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The possibility of combining different functionalities in a single device is of great relevance for further development of organic electronics in integrated components and circuitry. Organic light-emitting transistors (OLETs) have been demonstrated to be able to combine in a single device the electrical switching functionality of a field-effect transistor and the capability of light generation. A novel strategy in OLET realization is the tri-layer vertical hetero-junction. This configuration is similar to the bi-layer except for the presence of a new middle layer between the two transport layers. This “recombination” layer presents high emission quantum efficiency and OLED-like (Organic Light-Emitting Diode) vertical bulk mobility value. The key idea of the vertical tri-layer hetero-junction approach in realizing OLETs is that each layer has to be optimized according to its specific function (charge transport, energy transfer, radiative exciton recombination). Clearly, matching the overall device characteristics with the functional properties of the single materials composing the active region of the OFET, is a great challenge that requires a deep investigation of the morphological, optical and electrical features of the system. As in the case of the bi-layer based OLETs, it is clear that the interfaces between the dielectric and the bottom transport layer and between the recombination and the top transport layer are crucial for guaranteeing good ambipolar field-effect electrical characteristics. Moreover interfaces between the bottom transport and the recombination layer and between the recombination and the top transport layer should provide the favourable conditions for the charge percolation to happen in the recombination layer and form excitons. Organic light emitting transistor based on the tri-layer approach with external quantum efficiency out-performing the OLED state of the art has been recently demonstrated [Capelli et al., Nat. Mater. 9 (2010) 496-503] widening the scientific and technological interest in this field of research.

Many studies on the morphology, molecular orientation, device performance, substrate nature and growth parameter dependence have been carried out since the proposal of Sexithiophene (6T) for organic electronics [ ] However, these studies were mostly performed on films thicker than 20nm and without specifically addressing the relationship between morphology and molecular orientation within the nano and micro structures of ultrathin films of 0-3 monolayers. In 2004, the observation that in OFETs only the first few monolayers at the interface in contact with the gate insulator contribute to the charge transport [ ], underlined the importance to study submonolayer films and their evolution up to a few monolayers of thickness with appropriate experimental techniques. We present here a detailed Non-contact Atomic Force Microscopy and Scanning Tunneling Microscopy study on various substrates aiming at the investigation of growth mechanisms. Most reported similar studies are performed on ideal metals in UHV. However it is important to investigate the details of organic film growth on less ideal and even technological surfaces and device testpatterns. The present work addresses the growth of ultra thin organic films in-situ and quasi real-time by NC-AFM. An organic effusion cell is installed to evaporate the organic material directly onto the SPM sample scanning stage.

During the last decade advances in the field of sensor design and improved base materials have pushed the radiation hardness of the current silicon detector technology to impressive performance. It should allow operation of the tracking systems of the Large Hadron Collider (LHC) experiments at nominal luminosity (1034 cm-2s-1) for about 10 years. The current silicon detectors are unable to cope with such an environment. Silicon carbide (SiC), which has recently been recognized as potentially radiation hard, is now studied. In this work it was analyzed the effect of high energy neutron irradiation on 4H-SiC particle detectors. Schottky and junction particle detectors were irradiated with 1 MeV neutrons up to fluence of 1016 cm-2. It is well known that the degradation of the detectors with irradiation, independently of the structure used for their realization, is caused by lattice defects, like creation of point-like defect, dopant deactivation and dead layer formation and that a crucial aspect for the understanding of the defect kinetics at a microscopic level is the correct identification of the crystal defects in terms of their electrical activity. In order to clarify the defect kinetic it were carried out a thermal transient spectroscopy (DLTS and PICTS) analysis of different samples irradiated at increasing fluences. The defect evolution was correlated with the transport properties of the irradiated detector, always comparing with the un-irradiated one. The charge collection efficiency degradation of Schottky detectors induced by neutron irradiation was related to the increasing concentration of defects as function of the neutron fluence.

The assessment of medicines has moved from efficacy and safety to that of a benefit-risk balance and regulatory agencies and pharmaceutical companies are improving their processes in order to achieve greater consistency and transparency in decision-making. However, their efforts are largely independent and do not address the lack of consistency in decisions by different countries, albeit for the same medicine, resulting in the potential inaccessibility of important medicines. The aim of this study was the development and validation of a universal benefit-risk framework for use by regulatory authorities. A questionnaire, specifically developed for this study, was used to evaluate the current approaches to benefit-risk assessment of medicines by 14 regulatory agencies and 24 pharmaceutical companies. None of the 11 agencies (79%) and 20 companies (83%) that responded used a fully quantitative approach, but the majority used a qualitative system for benefit-risk assessment. The development of a universal benefit-risk framework for use by both regulators and industry, with the involvement of all stakeholders, was supported by the study participants. A comparison of the existing benefit-risk assessment frameworks used by agencies and companies identified the common elements. As no major differences were observed, an 8-step universal framework was developed which incorporated the other frameworks. To support the framework in the assessment of benefits and risks, a template for documenting the benefit-risk decision together with a user manual was also developed. Four regulatory agencies conducted a retrospective pilot study to investigate the feasibility of this framework, the benefit-risk template and user manual. Subsequently, a prospective study was conducted by TGA of Australia, Health Canada and HSA of Singapore. The agencies found the benefit-risk template was ‘fit for purpose’ in terms of the relevance of information supporting the benefit-risk decision, the documentation and communication and the relative importance and values of the benefits and risks. The results showed that the benefit-risk summary template was adequate to document benefits and risks, relevant summaries and ii conclusions for the emerging markets. The applicability and validity of the summary component of the benefit-risk template was evaluated by sixteen HSA clinical reviewers in a retrospective study. They found that the BR Summary Template was adequate to document benefits, risks, relevant summaries and conclusions. However, a revision of the BR Summary Template should include technical improvements and more details of safety information. The BR Summary Template was thought to be a useful tool for communicating benefit-risk decisions to a variety of stakeholders. The formats of publicly available reports from major regulatory agencies were compared and found to be generally similar. When compared to the BR Template, the listing of benefits and risks, assigning of weights and values, visualisation and a more detailed, systematic standardised structure were found to be absent. This research has demonstrated that the 8-step universal framework is of value for the assessment of benefits and risks of medicines by regulatory agencies and the template was found to be useful for documenting and communicating benefit-risk decisions.

Asthma is a chronic inflammatory disease of the airways characterised by early and late asthmatic responses (EAR & LAR) to allergen, airways hyperresponsiveness (AHR) to inhaled spasmogens, airway inflammation and airway oedema. Viral infections and lipopolysaccharide (LPS) from bacteria and environmental sources contribute to exacerbations of asthma and the development of insensitivity to corticosteroids. Complete insensitivity to oral corticosteroids is rare and most patients lie on a continuum of steroid responsiveness. This thesis aimed to examine the effect of viral infection and LPS in a guinea-pig model of asthma and determine the sensitivity to inhaled and systemic corticosteroids. Sensitised guinea-pigs challenged with ovalbumin displayed EAR, LAR, AHR to histamine, airways inflammation and airway oedema. Inoculation of guinea-pigs with parainfluenza-3 virus alone induced AHR to histamine and airway inflammation. However this response was not consistent. Inhaled LPS alone induced an immediate bronchoconstriction, AHR, airway inflammation and oedema and goblet cell hyperplasia. LPS co-administered with ovalbumin exacerbated the allergen response by lengthening the EAR, prolonging the bronchoconstrictor response to histamine, increasing airway inflammation and oedema and goblet cell hyperplasia. In guinea-pigs challenged with ovalbumin alone, treatment with inhaled fluticasone propionate (FP) and inhaled and systemic dexamethasone decreased the LAR, abolished AHR, airway inflammation and oedema. Responses to LPS alone were not reduced by inhaled dexamethasone or FP but partially reduced by systemic dexamethasone. Ovalbumin and LPS combined responses were insensitive to inhaled corticosteroids, except lavage fluid protein. These responses were partially sensitive to systemic dexamethasone, with the prolonged EAR, inflammation and airway oedema all reduced. The data in this thesis suggests that LPS inhalation exacerbates ovalbumin-induced functional and inflammatory responses rendering them insensitive to inhaled corticosteroids but partially sensitive to systemic corticosteroids. Thus, the experimental combination of ovalbumin with LPS might represent a useful preclinical model of corticosteroid-insensitive airway inflammation.

The action of thyroid hormone (TH) on cell growth, differentiation and survival during development may be of therapeutic relevance. The present study investigated the potential effects of long-term TH treatment on cardiomyocytes and on glioma tumour cell lines. This study employed neonatal cardiomyocytes, 1321N1 cell line, an astrocytoma grade II, and U87MG, a glioblastoma grade IV. Cells were exposed for 2 and 4 days in culture medium deprived of T3 (non-treated cells) and in a medium containing either 1 nM T3 (at near physiological range) or 500 nM T3 (supraphysiological). From the initial study on cardiomyocytes, the results show that phenylephryne (PE) can induce cell growth and this effect was mediated by T3. For the glioma cell lines the results show that T3 at 1 nM can promote cell re-differentiation in both cell lines. However, T3 had a preferential effect on suppressing cell proliferation only in the high grade glioma cell line. Thus, in 1321N1 cell line, T3 increased cell proliferation (2 days) which declined thereafter (4 days) without having any effect on cell survival. In U87MG cell line, T3 resulted in marked suppression of cell proliferation without increasing cell injury. At the molecular level, a 2.9 fold increase in the expression of TRα1 receptor was observed in U87MG cells as compared to 1321N1, p<0.05. TRβ1 receptor was undetectable in both cell lines. These changes corresponded to a distinct pattern of growth signalling activation induced by T3 treatment. The results also show that T3 had no significant effect on ERK activation in both cell lines, but significantly (p<0.05) increased phospho-Akt levels in 1321N1 cell line. At higher dose, T3 also induced cell differentiation in both cell lines and suppressed proliferation while increased cell injury in U87MG cells. It can be concluded from these results that T3 can re-differentiate glioma tumour cells. However, the effect of T3 on cell proliferation appears to be dependent on the type of tumour cell line with aggressive tumours to be more sensitive to thyroid hormone treatment. TRα1 receptor may, at least in part, be implicated in this response.

The contribution of over-the-counter (OTC) medicines sales data from pharmacies for public health (PH) has previously attracted interest in the UK. In this study, data for several OTC medicines were utilised to explore their contribution to (a) understand the impact of medicine reclassification or increased regulation on supply and (b) the surveillance of infectious diseases in the community in Wales. Following the reclassification of ophthalmic chloramphenicol (June 2005) an increase in primary care supply (OTC + prescription) of 54% (47,026 units) in eye drops and 29% (15,657 units) in eye ointment were observed (2004 to 2010). Despite this increase the items of eye drops prescribed were similar 12 months before and five years after the reclassification. The impact of regulatory changes concerning the non-prescription sale of opioid-containing analgesics was studied. In the 12 months following September 2009 legislative changes there was a significant fall in sales of codeine- and dihydrocodeinecontaining solid oral dosage forms (p<0.05). Similarly, following the pack size restriction of non-prescription pseudoephedrine and ephedrine products (April 2008), significant (p<0.05) year-on-year reductions in the total weight of pseudoephedrine sold were observed. Sales of non-prescription ophthalmic chloramphenicol were monitored on a small area basis in two areas with known outbreaks of infective conjunctivitis. In both areas sales data did not demonstrate the required sensitivity. When monitoring seasonal influenza, significant positive correlations were observed between cough/cold/flu medicines sales and indicators of influenza activity in Wales. In alignment with the professional standards for PH practice for pharmacy produced by the Royal Pharmaceutical Society, the work undertaken demonstrated a number of potential uses of medicines sales data for PH. Routine data collection, particularly if captured at time/point of sale, would further enhance its usefulness in detecting and tracking PH incidents.

Decision-making per se can be regarded as part art and part science in the development of new medicines. In the area of pharmaceutical development, decision-making plays a pivotal role in the continuation or the termination of further development or withdrawal of medicinal products. The decisions made at each stage have a direct impact on all stakeholders namely, pharmaceutical companies, regulators, payers and patients. What is lacking at present is a qualified understanding of the subjective decision-making approach, influences, behaviours and other factors which impact the decision-making of individuals and organisations involved in the delivery of new medicines. The aim of this study was, therefore, to develop and validate a generic instrument for appraising the quality of decision-making. Semi-structured interviews were carried out with 29 key decision-makers from the pharmaceutical industry, regulatory authorities and contract research organisations (CROs). They were invited to discuss all aspects, including their perception of decision-making and its role in drug development and regulatory review; decision making within their organisation; awareness and use of decision-making techniques; and impact and monitoring of decisions. Thematic analysis was carried out using NViVO 8 © software. A preliminary 94-item instrument was developed from the themes and the sub-themes that emerged from the interviews. Content validity was assessed using qualitative and quantitative data from an expert panel involving six key decision makers. A separate international cohort of 120 individuals working in the pharmaceutical industry, regulatory authority or CROs was recruited for factor analysis to reduce items. A further 78 individuals completed the final version of the QoDOS for construct validity and reliability. Most individuals interviewed were male (55% - n=16) and their level of experience ranged from 7 to 35 years. 32 themes and 90 sub-themes of aspects of decision-making were identified from the interviews. The median numbers of themes reported by experts was 6 (range = 1-10). The key themes included: quality and validity of the data; vii political, financial, competitor and reward influences; analytical and logical approach; overconfidence in own judgement; plunging in or procrastinating with decision-making; impact analysis of decisions; education and awareness of evolving decision-making techniques; and SWOT and alternate outcome planning. Relationships between the themes were identified. A 94-item generic instrument for assessing the quality of life decision-making, Quality of Decision-Making Orientation Scheme (QoDOS) ©, with a 5-point Likert response scale was developed. The content validity panel’s rating of each item on a 4-point scale for the 4 attributes showed “strongly agreed” or “agreed” (88%) with an ICC value of .89 (CI = 0.56 – 0.99) suggesting a high agreement between the panel members’ responses. This led to the reduction of 20 items and addition of two items as a result of cross-referencing with the qualitative data. Thus, the 76 items (version 2) emerged from content validation. Factor analysis produced a 47-item measure with four factors. The QoDOS showed high internal consistency (n = 120, Cronbach’s alpha = 0.89), high reproducibility (n = 20, ICC = 0.77) and a mean completion time of 10 minutes. 10 hallmarks of “Good Decision-Making Practice” (GDMP) were identified. The QoDOS is a valuable addition to the decision-making tool box of drug developers and regulators and has the potential to fill the missing gap of the entire process which is building quality into the lifecycle of medicine. The identification of ten hallmarks and generation of a framework for GDMP are also important contributions of this study to the field.

This thesis describes the efforts made to provide protein flexibility in a molecular modelling software application, which prior to this work, was operating using rigid proteins and semi flexible ligands. Protein flexibility during molecular modelling simulations is a non-­‐trivial task requiring a great number of floating point operations and it could not be accomplished without the help of supercomputing such as GPGPUs (or possibly Xeon Phi). The thesis is structured as follows. It provides a background section, where the reader can find the necessary context and references in order to be able to understand this report. Next is a state of the art section, which describes what had been done in the fields of molecular dynamics and flexible haptic protein ligand docking prior to this work. An implementation section follows, which lists failed efforts that provided the necessary feedback in order to design efficient algorithms to accomplish this task. Chapter 6 describes in detail an irregular – grid decomposition approach in order to provide fast non-­‐bonded interaction computations for GPGPUs. This technique is also associated with algorithms that provide fast bonded interaction computations and exclusions handling for 1-­‐4 bonded atoms during the non-­‐bonded forces computation part. Performance benchmarks as well as accuracy tables for energy and force computations are provided to demonstrate the efficiency of the methodologies explained in this chapter. Chapter 7 provides an overview of an evolutionary strategy used to overcome the problems associated with the limited capabilities of local search strategies such as steepest descents, which get trapped in the first local minima they find. Our proposed method is able to explore the potential energy landscape in such a way that it can pick competitive uphill solutions to escape local minima in the hope of finding deeper valleys. This methodology is also serving the purpose of providing a good number of conformational updates such that it is able to restore the areas of interaction between the protein and the ligand while searching for optimum global solutions.