Efficient Genotyping of KRAS Mutant Non-Small Cell Lung Cancer Using a Multiplexed Droplet Digital PCR Approach.

Droplet digital PCR (ddPCR) can be used to detect low frequency mutations in oncogene-driven lung cancer. The range of KRAS point mutations observed in NSCLC necessitates a multiplex approach to efficient mutation detection in circulating DNA. Here we report the design and optimisation of three discriminatory ddPCR multiplex assays investigating nine different KRAS mutations using PrimePCR™ ddPCR™ Mutation Assays and the Bio-Rad QX100 system. Together these mutations account for 95% of the nucleotide changes found in KRAS in human cancer. Multiplex reactions were optimised on genomic DNA extracted from KRAS mutant cell lines and tested on DNA extracted from fixed tumour tissue from a cohort of lung cancer patients without prior knowledge of the specific KRAS genotype. The multiplex ddPCR assays had a limit of detection of better than 1 mutant KRAS molecule in 2,000 wild-type KRAS molecules, which compared favourably with a limit of detection of 1 in 50 for next generation sequencing and 1 in 10 for Sanger sequencing. Multiplex ddPCR assays thus provide a highly efficient methodology to identify KRAS mutations in lung adenocarcinoma.

Heating the Early Universe : Numerical Methods and Their Analysis

During the epoch when the first collapsed structures formed (6<z<50) our Universe went through an extended period of changes. Some of the radiation from the first stars and accreting black holes in those structures escaped and changed the state of the Intergalactic Medium (IGM). The era of this global phase change in which the state of the IGM was transformed from cold and neutral to warm and ionized, is called the Epoch of Reionization.In this thesis we focus on numerical methods to calculate the effects of this escaping radiation. We start by considering the performance of the cosmological radiative transfer code C2-Ray. We find that although this code efficiently and accurately solves for the changes in the ionized fractions, it can yield inaccurate results for the temperature changes. We introduce two new elements to improve the code. The first element, an adaptive time step algorithm, quickly determines an optimal time step by only considering the computational cells relevant for this determination. The second element, asynchronous evolution, allows different cells to evolve with different time steps. An important constituent of methods to calculate the effects of ionizing radiation is the transport of photons through the computational domain or ``ray-tracing''. We devise a novel ray tracing method called PYRAMID which uses a new geometry - the pyramidal geometry. This geometry shares properties with both the standard Cartesian and spherical geometries. This makes it on the one hand easy to use in conjunction with a Cartesian grid and on the other hand ideally suited to trace radiation from a radially emitting source. A time-dependent photoionization calculation not only requires tracing the path of photons but also solving the coupled set of photoionization and thermal equations. Several different solvers for these equations are in use in cosmological radiative transfer codes. We conduct a detailed and quantitative comparison of four different standard solvers in which we evaluate how their accuracy depends on the choice of the time step. This comparison shows that their performance can be characterized by two simple parameters and that the C2-Ray generally performs best.

Understanding the impact of different cheese-making strategies on Mozzarella cheese properties

Le fromage Mozzarella entre dans la composition de plusieurs mets populaires d’Amérique du Nord. L’aptitude de ce fromage à être râpé et ses propriétés caractéristiques de cuisson en font un ingrédient idéal. Ces qualités sont attribuées principalement aux propriétés physiques particulières de ce fromage sous certaines conditions de cisaillement et de température. Le but de ce projet était d’évaluer l’impact de différentes stratégies couramment mises en oeuvre dans l’industrie fromagère sur la composition, la microstructure et les propriétés physiques du fromage. Diverses stratégies ont été étudiées : les conditions de filage du caillé lors du procédé de « pasta filata », l’addition de protéines sériques dénaturées, le contrôle de la minéralisation et le vieillissement du fromage. Les résultats ont démontré que le contrôle de l’intensité mécanique et thermique fournie lors du filage permettait respectivement de réduire les pertes de solides et d’améliorer la répartition de la phase aqueuse dans la matrice fromagère. L’aptitude au râpage du fromage peut être optimisée en combinant l’utilisation de plusieurs stratégies dont la réduction du calcium colloïdal, un temps de vieillissement adéquat et un râpage à basse température. Par ailleurs, des changements aux facteurs mentionnés précédemment sont apportés lors de l’ajout de protéines sériques dénaturées, ces dernières ayant un impact sur la composition et la structure du fromage. Des modèles prédictifs de l’aptitude au râpage ont été développés en sélectionnant uniquement les descripteurs de composition et de texture pertinents. La perception sensorielle du fromage cuit sur pizza et les propriétés physiques du fromage fondu ont été considérablement influencées par l’évolution physico-chimique du fromage au cours du vieillissement. L’utilisation d’une nouvelle approche pour la caractérisation des propriétés rhéologiques du fromage fondu sous fortes contraintes a permis d’établir de bonnes relations avec les descripteurs sensoriels de texture. Ce travail a permis de valider l’hypothèse que l’utilisation d’une ou plusieurs stratégies simples et accessibles pouvait être mise de l’avant afin d’optimiser les propriétés physiques du fromage Mozzarella. Cela contribue à une meilleure compréhension des facteurs pouvant être contrôlés afin de développer des fromages avec des attributs spécifiques, lorsqu’utilisés comme ingrédient.

Modélisation du comportement des bétons fibrés à ultra-hautes performances par la micromécanique : Effet de l'orientation des fibres à l'échelle de la structure

Cette thèse s’inscrit dans le contexte d’une optimisation industrielle et économique des éléments de structure en BFUP permettant d’en garantir la ductilité au niveau structural, tout en ajustant la quantité de fibres et en optimisant le mode de fabrication. Le modèle développé décrit explicitement la participation du renfort fibré en traction au niveau local, en enchaînant une phase de comportement écrouissante suivie d’une phase adoucissante. La loi de comportement est fonction de la densité, de l’orientation des fibres vis-à-vis des directions principales de traction, de leur élancement et d’autres paramètres matériaux usuels liés aux fibres, à la matrice cimentaire et à leur interaction. L’orientation des fibres est prise en compte à partir d’une loi de probabilité normale à une ou deux variables permettant de reproduire n’importe quelle orientation obtenue à partir d’un calcul représentatif de la mise en oeuvre du BFUP frais ou renseignée par analyse expérimentale sur prototype. Enfin, le modèle reproduit la fissuration des BFUP sur le principe des modèles de fissures diffuses et tournantes. La loi de comportement est intégrée au sein d’un logiciel de calcul de structure par éléments finis, permettant de l’utiliser comme un outil prédictif de la fiabilité et de la ductilité globale d’éléments en BFUP. Deux campagnes expérimentales ont été effectuées, une à l’Université Laval de Québec et l’autre à l’Ifsttar, Marne-la-Vallée. La première permet de valider la capacité du modèle reproduire le comportement global sous des sollicitations typiques de traction et de flexion dans des éléments structurels simples pour lesquels l’orientation préférentielle des fibres a été renseignée par tomographie. La seconde campagne expérimentale démontre les capacités du modèle dans une démarche d’optimisation, pour la fabrication de plaques nervurées relativement complexes et présentant un intérêt industriel potentiel pour lesquels différentes modalités de fabrication et des BFUP plus ou moins fibrés ont été envisagés. Le contrôle de la répartition et de l’orientation des fibres a été réalisé à partir d’essais mécaniques sur prélèvements. Les prévisions du modèle ont été confrontées au comportement structurel global et à la ductilité mis en évidence expérimentalement. Le modèle a ainsi pu être qualifié vis-à-vis des méthodes analytiques usuelles de l’ingénierie, en prenant en compte la variabilité statistique. Des pistes d’amélioration et de complément de développement ont été identifiées.

Development of a toolbox for the reduction of hordeins in barley malt beers

Gluten sensitive consumers and people suffering from coeliac disease account for up to 6% of the general population (Catassi et al., 2013). These consumers must avoid foods which contain gluten and related proteins found in wheat, rye or barley. Beer is produced from barley malt and therefore contains hordeins, (gluten like proteins). Beers labelled as gluten-free must contain below 10 mg/kg hordeins (10 mg/kg hordeins = 20 mg/kg gluten under current regulations) to be considered safe for gluten sensitive consumers. Currently there are a limited number of methods available for reducing beer hordeins, the studies outlined in this thesis provide a range of tools for the beverage industry to reduce the hordein content of beer It is well known, that during malting and brewing hordeins are reduced, but they still remain in beer at levels above 10 mg/kg. During malting, hordeins are broken down to form new proteins in the growing plant. Model malting and brewing systems were developed and used to test, how the modification of the malting process could be used to reduce beer hordeins. It was shown, that by using a controlled malting and brewing regime, a range of barley cultivars produced beer with significant differences in levels of hordeins. Beer hordeins ranged from 10 mg/kg to 60 mg/kg. Another study revealed that when malting was prolonged, to maximise breakdown of proteins, beer hordeins can be reduced by up to 44%. The natural breakdown of hordein during malting enhanced in a further study, when a protease was added to support the hordein degradation during steeping and germination. The enzyme addition resulted in a 46% reduction in beer hordeins 2 when compared to the control. All of the malt treatments had little or no impact on malt quality. The hordein levels can also be reduced during the beer stabilisation process. Levels of beer hordein were tested after stabilisation using two different concentrations of silica gel and tannic acid. Silica gel was very effective in reducing beer hordeins, 90% of beer hordeins were removed compared to the control beer. Beer hordeins could be reduced to below 10 mg/kg and the beer qualities such as foam, colour and flavour were not affected. Tannic acid also reduced beer hordein by up to 90%, but it reduced foam stability and affected beer flavours. A further study described treatment of beer with microbial transglutaminase (mTG), to create bonds between hordein proteins, which increased particle size and allowed removal during filtration. The addition of the mTG led to a reduction of the beer hordein by up to 96% in beer, and the impact on the resulting beer quality was minimal. These studies provide the industry with a toolbox of methods leading to the reduction of hordein in the final beer without negatively affecting beer quality.

Application of meta-analytical probabilistic approach for reliability benefits reflective optimal transmission costing – the case of India

In the deregulated Power markets it is necessary to have a appropriate Transmission Pricing methodology that also takes into account “Congestion and Reliability”, in order to ensure an economically viable, equitable, and congestion free power transfer capability, with high reliability and security. This thesis presents results of research conducted on the development of a Decision Making Framework (DMF) of concepts and data analytic and modelling methods for the Reliability benefits Reflective Optimal “cost evaluation for the calculation of Transmission Cost” for composite power systems, using probabilistic methods. The methodology within the DMF devised and reported in this thesis, utilises a full AC Newton-Raphson load flow and a Monte-Carlo approach to determine, Reliability Indices which are then used for the proposed Meta-Analytical Probabilistic Approach (MAPA) for the evaluation and calculation of the Reliability benefit Reflective Optimal Transmission Cost (ROTC), of a transmission system. This DMF includes methods for transmission line embedded cost allocation among transmission transactions, accounting for line capacity-use as well as congestion costing that can be used for pricing using application of Power Transfer Distribution Factor (PTDF) as well as Bialek’s method to determine a methodology which consists of a series of methods and procedures as explained in detail in the thesis for the proposed MAPA for ROTC. The MAPA utilises the Bus Data, Generator Data, Line Data, Reliability Data and Customer Damage Function (CDF) Data for the evaluation of Congestion, Transmission and Reliability costing studies using proposed application of PTDF and other established/proven methods which are then compared, analysed and selected according to the area/state requirements and then integrated to develop ROTC. Case studies involving standard 7-Bus, IEEE 30-Bus and 146-Bus Indian utility test systems are conducted and reported throughout in the relevant sections of the dissertation. There are close correlation between results obtained through proposed application of PTDF method with the Bialek’s and different MW-Mile methods. The novel contributions of this research work are: firstly the application of PTDF method developed for determination of Transmission and Congestion costing, which are further compared with other proved methods. The viability of developed method is explained in the methodology, discussion and conclusion chapters. Secondly the development of comprehensive DMF which helps the decision makers to analyse and decide the selection of a costing approaches according to their requirements. As in the DMF all the costing approaches have been integrated to achieve ROTC. Thirdly the composite methodology for calculating ROTC has been formed into suits of algorithms and MATLAB programs for each part of the DMF, which are further described in the methodology section. Finally the dissertation concludes with suggestions for Future work.

Développement et expérimentation d'algorithmes de réorientation pour un robot sériel en chute libre

Ce mémoire présente 2 types de méthodes pour effectuer la réorientation d’un robot sériel en chute libre en utilisant les mouvements internes de celui-ci. Ces mouvements sont prescrits à partir d’algorithmes de planification de trajectoire basés sur le modèle dynamique du robot. La première méthode tente de réorienter le robot en appliquant une technique d’optimisation locale fonctionnant avec une fonction potentielle décrivant l’orientation du système, et la deuxième méthode applique des fonctions sinusoïdales aux articulations pour réorienter le robot. Pour tester les performances des méthodes en simulation, on tente de réorienter le robot pour une configuration initiale et finale identiques où toutes les membrures sont alignées mais avec le robot ayant complété une rotation de 180 degrés sur lui-même. Afin de comparer les résultats obtenus avec la réalité, un prototype de robot sériel plan flottant possédant trois membrures et deux liaisons rotoïdes est construit. Les expérimentations effectuées montrent que le prototype est capable d’atteindre les réorientations prescrites si peu de perturbations extérieures sont présentes et ce, même si le contrôle de l’orientation est effectué en boucle ouverte.

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Effect of soil structure on temporal and spatial dynamics of bacteria

Soil is a complex heterogeneous system comprising of highly variable and dynamic micro-habitats that have significant impacts on the growth and activity of resident microbiota. A question addressed in this research is how soil structure affects the temporal dynamics and spatial distribution of bacteria. Using repacked microcosms, the effect of bulk-density, aggregate sizes and water content on growth and distribution of introduced Pseudomonas fluorescens and Bacillus subtilis bacteria was determined. Soil bulk-density and aggregate sizes were altered to manipulate the characteristics of the pore volume where bacteria reside and through which distribution of solutes and nutrients is controlled. X-ray CT was used to characterise the pore geometry of repacked soil microcosms. Soil porosity, connectivity and soil-pore interface area declined with increasing bulk-density. In samples that differ in pore geometry, its effect on growth and extent of spread of introduced bacteria was investigated. The growth rate of bacteria reduced with increasing bulk-density, consistent with a significant difference in pore geometry. To measure the ability of bacteria to spread thorough soil, placement experiments were developed. Bacteria were capable of spreading several cm’s through soil. The extent of spread of bacteria was faster and further in soil with larger and better connected pore volumes. To study the spatial distribution in detail, a methodology was developed where a combination of X-ray microtopography, to characterize the soil structure, and fluorescence microscopy, to visualize and quantify bacteria in soil sections was used. The influence of pore characteristics on distribution of bacteria was analysed at macro- and microscales. Soil porosity, connectivity and soil-pore interface influenced bacterial distribution only at the macroscale. The method developed was applied to investigate the effect of soil pore characteristics on the extent of spread of bacteria introduced locally towards a C source in soil. Soil-pore interface influenced spread of bacteria and colonization, therefore higher bacterial densities were found in soil with higher pore volumes. Therefore the results in this showed that pore geometry affects the growth and spread of bacteria in soil. The method developed showed showed how thin sectioning technique can be combined with 3D X-ray CT to visualize bacterial colonization of a 3D pore volume. This novel combination of methods is a significant step towards a full mechanistic understanding of microbial dynamics in structured soils.

Development of a whole cell biochip for toxicant detection.

In the development of biosensors for ecotoxicity testing it is desirable to produce a small, portable system that can be used in the field. Toxicity testing using bioluminescence is widely used in the laboratory utilising natural and genetically modified (lux/ luc-marked) bacteria and other microorganisms. It is currently not possible to use genetically manipulated microorganisms in field testing and a biosensor, therefore, that incorporates naturally luminescent organisms may be preferred. In the development of a biosensor it is aimed to use the naturally luminescent bacterium Vibrio fischeri as a toxicity detection system on a chip. The bacterium will be immobilised in a polymeric matrix. Current work deals with the optimisation of light output and light preservation within the bacterium prior to immobilisation in polyvinyl alcohol. An examination of a range of physicochemical conditions within the polymer will be made, including cell density, thickness of polymer film, growth and light induction environment, and, preservation conditions, in order to develop a testing system giving consistent results over the lifetime of the biosensor. Data will be presented on light production using different culture media for the growth of V. fischeri and retention of light under immobilised conditions. .

Status and management of spring-run chinook salmon

Runs have dwindled in many parts of California and additional protection or management actions are needed to protect the fish from further declines. The following is a report requested by the Fish and Game Commission on the status and current management of spring-run chinook salmon stocks. Fish counts presented in this report were developed by a variety of methods. Some of them are estimates of total run-size or spawning escapement, while others are indices of abundance derived from counts of maturing fish in their holding areas. It is important to note the stock assessment method used. Index area counts will always underestimate the true run size, often by a very large margin.

Predicting the performance of passenger ships using computer simulation

When designing a new passenger ship or naval vessel or modifying an existing design, how do we ensure that the proposed design is safe from an evacuation point of view? In the wake of major maritime disasters such as the Herald of Free Enterprise and the Estonia and in light of the growth in the numbers of high density, high-speed ferries and large capacity cruise ships, issues concerned with the evacuation of passengers and crew at sea are receiving renewed interest. In the maritime industry, ship evacuation models are now recognised by IMO through the publication of the Interim Guidelines for Evacuation Analysis of New and Existing Passenger Ships including Ro-Ro. This approach offers the promise to quickly and efficiently bring evacuation considerations into the design phase, while the ship is "on the drawing board" as well as reviewing and optimising the evacuation provision of the existing fleet. Other applications of this technology include the optimisation of operating procedures for civil and naval vessels such as determining the optimal location of a feature such as a casino, organising major passenger movement events such as boarding/disembarkation or restaurant/theatre changes, determining lean manning requirements, location and number of damage control parties, etc. This paper describes the development of the maritimeEXODUS evacuation model which is fully compliant with IMO requirements and briefly presents an example application to a large passenger ferry.

Optimising plant bed performance through adaptive research with the Australian sweetpotato industry

A key driver of Australian sweetpotato productivity improvements and consumer demand has been industry adoption of disease-free planting material systems. On a farm isolated from main Australian sweetpotato areas, virus-free germplasm is annually multiplied, with subsequent 'pathogen-tested' (PT) sweetpotato roots shipped to commercial Australian sweetpotato growers. They in turn plant their PT roots into specially designated plant beds, commencing in late winter. From these beds, they cut sprouts as the basis for their commercial fields. Along with other intense agronomic practices, this system enables Australian producers to achieve worldRSQUOs highest commercial yields (per hectare) of premium sweetpotatoes. Their industry organisation, ASPG (Australian Sweetpotato Growers Inc.), has identified productivity of mother plant beds as a key driver of crop performance. Growers and scientists are currently collaborating to investigate issues such as catastrophic plant beds losses; optimisation of irrigation and nutrient addition; rapidity and uniformity of initial plant bed harvests; optimal plant bed harvest techniques; virus re-infection of plant beds; and practical longevity of plant beds. A survey of 50 sweetpotato growers in Queensland and New South Wales identified a substantial diversity in current plant bed systems, apparently influenced by growing district, scale of operation, time of planting, and machinery/labour availability. Growers identified key areas for plant bed research as: optimising the size and grading specifications of PT roots supplied for the plant beds; change in sprout density, vigour and performance through sequential cuttings of the plant bed; optimal height above ground level to cut sprouts to maximise commercial crop and plant bed performance; and use of structures and soil amendments in plant bed systems. Our ongoing multi-disciplinary research program integrates detailed agronomic experiments, grower adaptive learning sites, product quality and consumer research, to enhance industry capacity for inspired innovation and commercial, sustainable practice change.

A petrographic investigation into the durability of common replacement sandstones to the crystallisation of de-icing salts

Scottish sandstone buildings are now suffering the long-term effects of salt-crystallisation damage, owing in part to the repeated deposition of de-icing salts during winter months. The use of de-icing salts is necessary in order to maintain safe road and pavement conditions during cold weather, but their use comes at a price. Sodium chloride (NaCl), which is used as the primary de-icing salt throughout the country, is a salt known to be damaging to sandstone masonry. However, there remains a range of alternative, commercially available de-icing salts. It is unknown however, what effect these salts have on porous building materials, such as sandstone. In order to protect our built heritage against salt-induced decay, it is vital to understand the effects of these different salts on the range of sandstone types that we see within the historic buildings of Scotland. Eleven common types of sandstone were characterised using a suite of methods in order to understand their mineralogy, pore structure and their response to moisture movement, which are vital properties that govern a stone’s response to weathering and decay. Sandstones were then placed through a range of durability tests designed to measure their resistance to various weathering processes. Three salt crystallisation tests were undertaken on the sandstones over a range of 16 to 50 cycles, which tested their durability to NaCl, CaCl2, MgCl2 and a chloride blend salt. Samples were primarily analysed by measuring their dry weight loss after each cycle, visually after each cycle and by other complimentary methods in order to understand their changing response to moisture uptake after salt treatment. Salt crystallisation was identified as the primary mechanism of decay across each salt, with the extent of damage in each sandstone influenced by environmental conditions and pore-grain properties of the stone. Damage recorded in salt crystallisation tests was ultimately caused by the generation of high crystallisation pressures within the confined pore networks of each stone. Stone and test-specific parameters controlled the location and magnitude of damage, with the amount of micro-pores, their spatial distribution, the water absorption coefficient and the drying efficiency of each stone being identified as the most important stone-specific properties influencing salt-induced decay. Strong correlations were found between the dry weight loss of NaCl treated samples and the proportion of pores <1µm in diameter. Crystallisation pressures are known to scale inversely with pore size, while the spatial distribution of these micro-pores is thought to influence the rate, overall extent and type of decay within the stone by concentrating crystallisation pressures in specific regions of the stone. The water absorption determines the total amount of moisture entering into the stone, which represents the total amount of void space for salt crystallisation. The drying parameters on the other hand, ultimately control the distribution of salt crystallisation. Those stones that were characterised by a combination of a high proportion of micro-pores, high water absorption values and slow drying kinetics were shown to be most vulnerable to NaCl-induced decay. CaCl2 and MgCl2 are shown to have similar crystallisation behaviour, forming thin crystalline sheets under low relative humidity and/or high temperature conditions. Distinct differences in their behaviour that are influenced by test specific criteria were identified. The location of MgCl2 crystallisation close to the stone surface, as influenced by prolonged drying under moderate temperature drying conditions, was identified as the main factor that caused substantial dry weight loss in specific stone types. CaCl2 solutions remained unaffected under these conditions and only crystallised under high temperatures. Homogeneous crystallisation of CaCl2 throughout the stone produced greater internal change, with little dry weight loss recorded. NaCl formed distinctive isometric hopper crystals that caused damage through the non-equilibrium growth of salts in trapped regions of the stone. Damage was sustained as granular decay and contour scaling across most stone types. The pore network and hydric properties of the stones continually evolve in response to salt crystallisation, creating a dynamic system whereby the initial, known properties of clean quarried stone will not continually govern the processes of salt crystallisation, nor indeed can they continually predict the behaviour of stone to salt-induced decay.

An investigation of the clinical utility of preoperative cardiopulmonary exercise testing in patients undergoing major pancreatic surgery

Pancreaticoduodenectomy with or without adjuvant chemotherapy remains the only modality of possible cure in patients with cancer involving the head of the pancreas and the periampullary region. While mortality rates after pancreaticoduodenectomy have improved considerably over the course of the last century, morbidity remains high. Patient selection is of paramount importance in ensuring that major surgery is offered to individuals who will most benefit from a pancreaticoduodenectomy. Moreover, identifying preoperative risk factors provides potential targets for prehabilitation and optimisation of the patient's physiology before undertaking surgery. In addition to this, early identification of patients who are likely to develop postoperative complications allows for better allocation of critical care resources and more aggressive management high risk patients. Cardiopulmonary exercise testing is becoming an increasingly popular tool in the preoperative risk assessment of the surgical patient. However, very little work has been done to investigate the role of cardiopulmonary exercise testing in predicting complications after pancreaticoduodenectomy. The impact of jaundice, systemic inflammation and other preoperative clinicopathological characteristics on cardiopulmonary exercise physiology has not been studied in detail before in this cohort of patients. The overall aim of the thesis was to examine the relationships between preoperative clinico-pathological characteristics including cardiopulmonary exercise physiology, obstructive jaundice, body composition and systemic inflammation and complications and the post-surgical systemic inflammatory response in patients undergoing pancreaticoduodenectomy. Chapter 1 reviews the existing literature on preoperative cardiopulmonary exercise testing, the impact of obstructive jaundice, perioperative systemic inflammation and the importance of body composition in determining outcomes in patients undergoing major surgery with particular reference to pancreatic surgery. Chapter 2 reports on the role of cardiopulmonary exercise testing in predicting postoperative complications after pancreaticoduodenectomy. The results demonstrate that patients with V˙O2AT less than 10 ml/kg/min are more likely to develop a postoperative pancreatic fistula, stay longer in hospital and less likely to receive adjuvant therapy. These results emphasise the importance of aerobic fitness to recover from the operative stress of major surgery without significant morbidity. Cardiopulmonary exercise testing may prove useful in selecting patients for intensive prehabilitation programmes as well as for other optimisation measures to prepare them for major surgery. Chapter 3 evaluates the relationship between cardiopulmonary exercise physiology and other clinicopathological characteristics of the patient. A detailed analysis of cardiopulmonary exercise test parameters in jaundiced versus non-jaundiced patients demonstrates that obstructive jaundice does not impair cardiopulmonary exercise physiology. This further supports emerging evidence in contemporary literature that jaundiced patients can proceed directly to surgery without preoperative biliary drainage. The results of this study also show an interesting inverse relationship between body mass index and anaerobic threshold which is analysed in more detail in Chapter 4. Chapter 4 examines the relationship between preoperative cardiopulmonary exercise physiology and body composition in depth. All parameters measured at cardiopulmonary exercise test are compared against body composition and body mass index. The results of this chapter report that the current method of reporting V˙O2, both at peak exercise and anaerobic threshold, is biased against obese subjects and advises caution in the interpretation of cardiopulmonary exercise test results in patients with a high BMI. This is particularly important as current evidence in literature suggests that postoperative outcomes in obese subjects are comparable to non-obese subjects while cardiopulmonary exercise test results are also abnormally low in this very same cohort of patients. Chapter 5 analyses the relationship between preoperative clinico-pathological characteristics including systemic inflammation and the magnitude of the postoperative systemic inflammatory response. Obstructive jaundice appears to have an immunosuppressive effect while elevated preoperative CRP and hypoalbuminemia appear to have opposite effects with hypoalbuminemia resulting in a lower response while elevated CRP in the absence of hypoalbuminemia resulted in a greater postoperative systemic inflammatory response. Chapter 6 evaluates the role of the early postoperative systemic inflammatory response in predicting complications after pancreaticoduodenectomy and aims to establish clinically relevant thresholds for C-Reactive Protein for the prediction of complications. The results of this chapter demonstrate that CRP levels as early as the second postoperative day are associated with complications. While post-operative CRP was useful in the prediction of infective complications, this was the case only in patients who did not develop a post-operative pancreatic fistula. The predictive ability of inflammatory markers for infectious complications was blunted in patients with a pancreatic fistula. Chapter 7 summarises the findings of this thesis, their place in current literature and future directions. The results of this thesis add to the current knowledge regarding the complex pathophysiological abnormalities in patients undergoing pancreaticoduodenectomy, with specific emphasis on the interaction between cardiopulmonary exercise physiology, obstructive jaundice, systemic inflammation and postoperative outcomes. The work presented in this thesis lays the foundations for further studies aimed at improving outcomes after pancreaticoduodenectomy through the development of individualised, goal-directed therapies that are initiated well before this morbid yet necessary operation is performed.