vehicle. In the same study, comparison of intranasal and intramuscular routes of administration showed that with these formulations, the nasal route could be as effective as intramuscular delivery, highlighting the potential of mucosal administration for these particulate delivery systems. Chitosan was co-administered with polymer microspheres. It was demonstrated that this strategy facilitates markedly enhanced immune responses in both magnitude and duration following intramuscular administration. We conclude that this combination shows potential for single dose administration of vaccines. In another study, we have shown that the addition of chitosan to alum adsorbed TT was able to enhance immune responses. PLA micro/nanospheres were prepared and characterised with discreet particle size ranges. A smaller particle size was shown to facilitate higher scrum IgG responses following nasal administration. A lower antigen loading was additionally identified as being preferential for the induction of immune responses in combination with the smaller particle size. This may be due to the fact that the number of particles will be increased when antigen loading is low, which may in turn facilitate a more widespread uptake of particles. PLA lamellar particles were prepared and characterised. Adsorbed TT was evaluated for the potential to engender immune responses in vivo. These formulations were shown to generate effective immune responses following intramuscular administration. Positively charged polyethylcyanoacrylate and PLA nanoparticies were designed and characterised and their potential as delivery vehicles for DNA vaccines was investigated. Successful preparation of particles with narrow size distribution and positive surface charge (imparted by the inclusion of chitosan) was achieved. In the evaluation of antibody responses to DNA encoded antigen in the presence of alum administered intranasally, discrimination between the groups was only seen following intramuscular boosting with the corresponding protein. Our study showed that DNA vaccines in the presence of either alum or Quil-A may advantageously influence priming of the immune system by a mucosal route. The potential for the combination of adjuvants, Quil-A and chitosan, to enhance antibody responses to plasmid encoded antigen co-administered with the corresponding protein antigen was shown and this is worthy of further investigation. The findings here have identified novel adjuvants and approaches to vaccine delivery. In particular, chitosan or vitamin E TPGS are shown here to have considerable promise as non-toxic, safe mucosal adjuvants. In addition, biodegradable mucoadhesive delivery systems, surface modified with chitosan in a single step process, may have application for other uses such as drug and gene delivery.

The evaluation and development of the lead authority partnership scheme as a central intervention strategy for health and safety enforcement by local authorities

The research comprises a suite of studies that examines and develops the Lead Authority Partnership Scheme (LAPS) as a central intervention strategy for health and safety by local authority (LA) enforcers. Partnership working is a regulatory concept that in recent years has become more popular but there has been little research conducted to investigate, explore and evaluate its practical application. The study reviewed two contrasting approaches to partnership working between LAs and businesses, both of which were intended to secure improvements in the consistency of enforcement by the regulators and in the health and safety management systems of the participating businesses. The first was a well-established and highly prescriptive approach that required a substantial resource commitment on the part of the LA responsible for conducting a safety management review (SMR) of the business. As a result of his evaluation of the existing ‘full SMR’ scheme, the author developed a second, more flexible approach to partnership working. The research framework was based upon a primarily qualitative methodology intended to investigate and explore the impact of the new flexible arrangements for partnership working. The findings from this study of the flexible development of the scheme were compared and contrasted with those from studies of the established ‘full SMR’ scheme. A substantial degree of triangulation was applied in an attempt to strengthen validity and broaden applicability of the research findings. Key informant interviews, participant observation, document/archive reviews, questionnaires and surveys all their particular part to play in the overall study. The findings from this research revealed that LAPS failed to deliver consistency of LA enforcement across multiple-outlet businesses and the LA enforced business sectors. Improvement was however apparent in the safety management systems of the businesses participating in LAPS. Trust between LA inspector and safety professional was key to the success of the partnerships as was the commitment of these key individuals. Competition for precious LA resources, the priority afforded to food safety over health and safety, the perceived high resource demands of LAPS, and the structure and culture of LAs were identified as significant barriers to LA participation. Flexible approaches, whilst addressing the resource issues, introduced some fresh concerns relating to credibility and delivery. Over and above the stated aims of the scheme, LAs and businesses had their own reasons for participation, notably the personal development of individuals and kudos for the organisation. The research has explored the wider implications for partnership working with the overall conclusion it is most appropriately seen as a strategic level element within a broader structured intervention strategy.