Vital signs can indicate patient deterioration prior to adverse events such as cardiac arrest, emergency admission to the intensive care unit (ICU), or death. However, many adverse events occur in wards outside the ICU where the level of care and the frequency of patient monitoring are lower than in the ICU. This thesis describes models for detection of deterioration in acutely ill patients in two environments: a step-down unit in which patients recovering from an ICU stay are continuously monitored, and a general ward where patients are intermittently monitored following upper gastrointestinal cancer surgery. Existing data fusion models for classification of vital signs depend on a threshold which defines a “region of normality”. Bradypnoea (low breathing rate) and bradycardia (low heart rate) are relatively rare, and so these two types of abnormalities tend to be misclassified by existing methods. In this thesis, techniques for selecting a threshold are described, such that the classification of vital-sign data is improved. In particular, the proposed approach reduces the misclassification of bradycardia and bradypnoea events, and indicates the type of abnormality associated with the deterioration in a patient’s vital signs. Patients recovering from upper gastrointestinal (GI) surgery have a high risk of emergency admission to the ICU. At present in the UK, most intermediate and general wards outside the ICU depend on intermittent, manual monitoring using track-and-trigger systems. Both manual and automated patient monitoring systems are reported to have high false alert rates. The models described in this thesis take into account the low monitoring frequency in the upper GI ward, such that the false alert rate is reduced. In addition to accuracy, early detection of deterioration is a highly desirable feature in patient monitoring systems. The models proposed in this thesis generate alerts for patients earlier than the early warning systems which are currently in use in hospitals in the UK. The improvements to existing models proposed in this thesis could be applied to continuous and intermittently acquired vital-sign data from other clinical environments.

Cellular communication requires the transport of chemical messengers between intracellular compartments and from cell to cell. The regulated exocytosis of a secretory vesicle at the plasma membrane involves the merger of two bilayers, with markedly different lipid composition, within a millisecond time scale. The spatial and temporal control of the protein and lipid complement at these fusion sites is essential. A highly conserved family of proteins are known to drive this fusion event; SNAP-25 and syntaxin-1 (t-SNAREs) associate at the plasma membrane in a 1:1 stoichiometry to provide a binding site for the vesicle-membrane protein synaptobrevin (v-SNARE). The formation of this complex and subsequent fusion requires accessory proteins for efficient calcium-triggered exocytosis; which of these proteins facilitate the initial attachment of vesicle to the plasma membrane prior to fusion is still under debate. Specific sites for vesicle fusion have been proposed and the organisation of lipids and proteins at these fusion sites has been extensively investigated with limited spatial and temporal resolution; however the presence of raft-forming lipids at these sites as well as the arrangement of SNARE proteins at the molecular level is still under contention. The data presented within this thesis aims to elucidate the protein and lipid environment at the fusion site using super-resolution microscopy and advanced vesicle tracking. Under diffraction-limited microscopy the t-SNAREs are visualised as 200 nm homogenous clusters; however I have used single molecule localisation microscopy to reveal a more complex heterogeneous molecular arrangement. Quantification of lipid order exclusively at the plasma membrane provided insight into the influence of cholesterol-induced lipid arrangement on SNAP-25 localisation. In addition the t-SNARE interaction was investigated using TCSPC-FLIM identifying two lipid-order-dependent conformations in distinct clusters at the plasma membrane. Extensive vesicle tracking at optimum sampling rates demonstrated the ‘sampling’ behaviour of LDCVs and allowed characterisation of vesicle fusion sites. In summary I find that vesicles exhibit preference for residence and probably fusion at regions of plasma membrane with a low t-SNARE density; these proteins appear to exert control over exocytosis by adopting alternative conformations that are under cholesterol-induced regulation.

Investigations of tokamak dynamics, especially as they relate to the challenge of burn control, require an accurate representation of energy and particle confinement times. While the ITER-98 scaling law represents a correlation of data from a wide range of tokamaks, confinement scaling laws will need to be fine-tuned to specific operational features of specific tokamaks in the future. A methodology for developing, by regression analysis, tokamak- and configuration-specific confinement tuning models is presented and applied to DIII-D as an illustration. It is shown that inclusion of tuning parameters in the confinement models can significantly enhance the agreement between simulated and experimental temperatures relative to simulations in which only the ITER-98 scaling law is used. These confinement tuning parameters can also be used to represent the effects of various heating sources and other plasma operating parameters on overall plasma performance and may be used in future studies to inform the selection of plasma configurations that are more robust against power excursions.

Many technological hurdles remain before a viable commercial magnetic fusion energy reactor can be constructed, including the development of plasma-facing components with long lifetimes that can survive the harsh environment inside a reactor. One such component, the divertor, which maintains the purity of the plasma by removing fusion byproducts from the reactor, must be able to accommodate very large incident heat fluxes of at least 10 MW/m^2 during normal operation. Modular helium-cooled tungsten divertors are one of the leading divertor designs for future commercial fusion reactors, and a number of different candidates have been proposed including the modular He-cooled divertor concept with pin array (HEMP), the modular He-cooled divertor concept with multiple-jet-cooling (HEMJ), and the helium-cooled flat plate (HCFP). These three designs typically operate with helium coolant inlet temperatures of 600 °C and inlet pressures of 10 MPa. Performing experiments at these conditions to evaluate the thermal performance of each design is both challenging and expensive. An alternative, more economical approach for evaluating different designs exploits dynamic similarity. Here, geometrically similar mockups of a single divertor module are tested using coolants at lower temperatures and pressures. Dynamically similar experiments were performed on an HEMP-like divertor with helium and argon at inlet temperatures close to room temperature, inlet pressures below 1.4 MPa, and incident heat fluxes up to 2 MW/m^2. The results are used to predict the maximum heat flux that the divertor can accommodate, and the pumping power as a fraction of incident thermal power, for a given maximum tungsten temperature. A new nondimensional parameter, the thermal conductivity ratio, is introduced in the Nusselt number correlations which accounts for variations in the amount of conduction heat transfer through the walls of the divertor module. Numerical simulations of the HCFP divertor are performed to investigate how the thermal conductivity ratio affects predictions for the maximum heat flux obtained in previous studies. Finally, a helium loop is constructed and used to perform dynamically similar experiments on an HEMJ module at inlet temperatures as high as 300 °C, inlet pressures of 10 MPa, and incident heat fluxes as great as 4.9 MW/m^2. The correlations generated from this work can be used in system codes to determine optimal designs and operating conditions for a variety of fusion reactor designs.

Background: Leading researchers have called for more sophisticated research designs in caregiver intervention research; by using theoretically grounded interventions, considering the likely mechanism of action and using appropriate outcome measures. This thesis comprises a systematic review which evaluates the match between psychosocial interventions for dementia caregiver burden and the burden measure used to evaluate them and an empirical study which tests the psychometric properties of two caregiving outcome measures developed in Spain (Caregiver Guilt Questionnaire - CGQ and Dysfunctional Thoughts about Caregiving Questionnaire - DTACQ). The empirical study also considers the role of guilt and cognition (conceptualized as dysfunctional thoughts in Cognitive Behavioural Therapy and cognitive fusion in Acceptance and Commitment Therapy) in predicting depression in dementia caregivers. Systematic review: Results for the effectiveness of psychosocial interventions to reduce dementia caregiver burden are mixed. Caregiver burden is inconsistently defined and measured, which may contribute to the mixed results. This review sought to systematically evaluate the match between psychosocial interventions for dementia caregiver burden and the burden measure used to evaluate them. A systematic search identified 15 studies using the 22 item Zarit Burden Interview as an outcome measure. A systematic review using specified quality criteria indicated a low level of congruence between the content of the psychosocial interventions and the content of the Zarit Burden Interview used to evaluate the interventions in the majority of studies. Methods: 221 informal familial dementia caregivers completed a cross sectional postal questionnaire survey. Results: Using exploratory factor analysis, the factor structures of the CGQ and DTACQ identified in the Spanish development studies were replicated in this study. Adequate internal consistencies were found for both scales. Convergent validity was established for the CGQ with the measures of guilt and depression. The DTACQ correlated positively with general dysfunctional attitudes and negatively with amount of support received as predicted, but did not correlate significantly with depression. A multiple regression analysis identified caregiver guilt and cognitive fusion, but not dysfunctional attitudes as significant predictors of depression in dementia caregivers. Conclusion: The CGQ appears to be a reliable and valid measure of caregiver guilt in a British population of dementia caregivers, although further research is recommended to develop the DTACQ. The relative strength of cognitive fusion as a predictor of caregiver depression suggests that the way in which an individual relates to their thoughts should be tested as a mechanism of change in dementia caregiver interventions.

published_or_final_version / abstract / Comparative Literature / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

Many technical hurdles remain to be overcome before an advanced fuel cycle in which minor actinides from spent nuclear fuel are used to generate power. Three such issues were addressed: criticality safety of minor actinides as compared to currently used fissile isotopes; accuracy of evaluated nuclear data for selected minor actinide high energy fission cross-sections; and the preliminary design optimization of a minor actinide burning/breeding fission blanket in a fission fusion hybrid reactor concept. For minor actinide compositions found in spent fuel, current safety measures for actinide solutions were found to be adequate, though concerns may remain for unmoderated transuranic materials. Additionally, computational results indicated a 5-10% error in the fission cross-section of some minor actinides above the fast fission threshold. Finally, a relatively tall annular fission blanket was found to be the most ideal configuration for the UT fission- fusion hybrid reactor concept, satisfying criticality and power output criteria. / text

L’immunothérapie anticancéreuse est basée sur la capacité du système immunitaire à reconnaître les cellules tumorales comme étrangères et à les éliminer. Les stratégies immunothérapeutiques abordées dans ce travail, incluent l’activation du système immunitaire par l’expression de facteurs immunomodulateurs (l’interleukine-2) via l’utilisation d’un vecteur dérivé du parvovirus MVM, ou par présentation des antigènes tumoraux par la machinerie des cellules dendritiques (DC), via la génération d’hybrides entre DC et cellules tumorales (TC). L’intérêt majeur du parvovirus autonome MVM en tant que vecteur pour la thérapie génique du cancer vient de son expression préférentielle dans les cellules transformées (oncotropisme) et de son aptitude à lyser celles-ci (oncolyse). Les vecteurs générés au laboratoire conservent l’unité de transcription NS et expriment l’IL2 humaine sous contrôle du promoteur P38, à la place des protéines de capside. Malgré les améliorations apportées à la production de vecteurs recombinants, la faible concentration des stocks reste un problème. Il a été montré que, de nombreux virus sont mieux produits en conditions de faible tension en oxygène (hypoxie). Nous avons tenté d’améliorer les titres des vecteurs en les produisant sous faible tension d’oxygène mais sans y parvenir (annexe 1). Dans un modèle in vivo utilisant la lignée de mélanome K-1735 dans des souris immunocompétentes, des cellules tumorales infectées in vitro avant leur implantation en sous-cutané ont montré un effet anti-tumoral du vecteur MVM/IL2 (annexe 2). Afin de mettre en évidence l’apport de l’oncolyse parvovirale dans l’activité anti-tumorale, nous avons mis au point des expériences, dans le même modèle de tumeur, visant à comparer l’efficacité du vecteur MVM/IL2 à celle d’autres vecteurs, Ad/IL2 et Rétrovirus/IL2, ne possédant pas d’activité oncolytique. Dans le but de mettre en évidence une éventuelle réponse immune in vivo, nous avons utilisé le modèle de tumeur TC-1 mais ce modèle s’est montré moins sensible à l’effet du vecteur MVM/IL2 et nous n’avons pas pu démontrer d’activation de cellules cytotoxiques spécifiques de la tumeur. Il a été proposé d’utiliser des hybrides entre DC/TC pour la vaccination anti-tumorale pour optimaliser la présentation des antigènes tumoraux. Une lignée cellulaire exprimant la protéine fusogène du virus de la leucémie du Gibbon (GaLV-FMG, Gibbon ape leukemia virus) a été dérivée de la lignée cellulaire CHO (cellules ovariennes de hamster chinois) au laboratoire. Cette lignée CHO-FMG, utilisée comme partenaire intermédiaire, a permis la fusion entre cellules tumorales et dendritiques (annexe 3). Nous avons montré que l’expression transitoire après infection par un vecteur AAV-FMG ou après transfection transitoire ne génère pas un pourcentage significatif d’hybrides. En effet, le niveau d’expression ainsi que le pourcentage de cellules transduites exprimant FMG s’est révélé trop faible. Ceci a mis en valeur l’efficacité de la lignée stable CHO-FMG comme intermédiaire de la fusion. De plus, nous avons intégré dans la lignée fusogène, le gène de l’interleukine-2, qui devrait permettre d’augmenter l’efficacité de l’induction de la réponse immune. L’activation des cellules effectrices de l’immunité anti-tumorale via la présentation antigénique et/ou par des cytokines est au centre de ce travail. Une meilleure compréhension des mécanismes sous-jacents devrait permettre d’améliorer ces systèmes de vaccination non-conventionnels.

<p>Karolinska universitetssjukhuset bildades i januari 2004 genom en sammanslagning av tidiga-re Huddinge Universitetssjukhus och Karolinska sjukhuset. Medias bevakning av organisa-tionsförändringen har varit omfattande och de politiska beslutsfattarna har jobbat med att förmedla bakgrunden till sammanslagningen. Fusionen genomfördes för att effektivisera sjukvården och därmed förbättra vårdkvaliteten. En viktig del i effektiviseringsprocessen var att koncentrera den högspecialiserade vården och på så sätt även stärka dess konkurrenskraft. Syftet med denna uppsats var att ta reda på om patienterna vid Karolinska Universitetssjukhuset har uppfattat några effekter i form av förbättrad vårdkvalitet samt om det finns skillnader mellan beslutsfattarnas och patienternas uppfattning om avsikterna till sammanslagningen. Detta har undersökts med hjälp av en kvantitativ enkätundersökning bland patienter på sjuk-huset.</p><p>Undersökningen visar att patienternas uppfattning om den främsta avsikten till fusionen inte överensstämmer med ansvariga beslutsfattares. Patienterna tror att den främsta avsikten till sammanslagningen var ekonomiska fördelar. En orsak till detta kan vara en allmän uppfatt-ning om att förändringar i offentlig verksamhet enbart sker för att spara pengar, en annan för-klaring är troligtvis medias bevakning och fokusering på kostnaderna för sammanslagningen. Få patienter uppfattar någon skillnad i vårdkvaliteten före och efter sammanslagningen, vilket eventuellt kan bero på att den genomfördes så pass nyligen. Detta behöver i sig inte betyda att det inte finns några skillnader utan snarare att eventuella effekter är lättare att mäta på längre sikt. Det fanns heller inte några stora skillnader i jämförelsen av den förväntade och upplevda vårdkvaliteten. Resultatet är intressant då kundundersökningar gällande service och kvalitet ofta visar på motsatsen, dvs. att kunder har relativt höga förväntningar i förhållande till vad de sedan upplever att de får.</p>