Dissertations / Theses on the topic 'Non-invasive treatment'

Le syndrome d'apnée du sommeil (SAS) est une maladie multifactorielle caractérisée par des épisodes récurrents de pauses respiratoires ou des réductions significatives de l'amplitude respiratoire pendant le sommeil. Ces épisodes peuvent provoquer des réactions cardiorespiratoires aiguës; délétères à long terme. Plusieurs thérapies ont été proposées, étant la pression positive continue des voies respiratoires (CPAP) le traitement de référence. Malgré ces excellents résultats chez les patients symptomatiques, le taux de refus initial est de 15% et une adhésion à long terme est difficile à atteindre. Par conséquent, le développement de méthodes de traitement non invasives, avec une meilleure acceptabilité, reste d’une importance majeure. Dans ce contexte, l’hypothèse qui sous-tend ce travail est qu’une stimulation kinesthésique contrôlée, délivrée au cours de la phase précoce de l’apnée, peut réduire la durée des événements respiratoires et, par la suite, limiter les désaturations d’oxygène associées, par une activation contrôlée du réflexe de sursaut. La première partie de ce manuscrit est consacrée à la description d'un nouveau système (PASITHEA) de surveillance en temps réel et de neuromodulation thérapeutique, qui fonctionne comme un dispositif polyvalent de diagnostic et de traitement de SAS par stimulation kinesthésique. Les principales contributions de cette thèse se concentrent sur les aspects du traitement du signal et du contrôle de ce système, ainsi que sur l'électronique associée. Une autre contribution est liée à l'évaluation de ces méthodes et dispositifs par des protocoles cliniques spécifiques. Dans une deuxième partie, nous proposons une première méthode de contrôle On/Off optimale pour délivrer la stimulation, en utilisant comme variable de contrôle la sortie d'un détecteur d'événements respiratoires en temps réel. Lors de la détection d'un événement, une stratégie de stimulation unique avec amplitude de stimulation constante est appliquée, cette dernière a été mise en œuvre dans le cadre d'un premier protocole clinique dédié à l'évaluation de la réponse du patient au traitement. Les résultats ont montré que 75% des patients répondaient correctement au traitement en termes de durées des épisodes respiratoires. De plus, des diminutions significatives de la variabilité du SaO2 ont également été constatées lors de la mise en œuvre d'une nouvelle méthode d'analyse aiguë. Puisque nous avons supposé qu'une sélection inappropriée des patients pourrait expliquer l'absence de réponse observée chez 25% des patients. Nous avons proposé une méthode pour différencier les patients qui pourraient bénéficier de cette thérapie, basée sur l'estimation d'indices de variabilité cardiaque. Les résultats de ces analyses ont montré que l'efficacité de cette thérapie semble corrélée à un système nerveux autonome fonctionnel. Enfin, une méthode améliorée de contrôle en boucle fermée, intégrant des correcteurs proportionnels-dérivés (PD) couplés et simultanés a été proposée afin de modifier de façon adaptative l’amplitude de stimulation kinesthésique délivrée au patient par le système thérapeutique, en utilisant comme variables de contrôle des signaux physiologiques enregistrés en temps réel. Un deuxième protocole clinique visant à valider l'algorithme de contrôle de la stimulation kinesthésique adaptative spécifique au patient a été initié. Plusieurs améliorations ont été effectuées à la première version du système afin de permettre l'intégration du contrôleur proposé. Les résultats préliminaires de cette étude ont validé le fonctionnement de notre contrôleur et ont montré que notre système était capable de fournir une stimulation kinesthésique adaptative en fonction des réponses propres au patient. Une autre phase de cette étude, mettant en œuvre le contrôleur avec un ensemble des paramètres de contrôle présélectionnés, est actuellement en cours
Sleep apnea syndrome (SAS) is a multifactorial disease characterized by recurrent episodes of breathing pauses or significant reductions in respiratory amplitude during sleep. These episodes may provoke acute cardiorespiratory responses along with alterations of the sleep structure, which may be deleterious in the long term. Several therapies have been proposed for the treatment of SAS, being continuous positive airway pressure the gold standard treatment. Despite its excellent results in symptomatic patients, there is a 15% initial refusal rate and long term adherence is difficult to achieve in minimally symptomatic patients. Therefore, the development of non-invasive SAS treatment methods, with improved acceptability, is of major importance. The objective of this PhD thesis is to propose new signal processing and control methods of non-invasive neuromodulation for the treatment of SAS. The hypothesis underlying this work is that bursts of kinesthetic stimulation delivered during the early phase of apneas or hypopneas may elicit a controlled startle response that can activate sub-cortical centers controlling upper airways muscles and the autonomic nervous system, stopping respiratory events without generating a cortical arousal. In this context, the first part of this manuscript is dedicated to the description of a novel real-time monitoring and therapeutic neuromodulation system, which functions as a multi-purpose device for SAS diagnosis and treatment through kinesthetic stimulation. This system has been developed in the framework of an ANR TecSan project led by our laboratory, with the participation of Sorin CRM SAS. The main contributions in this thesis are focused on the signal processing and control aspects of this system, as well as the electronics associated. Another contribution is related to the evaluation of these methods and devices through specific clinical protocols. In a second part, we propose a first optimal On/Off control method for delivering kinesthetic stimulation, using as control variable the output of a real-time respiratory event detector. A unique stimulation strategy where a constant stimulation amplitude is applied upon event detention was implemented in a first clinical protocol, dedicated to assessing the patient response to therapy. Results showed that 75% of the patients responded correctly to therapy, showing statistically significant reductions in respiratory event durations. Also, significant decreases in the SaO2 variability were also found when implementing a novel acute analysis method. Since we hypothesized that inappropriate patient selection could explain the observed lack of response in 25% of patients, we proposed a method to differentiate patients who could benefit from this therapy based on the estimation of complexity-based indexes of heart rate variability. Results of these analyses showed that the effectiveness of this therapy seems correlated to a functional autonomic nervous system. Finally, an improved closed-loop control method integrating concurrent, coupled proportional-derivative (PD) controllers in order to adaptively change the kinesthetic stimulation was proposed. It uses as control variables three physiological signals recorded in real-time: Nasal pressure, oxygen saturation and the electrocardiogram signal. A second clinical protocol with the main objective of validating the control algorithm for patient-specific adaptive kinesthetic stimulation was launched. Several improvements to the first version of the system were developed to allow the integration of the proposed controller. Preliminary results from the first phase of this study validated the proposed controller operation and showed that the controller was able to provide adaptive kinesthetic stimulation in function of the patient-specific responses. A second phase of this study implementing the proposed controller and the set of the selected control parameters from the first phase is currently ongoing

Chemoprevention is becoming a highly promising approach to lowering the incidence of cancers. There is, however, insufficient data to determine whether these agents are safe to be used alongside established treatment regimens such as chemotherapy. Non-muscle invasive bladder cancer is readily treatable with surgery (TURBT), yet there is a high rate of recurrence (~60%), 20-30% of patients recurring with the muscle invasive form of the disease, making it a good candidate for chemopreventive intervention. Anthocyanins are one example of dietary compounds currently under investigation as chemopreventive agents. They have been found excreted in the urine of mice at levels capable of causing 50% growth inhibition in cancer cell lines, making them potential bladder cancer chemopreventive agents. Mirtoselect, a standardised bilberry extract containing a mixture of 15 different anthocyanins, was investigated in vitro as a potential chemopreventive agent for bladder cancer alongside chemotherapeutic agent mitomycin C (MMC). Mirtoselect itself was found to inhibit cell survival and growth, causing significant a decrease in clonogenic cell survival, as well as causing an increase in apoptosis in two of the bladder cancer cell lines investigated. In combined studies mirtoselect pre-treatment did not inhibit the effects of MMC in measures of growth, cell survival, apoptosis, cell cycle distribution or DNA damage. In fact, there was a mirtoselect dependent increase in MMC-induced crosslinks, an enhancement of MMCs anti-proliferative effects at low concentrations of mirtoselect and in some instances apoptosis was greater than additive. Furthermore mirtoselect was shown to enhance the DNA damaging effects of radiation. Mirtoselect itself appears to be a good chemopreventive candidate for non-muscle invasive bladder cancer. In combination it does not appear to interfere with the cytotoxic actions of MMC, potentially enhancing its effects, and could also provide a therapeutic advantage in radiotherapy, therefore warranting further investigation for use in clinic.

Chronic non-specific low back pain (CNSLBP) is a widespread but poorly understood condition that places a substantial burden on the sufferer, health services and the wider economy. Existing approaches to management do not demonstrate impressive levels of effectiveness. There is growing evidence that CNSLBP is associated with significant alterations in central nervous system (CNS) structure and function, suggesting a possible role for the brain in the aetiology of the condition, and presenting a case for novel therapies which aim to treat CNSLBP by affecting brain function. One such potential therapeutic approach is non-invasive brain stimulation (NIBS). Following a literature review discussing the epidemiology and management of low back pain, the evidence for altered CNS function and the potential role of brain stimulation in CNSLBP and chronic pain generally this thesis includes 3 original scientific studies: (i) A Cochrane systematic review of the effectiveness of NIBS techniques for the treatment of chronic pain; (ii) A randomised double-blind exploratory study of transcranial direct current stimulation of the motor cortex in the treatment of CNSLBP; (iii) Is blinding to the stimulation condition maintained in trials comparing 2mA tDCS with sham stimulation? A randomised cross-over study. Results: There is limited existing evidence that some forms of NIBS may have a beneficial effect on chronic pain, though caution is warranted. Exploratory data from study 2 is not suggestive that tDCS to the motor cortex is effective for treating CNSLBP. Commonly used sham controls in trials of tDCS do not ensure adequate blinding, and so introduce a potential source of bias to the existing evidence base. Conclusion: Further research is required to establish the value of NIBS as a treatment for chronic pain and CNSLBP. Future research in tDCS will need to develop and employ fully validated sham controls to ensure adequate blinding. NIBS cannot currently be recommended for the treatment of CNSLBP.

This thesis has investigated the efficacy of non-invasive ventilation in subjects with congestive heart failure (CHF) and Cheyne—Stokes respiration (CSR). The effect of this therapy on sleep, breathing and haemodynamic variables has been examined. This thesis also describes the morphology and magnitude of the blood pressure (BP) and heart rate (HR) oscillations associated with CSR and elucidates contributing factors to the changes observed. Chapter 1 - literature review - outlines the presentation and treatment of CSR in patients with CHF. Cheyne-Stokes respiration is described with particular emphasis on the polysomnographic features and haemodynamic consequences of this breathing pattern. The mechanisms postulated for the genesis of CSR are reviewed. The prevalence and consequences of CSR are discussed, highlighting the clinical features and their effects on prognosis. The proposed treatments are considered, with attention being paid to the mechanisms of action, the effect on sleep, breathing, haemodynamics and the clinical utility of each therapy. Special emphasis is placed on oxygen and continuous positive airway pressure (CPAP) therapy. It is proposed that given the lack of universal acceptance of any one treatment modality, the role of new therapies that emulate the positive effects of current treatments, warrant further investigation. A review of noninvasive ventilation including a survey of its historical use, methodological considerations, physiological consequences and clinical applications has been undertaken.

La technique de haute intensité ultrasons focalisés (HIFU) est maintenant largement utilisée pour le traitement du cancer, grâce à son avantage non-invasif. Dans un système de HIFU, une matrice de transducteurs à ultrasons est pilotée en phase pour produire un faisceau focalisé d'ultrasons (1M ~ 10 MHz) dans une petite zone de l'emplacement de la cible sur le cancer dans le corps. La plupart des systèmes HIFU sont guidées par imagerie par résonance magnétique (IRM) dans de nos jours. Dans cette étude de doctorat, un amplificateur de puissance de classe D en demi-pont et un système d'accord automatique d'impédance sont proposés. Tous deux circuits proposés sont compatibles avec le système IRM. L'amplificateur de puissance proposé a été réalisé par un circuit imprimé (PCB) avec des composants discrets. Selon les résultats du test, il a rendement de conversion en puissance de 82% pour une puissance de sortie conçue de 1,25W à une fréquence de travail de 3MHz. Le système d'accord automatique d'impédance proposé a été conçu en deux versions: une version en PCB et une version en circuit intégré (IC). Contrairement aux systèmes d'accord automatique proposés dans la littérature, il n'y a pas besoin de l'unité de microcontrôleur (MCU) ou de l'ordinateur dans la conception proposée. D'ailleurs, sans l'aide de composants magnétiques volumineux, ce système d'auto-réglage est entièrement compatible avec l'équipement IRM. La version en PCB a été conçue pour vérifier le principe du système proposé, et il est également utilisé pour guider à la conception du circuit intégré. La réalisation en PCB occupe une surface de 110cm². Les résultats des tests ont confirmé la performance attendue. Le système d'auto-tuning proposé peut parfaitement annuler l'impédance imaginaire du transducteur, et il peut également compenser l'impédance de la dérive causée par les variations inévitables (variation de température, dispersion technique, etc.). La conception du système d'auto-réglage en circuit intégré a été réalisé avec une technologie CMOS (C35B4C3) fournies par Austrian Micro Systems (AMS). La surface occupée par le circuit intégré est seulement de 0,42mm². Le circuit intégré conçu est capable de fonctionner à une large gamme de fréquence tout en conservant une consommation d'énergie très faible (137 mW). D'après les résultats de la simulation, le rendement de puissance de ce circuit peut être amélioré jusqu'à 20% comparant à celui utilisant le réseau d'accord statique
High intensity focused ultrasound (HIFU) technology is now broadly used for cancer treatment, thanks to its non-invasive property. In a HIFU system, a phased array of ultrasonic transducers is utilized to generate a focused beam of ultrasound (1M~10MHz) into a small area of the cancer target within the body. Most HIFU systems are guided by magnetic resonance imaging (MRI) in nowadays. In this PhD study, a half-bridge class D power amplifier and an automatic impedance tuning system are proposed. Both the class D power amplifier and the auto-tuning system are compatible with MRI system. The proposed power amplifier is implemented by a printed circuit board (PCB) circuit with discrete components. According to the test results, it has a power efficiency of 82% designed for an output power of 3W at 1.25 MHz working frequency. The proposed automatic impedance tuning system has been designed in two versions: a PCB version and an integrated circuit (IC) version. Unlike the typical auto-impedance tuning networks, there is no need of microprogrammed control unit (MCU) or computer in the proposed design. Besides, without using bulky magnetic components, this auto-tuning system is completely compatible with MRI equipment. The PCB version was designed to verify the principle of the proposed automatic impedance tuning system, and it is also used to help the design of the integrated circuit. The PCB realization occupies a surface of 110cm². The test results confirmed the expected performance. The proposed auto-tuning system can perfectly cancel the imaginary impedance of the transducer, and it can also compensate the impedance drifting caused by unavoidable variations (temperature variation, technical dispersion, etc.). The IC design of the auto-tuning system is realized in a CMOS process (C35B4C3) provided by Austrian Micro Systems (AMS). The die area of the integrated circuit is only 0.42mm². This circuit design can provide a wide working frequency range while keeping a very low power consumption (137 mW). According to the simulation results, the power efficiency can be improved can up to 20% by using this auto-tuning circuit compared with that using the static tuning network

Approximately 70-85% of bladder cancer patients present with non-muscle invasive bladder cancer (NMIBC). These patients are usually treated by surgical resection of bladder tumours followed by the intravesical administration of anticancer drugs such as mitomycin C (MMC), doxorubicin or gemcitabine. However the recurrence rate after 5 years remains high (70%) so that the development of more effective chemotherapeutic strategies is essential. We have previously shown that hyperbranched polyglycerol (HPG-C₈/₁₀-MePEG-NH₂) nanoparticulate carriers of docetaxel (DTX) offered an improved and effective formulation of the drug for intravesical delivery in mice. The present work describes the effect of concentration and exposure times of three HPG-C₈/₁₀-MePEG-NH₂’s with increasing degrees of amineation on ex vivo porcine bladder tissue morphology and the tissue depth uptake of DTX. The results demonstrated the exfoliation of porcine bladder tissues in a time and concentration-dependent manner. Exfoliation and DTX uptake was significantly enhanced upon treatment with medium or high-density HPG-C₈/₁₀-MePEG-NH₂’s, as compared to a commercially available DTX/polysorbate 80 formulation. Further studies on the local effect of the chemotherapeutic agents MMC, doxorubicin and gemcitabine, on ex vivo porcine bladder tissue showed that these drugs all caused exfoliation of urothelium and were well taken up by the bladder tissue with no additional effect of HPG-C₈/₁₀-MePEG-NH₂ pre-treatment. The exfoliating effect of these three drugs was shown to enhance the bladder tissue uptake of paclitaxel (PTX) or DTX when the bladder was exposed to combinations of taxanes with either MMC, doxorubicin or gemcitabine. Generally, the exfoliation effect of HPG-C₈/₁₀-MePEG-NH₂’s, MMC, doxorubicin and gemcitabine is attributed to an interaction of the positively charged amine groups on all these agents with the negatively charged mucosal surface. This binding may modulate tight junction protein function followed by exfoliation of the protective urothelial layer so that drugs may penetrate the exposed underlying tissue. In conclusion this thesis supports a novel role of DTX loaded-HPG-C₈/₁₀-MePEG-NH₂ nanoparticles as an improved drug delivery vehicle for the potential chemotherapeutic treatment of bladder cancer. Additionally, data suggests promising strategies for intravesical combination drug therapies, to enhance the uptake of taxanes with potential additive therapeutic effects for improved efficacy in the treatment of NMIBC.
Pharmaceutical Sciences, Faculty of
Graduate

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality throughout the world. When we began this project our knowledge about the outcome of COPD patients admitted to the ICU in Sweden was scarce. Aims: To investigate the characteristics, survival and health-related quality of life (HRQL) of COPD patients admitted to Swedish ICUs. To investigate how ICU personnel decide whether to use invasive or non-invasive ventilatory treatment (NIV) of the newly admitted COPD patient in need of ventilatory support. To investigate outcome according to mode of ventilation. Material and methods: Detailed data, including HRQL during recovery, from COPD patients admitted to ICUs that participated in the Swedish intensive care registry were analysed. A questionnaire was distributed to personnel in 6 of the participating ICUs in order to define factors deemed important in making the choice between invasive and non-invasive ventilation immediately after admission. The answers were analysed. Results: The proportion of COPD patients admitted to Swedish ICUs in need of ventilatory support is 1.3-1.6 % of all admissions. The patients are around 70 years-old and are severely ill on admission, with high respiratory rates and most have life-threatening disturbances in their acid-base balance and blood gases. There are more women than men. The short- and long-term mortality is high despite intensive care treatment. The majority of patients are treated with NIV. The length of stay on the ICU is shorter when NIV is used. The choice between NIV and invasive ventilation in these patients may be irrational. It is guided by current guidelines, but other non-patient-related factors seem to influence this decision. NIV seems to be preferable to invasive ventilation at admission, not only according to short-term benefits but also to long-term survival. Failure of NIV followed by invasive ventilation does not have a poorer prognosis than directly employing invasive ventilation. The health-related quality of life of COPD patients after treatment on Swedish ICUs is lower than in the general population. However it does not decline between 6 and 24 months after ICU discharge. After 24 months the HRQL is quite similar to that of COPD patients not treated on the ICU. Conclusions: COPD patients in need of ventilatory support admitted to Swedish ICUs are severely ill on admission, and their short- and long-term mortality is high despite ICU care and ventilatory treatment. Non-invasive ventilation should be the first line treatment on admission. NIV has short- and long-term benefits compared to invasive ventilation, without increasing mortality risk in case of failure. After discharge from the ICU and recovery, the HRQL of COPD patients is lower than in the general population, but comparable to COPD patients not treated on the ICU.

Les ultrasons focalisés de hautes intensités ont la capacité de déposer de l'énergie ultrasonore localement et de façon non invasive dans les tissus biologiques. Il est possible d'exploiter les effets mécaniques et/ou thermiques en fonction des paramètres ultrasonores utilisés. Guidée par un système d'Imagerie de Résonance Magnétique, cette technologie se voit dotée d'une modalité de planification et le suivi en temps réel de la procédure. Les applications actuelles des ultrasons focalisés guidés par IRM sont sur des organes fixes, notamment le cerveau et l'os ou le fibrome utérin. Dans le cas du cœur, d'une part la présence de mouvements cardiaques et respiratoires constitue une difficulté importante, tant pour le traitement ultrasonore (balistique) que pour l'IRM de température (artéfacts sur les images). D'autre part, la cage thoracique joue le rôle de barrière pour la propagation des ultrasons. Dans ce travail de thèse, un ensemble de techniques nouvelles pour l'ablation et la stimulation cardiaque non invasive par ultrasons focalisés guidés par IRM a été développé. Une première étude montre la faisabilité technique de contrôler le rythme cardiaque par des impulsions ultrasonores brèves dirigées vers le myocarde. L'influence des paramètres des impulsions a été étudiée quantitativement sur cœur isolé battant puis in vivo sur un modèle préclinique. Pour cela, un dispositif original a été développé. Une seconde étude présente de nouvelles méthodes rapides d'IRM permettant de cartographier simultanément la température et le déplacement local induit par les ultrasons focalisés. La méthode est validée sur le foie sur un modèle préclinique, et démontre qu'il est possible de corréler la dose thermique obtenue par thermométrie IRM à un changement des propriétés mécaniques des tissus traités mesurés simultanément. Une troisième étude a consisté à développer une technique de mesure de position de la cible en 3D temps réel par quelques éléments de l'émetteur ultrasonore opérant en réception. Cette mesure permet de corriger dynamiquement la position du foyer ultrasonore pour maximiser le dépôt d'énergie au point ciblé, le tout monitoré par thermométrie IRM temps réel à une cadence de 10 images par seconde. Là encore, une validation préclinique est présentée. Ce travail de thèse propose donc des avancées importantes pour lever les verrous actuels de la technologie permettant d'envisager des traitements non invasifs des pathologies cardiaques par voie non invasive, le tout guidé par IRM en temps réel
High intensity focused ultrasound has the ability to deposit ultrasonic energy locally and non-invasively into biological tissues. It is possible to exploit the mechanical and/or thermal effects according to the ultrasonic parameters used. Guided by a Magnetic Resonance Imaging (MRI) scanner, this technology is equipped with a planning modality and real-time monitoring of the procedure. As of now, applications of MRI-guided focused ultrasound are on fixed organs, including brain and bone or uterine fibroid. For the heart, the presence of cardiac and respiratory movements constitutes an important difficulty, both for the ultrasonic (ballistic) treatment and for the temperature monitoring under MRI (artefacts on images). In addition, the rib cage acts as a barrier for the propagation of ultrasounds. In this thesis work, a set of new technological development have been developed for ablation and non-invasive cardiac stimulation using focused MRI-guided ultrasound. A first study shows the technical feasibility of controlling heart rhythm by short ultrasound pulses targeted to the myocardium. The influence of the parameters of the pulses (duration, amplitude, emission time in the cardiac cycle) were studied quantitatively on isolated beating heart then in vivo on a preclinical model. For this, an original device was developed. A second study presents new rapid MRI methods for simultaneously mapping the temperature and local displacement induced by focused ultrasound. The method is validated on the liver on a preclinical model and demonstrates that it is possible to correlate the thermal dose obtained by MR-thermometry with a change in the mechanical properties of the treated tissues measured simultaneously. A third study consisted in developing a technique for measuring the position of the target in 3D real-time using some elements of the ultrasonic transmitter as receivers. This measure allows to dynamically correct the position of the ultrasonic focus to maximize energy deposition at the targeted point. In addition, we monitored in real-time the procedure using MR-thermometry at a rate of 10 images per second. Here again a preclinical validation is presented. This thesis work proposes important advances to remove the current locks of the technology allowing to envision noninvasive treatments of cardiac pathologies, all guided by MRI in real-time

Major depression is a common and debilitating condition. However, initial treatment is ineffective for almost half of all patients. This thesis aims to clarify the mechanisms of a novel putative treatment for depression, transcranial direct current stimulation (tDCS), which targets the dorsolateral prefrontal cortex (DLPFC). The first experimental chapter tests whether DLPFC tDCS alters emotional face perception, akin to the acute effects of antidepressant drugs. Our analyses revealed that tDCS does not exert an antidepressant-like effect on emotion perception, but may affect non-emotional cognition. The second experimental chapter examines neural activation in depressed patients, unaffected first-degree relatives of depressed patients, and healthy controls during the n-back working memory task and a facial emotion processing task. During the n-back, depressed patients showed pronounced DLPFC hypoactivation, while at-risk participants were indistinguishable from healthy controls, consistent with the hypothesis that DLPFC dysfunction might be a useful target for depression treatment. In the final two chapters, I report results from a double-blind randomized controlled trial that for the first time tested DLPFC tDCS as an augmentation strategy to psychotherapy in depression, measuring its neural, cognitive, and clinical effects. On the primary outcome measure (observer-rated depressive symptoms) active tDCS did not show a significant improvement over sham stimulation, although the difference was in the hypothesised direction. However, baseline DLPFC activation during the n-back strongly predicted clinical outcome, with this association specific to the active tDCS condition. Thus, baseline DLPFC activation might serve as a putative ‘biomarker’ for clinical response to tDCS. In the general discussion, these experimental findings are discussed in the context of contemporary theories of depression. This thesis adds new insights into the possible mechanisms of tDCS as a treatment for depression. It also demonstrates the added value of neuroimaging to psychiatry clinical trials, highlighting a potential role for predicting treatment outcome.

The persistence of retinopathy of prematurity (ROP) in both the developed and the developing world remains a serious cause for concern. Some 75 years after its first clinical description, we still lack an easily applied strategy to reduce the deleterious effects of oxygen (O2) on the developing retinal vasculature. The aim of the work detailed in this thesis is to provide an early, non-invasive intervention for ROP by targeting the initiating event in the disease – hyperoxia in the retina - rather than treating the downstream effects of hyperoxia, as is presently the case. The hypothesis tested in this thesis is that dark-rearing (DR) infants at risk of ROP during supplemental O2 therapy will increase the metabolic rate of photoreceptors and increase O2 consumption in the retina, offsetting retinal hyperoxia. This thesis provides proof-of-principle that DR can normalize vascular development in the presence of supplemental O2 by maintaining ‘physiological hypoxia’ during the hyperoxic (Phase 1) of ROP, and shows that DR preserves the density and extent of retinal vessels, and reduces the severity of pre-retinal neovascularization in Phase 2 of an established rat model of ROP. In addition, the thesis presents a normative dataset for the rate of retinal vascularization in human infants under “physiological hypoxia” in utero, and provides data towards a criteria for the clinical dentification of “delayed retinal vascularization’ as a basis for initiation of laser treatment, or the application of antivascular endothelial growth factor (VEGF) therapy for infants at risk of progressing to sight-threatening stages of ROP. Finally, the thesis presents data examining the hitherto unidentified system of lymphatic vessels in the human choroid. These observations provide the foundation for further studies exploring the roles of lymphatics in posterior eye diseases, and investigations of novel therapeutic targets in these diseases, such as the lymphangiogenic factors VEGF-C & D.

Immunotherapy has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC) and resulted in a higher response rate, and improved overall survival, with some deriving durable long-term benefits. However, the majority of patients do not derive clinical benefit from immunotherapy and the adverse events associated with this treatment remains challenging, not only due to the significant morbidity that impairs patients’ quality of life but also the additional financial burden on the health system. Currently, the programmed death ligand -1 (PD-L1) tumour proportion score (TPS) and tumour mutation burden (TMB) are the only Food and Drug Administration (FDA) approved biomarkers that identify patients with NSCLC who will benefit the most from anti-PD1/PD-L1 therapy. Both have several limitations. In particular, patients with PD-L1 TPS of less than 1% or low TMB still derive benefit from the immunotherapy and some with high PD-L1 expression ( > 50%) or high TMB will not respond to anti-PD-L1/ PD1 therapies. Additionally, there are no biomarkers approved for clinical use to predict the development of immune related adverse events (irAEs). Therefore, research exploring additional biomarkers that might add value to PD-L1 TPS or be used as an alternative is necessary. Those can be used to guide selection of the appropriate therapy for each patient based on the likelihood of clinical benefit while minimising the risk of developing adverse events. Genomic human leukocyte antigen (HLA) has an important role in the activation process of the immune system. HLA presents cellular peptides and engages T-cell receptors (TCR) to activate T cells and to induce an immune response to foreign tissue, pathogens or abnormal antigens. Thus, both are central to the anti-tumour response unleashed by the immune checkpoint inhibitors. Recently, the association between genomic HLA-I homozygosity and worse survival outcomes among lung and melanoma patients treated with immunotherapy has been the subject of various studies with differing findings. Additionally, few studies have shown the association between TCR diversity and immunotherapy response and/or survival outcomes. Pre-treatment TCR repertoire is thought to reflect the ability of the immune system to recognise the tumour neoantigens and attack cancer tissue. The studies in this thesis provide evidence about the association between genomic HLA and circulating pre-treatment TCR repertoire diversity, and clinical outcome among patients treated with immunotherapy alone or in combination with chemotherapy. The thesis is comprised of 6 chapters: a comprehensive literature review with theoretical framework (Chapter 1); four results chapters (Chapter 2-5); and a final chapter with general discussion and future direction (Chapter 6). The first chapter of the thesis includes an overview of the current immunotherapy treatment available for patients with locally advanced and metastatic NSCLC and PD-L1 as an approved FDA biomarker and its limitations (Chapter 1). The potential role of genomic HLA and the pre-treatment TCR repertoire as biomarkers for clinical outcomes and immune related toxicities (irAEs) was discussed in the context of the current evidence. Chapter 2 showed that genomic HLA-I, but not HLA-II, homozygosity at one or more HLA-I loci is associated with worse survival among patients with advanced unresectable NSCLC patients treated with single agent immunotherapy in the first- or second-line setting (Chapter 2). This association is more pronounced among patients with high PD-L1 (TPS ≥ 50%). In Chapter 3, it showed that this association is not observed among patients treated with immunotherapy in combination with chemotherapy in the first line setting. Chapter 4 shows that homozygosity at one or more HLA-I loci was found to be protective against the development of irAEs. We confirmed that the development of irAEs seems to be associated with a favourable clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). Finally, the role of pre- treatment TCR repertoire diversity and its association with clinical outcomes and irAEs were highlighted in Chapter 5. TCR diversity was assessed using multiple variables. However, only the number of unique clones was found to be correlated with improved CBR among patients treated with pembrolizumab in the first line setting. All the investigated variables; increased number of unique clones or Shannon diversity, reduced evenness or convergence; were individually associated with improved PFS among patients treated with pembrolizumab in combination with chemotherapy. A model score incorporating all four TCR diversity variables was associated with PFS among patients treated with pembrolizumab alone and with CBR and OS among those treated with pembrolizumab in combination with chemotherapy. Chapter 6 provides a general discussion of the studies covered in this thesis, their key findings in the context of the current literature and their limitations. The role of non-invasive biomarkers as potential biomarkers for patients treated with immunotherapy is highlighted and future studies towards validation and clinical implementation are proposed. Overall, Genomic HLA-I might be more informative among patients treated with immunotherapy alone compared to pre-treatment TCR diversity role, which is more pronounced among those treated with immunotherapy in combination with chemotherapy.

High Intensity Focused Ultrasound (HIFU) is a non-invasive, non-ionising technology which can selectively occlude blood vessels. In Twin-Twin Transfusion Syndrome (TTTS), anastomotic placental vessels in a shared placenta allow uneven blood distribution between the twins. Despite advances in prenatal and neonatal care, TTTS remains the leading cause of death and disability in twins. Invasive fetoscopic laser can divide anastomoses, with risks of miscarriage, placental haemorrhage, extreme prematurity or second trimester rupture of membranes. Fetoscopic laser has undergone improvements in technology and therapeutic protocols over two decades, but it still does not consistently improve survival or decrease severe neurological morbidity in surviving twins. Hence, it is only used in severe cases, where benefits outweigh risks, and over 16-18 weeks gestation, after chorion and amnion fusion. This represents an unmet clinical need, which could be addressed by ultrasound-guided HIFU (USgHIFU). Selective occlusion of placental vessels using HIFU has not been described. Ultrasound identification of placental vascular anastomoses in humans is described, but is not in routine clinical use. Therefore, we tested the efficacy and safety of using USgHIFU as a non-invasive method of placental vascular occlusion in the pregnant sheep. An iterative study design in six animal groups was used. Treatment protocols for ultrasound guidance and HIFU delivery were developed in three animal groups. The efficacy and rates of associated direct and indirect iatrogenic harm of each version of the protocol was tested in another three animal groups, using invasive and non-invasive measures. Overall, transdermal USgHIFU occluded 97% of target placental vessels in the most developed treatment protocol. This persisted for 21 days and showed evidence of permanent vessel occlusion by fibrosis obliterans. This was achieved without significant adverse events, although maternal skin (2%), uterine (1%) and fetal skin burns (1%) were observed. There were no long term effects (up to 21 d) of the technique based on assessment of maternal and fetal cardiovascular, metabolic, endocrine and obstetric outcomes, or evidence of fetal compromise. This study is proof of principle that USgHIFU can be used to occlude placental vessels in the pregnant sheep. There is a low rate of direct iatrogenic harm and no evidence of indirect harm associated with the technique. As such, this supports the concept of future translational studies to develop USgHIFU as a treatment for TTTS in humans.

The purpose of the project which led to the writing of this thesis was to: 1) Establish the accuracy, limitations and practicality of a simple isotope test, the mean Cerebral Transit Time (MCTT), developed in the Western General Hospital, Edinburgh, and its ability to diagnose the pattern of cerebral arterial occlusion in acute ischaemic stroke; 2) Study the effect of early reperfusion of the cerebral infarct on swelling of the infarct in the acute stage, and clinical outcome in patients with symptoms of extensive acute cerebral ischaemia; 3) Perform an overview analysis of thrombolytic therapy for acute ischaemic stroke; 4) Set up a pilot randomised controlled trial of intra-arterial thrombolysis in acute ischaemic stroke. The Thesis is divided into four parts. Part One describes: a) the background to current understanding of the aetiology and pathogenesis secondary treatment of, and possible primary treatments for acute ischaemic stroke; b) the anatomy and physiology of the cerebral circulation; c) imaging methods for investigating the cerebral circulation and brain parenchyma. Part Two describes a study in 120 acute stroke patients. Part Three is the relationship between reperfusion of the infarct shown by TCD, the amount of swelling in the infarct in the acute stag shown by CT brain scan, and clinical outcome. Part Four contains a review of all publications on thrombolysis in stroke patients.

Els Glioblastomes (GB) son tumors cerebrals invasius, amb mal pronòstic i resposta pobra a la teràpia. Aquesta tesi pretén millorar el tractament del GB preclínic mitjançant la immunitat relacionada amb el càncer i el seguiment no invasiu de la resposta amb Imatge Espectroscòpica de Ressonància Magnètica (IERM). El model de GB GL261 ha estat escollit per ser immunocompetent i adequat per a estudis de teràpia. S’ han investigat tres estratègies terapèutiques: a) quimioteràpia (Temozolamida, TMZ), en protocol metronòmic respectuós amb el sistema immune (Immune-Enhancing Metronomic Schedule, IMS-TMZ), b) un inhibidor de punt de control immunològic (Programmed cell death protein 1, anticòs anti-PD-1), i c) combinació de TMZ+anti-PD-1 en IMS. Diferents tipus de dany cel·lular desencadenats per la teràpia estimulen la resposta immune anti-càncer. El nostre objectiu ha estat, per una banda, induir dany cel·lular immunogènic, preservant les cèl·lules del sistema immune (IMS-TMZ). Per altra banda, contrarestar la immunosupressió al tumor (anti-PD-1). El protocol de IMS-TMZ ha millorat la supervivència dels ratolins amb GB GL261, sobrepassant resultats previs del grup. La teràpia amb anti-PD-1 ha estat efectiva en dosis elevades (500/250 μg), tot i que diferències al volum tumoral a l’ inici de la immunoteràpia impacten en la seva eficàcia. La teràpia combinada anti-PD-1+TMZ en IMS ha resultat millor que les teràpies per separat. Aquests resultats recolzen la participació del sistema immune en la resposta a la teràpia en GB. Estudis del nostre grup amb imatges nosològiques basades en IERM apunten a que els canvis al patró metabolòmic estarien relacionats amb l’ acció del sistema immune sobre els tumors, actuant com marcador vicari de resposta a la teràpia. Ens hem preguntat si els mateixos canvis metabolòmics s’ apreciarien si aquest sistema s’ apliqués a estratègies d’ immunoteràpia. S’ ha seguit amb aquest sistema l’ evolució de ratolins amb tumors GL261 tractats amb IMS-TMZ, IMS-anti-PD-1 i IMS-anti-PD-1/TMZ. El protocol de IMS-TMZ produeix oscil·lació de canvis al patró metabolòmic, amb freqüència de 6 dies. Aquest comportament s’ ha confirmat en ratolins tractats amb immunoteràpia, sola o en combinació, suggerint que els canvis al patró metabolòmic son comuns a diferents estratègies terapèutiques, sempre que hi hagi estímul i atracció del sistema immune amb atac productiu a les cèl·lules tumorals. Això obre camí per l’ ús traslacional del biomarcador basat en MRSI en la teràpia personalitzada en pacients de GB, incloent l’ immunoteràpia, per la qual encara no es disposa de biomarcadors no invasius fiables. La participació del sistema immune també es veu recolzada pel percentatge d’ animals curats observats en aquesta tesi (50-100% depenent de la teràpia), els quals han presentat memòria immune contra subsegüents intents de generació del mateix tipus de tumor. La resistència a TMZ es una de las causes del fracàs de la quimioteràpia adjuvant en el tractament de GB. Hem investigat el rol de la O6-methylguanine-DNA-methyltransferase (MGMT) y programmed death-ligand 1 (PD-L1) en la quimioresistència, utilitzant western-blot, en tumors que escapen a la teràpia IMS-TMZ després de presentar resposta transitòria. L’ expressió de PD-L1 es triplica en aquests tumors en comparació amb controls, indicant que aquests nivells podrien ser rellevants en la resistència a la TMZ in vivo, tenint la teràpia anti-PD-1 potencial per a ‘rescatar’ tumors escapant de la teràpia amb TMZ. La combinació d’ oncologia i immunologia pot obrir camí cap a una millora de l’ eficàcia de la teràpia i dels resultats obtinguts amb els pacients de GB.
Los Glioblastomas (GB) son tumores cerebrales invasivos, con mal pronóstico y respuesta pobre a la terapia. Esta tesis pretende mejorar el tratamiento del GB preclínico utilizando la inmunidad relacionada con el cáncer y el seguimiento no invasivo de la respuesta mediante Imagen Espectroscópica de Resonancia Magnética (IERM). El modelo de GB GL261 fue escogido por ser inmunocompetente y adecuado para estudios de terapia. Se investigaron tres estrategias terapéuticas: a) quimioterapia (Temozolamida, TMZ), en protocolo metronómico respetuoso con el sistema inmune (Immune-Enhancing Metronomic Schedule, IMS-TMZ), b) un inhibidor de punto de control inmunológico (Programmed cell death protein 1, anticuerpo anti-PD-1), y c) combinación de TMZ+anti-PD-1 en IMS. Diferentes tipos de daño celular desencadenados por la terapia estimulan la respuesta inmune anti-cáncer. Nuestro objetivo fue, por un lado, inducir daño celular inmunogénico, preservando las células del sistema inmune (IMS-TMZ). Por otro lado, contrarrestar la inmunosupresión en el tumor (anti-PD-1). El protocolo de IMS-TMZ ha mejorado la supervivencia de los ratones con GB GL261, sobrepasando resultados previos del grupo. La terapia con anti-PD-1 fue efectiva en doses elevadas (500/250 μg), aunque diferencias en el volumen tumoral al inicio de la inmunoterapia impactan en su eficacia. La terapia combinada anti-PD-1+TMZ en IMS ha resultado mejor que las terapias por separado. Estos resultados respaldan la participación del sistema inmune en la respuesta a la terapia en GB. Estudios de nuestro grupo con imágenes nosológicas basadas en IERM apuntan a que los cambios en el patrón metabolómico estarían relacionados con la acción del sistema inmune sobre los tumores, actuando como marcador subrogado de respuesta a la terapia. Nos hemos preguntado si los mismos cambios metabolómicos se apreciarían si este sistema fuese aplicado a estrategias de inmunoterapia. Se siguió con dicho sistema la evolución de ratones con tumores GL261 tratados con IMS-TMZ, IMS-anti-PD-1 e IMS-anti-PD-1/TMZ. El protocolo de IMS-TMZ produce oscilación de cambios en el patrón metabolómico, con una frecuencia de 6 días. Dicho comportamiento se ha confirmado en ratones tratados con inmunoterapia, sola o en combinación, sugiriendo que los cambios en el patrón metabolómico son comunes a distintas estrategias terapéuticas, siempre que haya estímulo y atracción del sistema inmune con ataque productivo a las células tumorales. Ello abre el camino para un uso traslacional del biomarcador basado en MRSI para terapia personalizada en pacientes de GB, incluyendo inmunoterapia, para la cual aún no se dispone de biomarcadores no invasivos fiables. La participación del sistema inmune también es respaldada por el porcentaje de animales curados observados en esta tesis (50-100% dependiendo de la terapia), los cuales presentaron memoria inmune contra subsecuentes intentos de generación del mismo tipo de tumor. La resistencia a TMZ es una de las causas del fracaso de la quimioterapia adyuvante en el tratamiento de GB. Hemos investigado el papel de la O6-methylguanine-DNA-methyltransferase (MGMT) y programmed death-ligand 1 (PD-L1) en la quimioresistencia, utilizando western-blot, en tumores que escapan a la terapia IMS-TMZ después de presentar respuesta transitoria. La expresión de PD-L1 se triplica en esos tumores en comparación con controles, indicando que dichos niveles podrían ser relevantes en la resistencia a la TMZ in vivo, teniendo la terapia anti-PD-1 potencial para ‘rescatar’ tumores escapando de la terapia con TMZ. La combinación de oncología e inmunología guiará el camino para una mejorar tanto la eficacia de la terapia como los resultados obtenidos con pacientes de GB.
Glioblastomas (GB) are invasive brain tumours associated with poor prognosis and limited response to therapy. This thesis focused in improving preclinical GB treatment through cancer-related immunity and Magnetic Resonance Spectroscopic Imaging (MRSI)-based non-invasive response follow-up. The GL261 GB was chosen since it is an immunocompetent preclinical model suitable for studying therapies. Three therapeutic strategies have been tested: a) chemotherapy (Temozolomide, TMZ), administered in an Immune-Enhancing Metronomic Schedule (IMS-TMZ), b) immune checkpoint inhibitor (Programmed cell death protein 1, PD-1 antibody) and c) IMS-anti-PD-1/TMZ combination therapy. Anti-tumour immune responses can be stimulated by therapies targeting different aspects of cell damage. We aimed, on one hand, to induce immunogenic tumour cell damage while sparing replicating immune system cells (with IMS-TMZ). On the other hand, we wanted to counteract the immune suppression within the tumour (anti-PD-1 immunotherapy). IMS-TMZ significantly improved survival in GL261 GB-bearing mice in comparison with standard TMZ treatment, confirming and surpassing results reported by our group. Anti-PD-1 monotherapy was effective when applied at high dose (500/250 μg), although care should be taken since results suggest that differences in tumour volume at immunotherapy starting time can have great impact in its efficacy. As expected, the IMS-anti-PD-1/TMZ combination therapy showed a great beneficial effect, with much better therapeutic outcome than monotherapies administration. These results support the fact that the host immune system is clearly involved in GB response processes. Previous studies from our group with MRSI-based nosological images pointed that the metabolomic pattern changes could be linked to host immune system local effects onto tumours, acting as a surrogate biomarker of therapy response. Accordingly, we wondered whether the application of this non-invasive MRSI approach in evaluating immunotherapeutic strategies would reflect the same type of metabolomics changes. Thus, the evolution of GL261-tumor bearing mice treated with IMS-TMZ, IMS-anti-PD-1 and IMS-anti-PD-1/TMZ was evaluated using the same MRSI-based nosological images approach. Results confirmed that the IMS-TMZ protocol consistently produced the expected oscillatory changes in the MRSI metabolomics pattern, with a frequency of ca. 6 days. This oscillatory behaviour was also confirmed in mice treated with immunotherapy both in combination with TMZ and as monotherapy, hinting that the observed spectral pattern changes observed during therapy response are shared by different therapeutic strategies, provided the host immune system is elicited and is able to productively attack tumour cells. This opens the way for a translational use of the MRSI-based biomarker for patient-tailored GB therapy, including immunotherapy, for which reliable non-invasive biomarkers are still missing. The participation of immune system is also supported by the rate of cured animals observed in this thesis (range 50 - 100 % depending on the treatment), which also held long-term immune memory against tumour cell re-challenge. Resistance to TMZ treatment is one of the main reasons for the chemotherapy failure in adjuvant treatment of GB. We investigated the relevance of O6-methylguanine-DNA-methyltransferase (MGMT) and programmed death-ligand 1 (PD-L1) content in chemoresistance, by western-blot (WB) analysis, with special focus on tumours escaping therapy after transient response. Result showed a 3-fold increase in PD-L1 expression in IMS-TMZ relapsing tumours in comparison with control tumours, indicating that PD-L1 can be involved in TMZ resistance for GL261 GB in vivo. Accordingly, anti-PD1 therapy may have potential to ‘rescue’ tumours escaping from TMZ therapy. Appropriate combination of oncology and immunology will pave the way for improving GB treatment and patient outcome.

The overall aim of this thesis was to elucidate and investigate psychophysiological aspects and effects of acupuncture and needle stimulation. Within this framework emphasis was directed toward the effects of needle stimulation (acupuncture) on muscle blood flow in the tibialis anterior and trapezius muscles in healthy subjects and patients suffering from chronic muscle pain. This study also included evaluation of a new application of photoplethysmography in noninvasive monitoring of muscle blood flow. The evaluation was based on experiments known to provocate skin or muscle blood flow. The psychological aspects studied comprised the effects of manual acupuncture on pain in fibromyalgia patients and the effects of electro-acupuncture on psychological distress and vasomotor symptoms in postmenopausal women in the clinical context. The results showed that photoplethysmography have potential to noninvasively monitor muscle blood flow and to discriminate between blood flow in skin and muscle, although some considerations still have to be accounted for. It was further shown that muscle blood flow change in response to needle stimulation differed between healthy subjects and patients. Deep needle stimulation in the muscle of healthy subjects consistently increased muscle blood flow more than subcutaneous needle stimulation. In the painful trapezius muscle of FMS patients, however, subcutaneous needling was equal or even more effective in increasing muscle blood flow than deep intramuscular stimulation. Generally, needle stimuli had weak effect on blood flow in the trapezius muscle of the severely affected trapezius myalgia patients, possibly depending on older age and lesser number of patients included in the study. The different patterns of blood flow response to needle stimulation between healthy subjects and patients with chronic muscle pain might be a manifestation of altered somatosensory processing in the patients. The clinical studies showed that best pain relief of acupuncture in FMS patients was achieved in the neck-shoulder region, while the effect on the generalised symptoms was of short duration. Well-being and sleep was found to best predict treatment outcome. The results suggest that acupuncture treatment may be used for the alleviation of neck-shoulder pain, primarily, but it is not an alternative as the sole treatment. Electro-acupuncture, significantly decreased psychological distress and climacteric symptoms in postmenopausal women, but not better than a (near-) placebo control, implying pronounced non-specific effects.
Akupunktur ingår som en del i traditionell kinesisk medicin (TCM) och har använts i över 2000 år för att lindra sjukdom och symptom. I Sverige blev akupunktur godkänd som smärtlindringsmetod inom Hälso- och Sjukvården 1984. Sedan nästan 10 år är akupunktur jämställd med övrig behandling i sjukvården vilket innebär, att akupunktur kan användas även för behandling av annat än smärta. Förutsättningen är emellertid, att det finns tillräckligt med vetenskapliga belägg, s.k. evidens, för detta. I de allra flesta fall saknas det idag. För att säkerställa att evidens föreligger krävs omfattande forskning om effekter av akupunktur. Syftet med de olika studierna i avhandlingen var att belysa och studera psykologiska och fysiologiska aspekter och effekter av akupunktur och nålstimulering. Effekt på blodflöde i hud och muskel undersöktes på friska personer och på patienter med kronisk muskelsmärta. Normalt krävs ett mindre kirurgiskt ingrepp för att mäta blodflöde i muskel, men i dessa studier användes en mätmetod, som enkelt och utan ingrepp (icke-invasivt) i normala fall används för att mäta blodflöde i huden, s.k. fotopletysmografi (PPG, eng.). Med hjälp av ny teknik användes PPG i dessa studier för att mäta även muskelblodflöde. En studie för utvärdering av den nya PPG-tekniken ingick också i avhandlingen. Utvärderingen av mätmetoden visade goda möjligheter att mäta muskelblodflöde icke-invasivt med hjälp av PPG. Hos friska personer blev effekten på blodflödet störst vid djup stimulering i muskeln och där den s.k. DeQi-känslan framkallades (som vid klassisk akupunktur). Hos patienter med fibromyalgi var nålstimulering i huden lika, eller t.o.m. mer, effektiv att öka muskelblodflödet i skuldran än den djupa nålstimuleringen. De olika mönstren av blodflödesökning mellan de friska personerna och patienterna kan bero på ett förändrat reaktionssätt i nervsystemet som svar på smärtsam stimulering. I två kliniska studier studerades den smärtlindrande effekten av manuell akupunktur vid fibromyalgi och effekten av elektroakupunktur på stress och klimakteriebesvär hos kvinnor i övergångsåldern. Akupunktur vid fibromyalgi visade sig ha bäst smärtlindrande effekt i nack-skulderområdet, medan effekten på de generella symptomen var kortvarig. Patienter som mådde och sov relativt bra erhöll bäst effekt. Efter en behandlingsserie, bestående av elektroakupunktur, minskade stress och klimakteriebesvär påtagligt hos kvinnorna i övergångsåldern, men inte mer än hos en grupp kvinnor, som fick en kontrollbehandling bestående av mycket ytligt placerade nålar i huden. Detta tyder på att en betydlig del av behandlingsresultatet utgjordes av ospecifika effekter eller, s.k. eller placeboeffekter.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006.
Includes bibliographical references (p. 281-301).
This thesis will explore the use of Transcranial Magnetic Stimulation (TMS) and Transcranial DC Stimulation (tDCS) as modalities for neuropathology treatment by means of both experimental and modeling paradigms. The first and primary modality that will be analyzed is Transcranial Magnetic Stimulation (TMS). TMS is a technique that uses the principle of electromagnetic induction to focus induced currents in the brain and modulate cortical function. These currents can be of sufficient magnitude to depolarize neurons, and when these currents are applied repetitively (repetitive Transcranial Magnetic Stimulation (rTMS)) they can modulate cortical excitability, decreasing or increasing it, depending on the parameters of stimulation. This thesis will explore important facets of the electromagnetic field distributions and fundamental electromagnetic interactions to lay the foundation for future development of a more complete neural model and improved stimulation techniques. First, TMS will be analyzed as a technique used in normal healthy subjects. Finite element modeling (FEM) studies will be explored for realistic healthy human head models with a particular focus placed on the TMS induced cortical currents and their dependency on coil position, normal tissue anatomy, and the electromagnetic tissue properties.
(cont.) This component of the thesis will also include experimental work focused on exploring the in-vivo tissue conductivity and permittivity values used in TMS studies and their impact on stimulation (including a detailed literature review). The next component of the thesis will explore the use of TMS in subjects suffering from various pathologies. The first pathological condition that will be analyzed is cortical stroke. FEM studies will be evaluated and compared to the healthy head models to assess how the cortical modifications brought on at an infarction site can alter the TMS induced current densities. We will also include a laboratory study that assesses the efficacy of TMS in stroke treatment, where repetitive TMS (rTMS) was applied to the unaffected hemisphere to decrease inter-hemispheric inhibition of the lesioned hemisphere and improve motor function in stroke patients. Next, the use of TMS in conditions of brain atrophy will be assessed through modeling analyses. This component will also include an evaluation of the clinical work in the field and ways in which the current density alterations caused by the atrophy have led to clinical misconceptions. Transcranial DC Stimulation (tDCS) will be the second modality analyzed through modeling and experimental work.
(cont.) In tDCS, the cerebral cortex is stimulated through a weak dc current in a non-invasive and painless manner and can modulate cortical excitability like TMS. We will define finite element head models of tDCS for both normal and pathologic cases and evaluate the use of tDCS in the clinic in a stroke treatment experiment (analogous to the one completed with TMS). Finally, we will assess and compare these forms of brain stimulation to other forms of neurological treatment and conclude with proposed future improvements to the field of non-invasive brain stimulation.
by Tim Wagner.
Ph.D.

Intravesical Bacillus Calmette–Guérin (BCG) immunotherapy is the main treatment for bladder high-grade non-muscle invasive transitional cell carcinoma (HGNMITCC) following initial resection. Unfortunately, about 30% of patients will not respond to treatment and they carry a high risk of disease progression. The alternative, radical cystectomy, has major risks with high morbidity and mortality. The ability to predict the response to BCG treatment would be a useful tool in the selection of appropriate treatment modalities. This study investigated a variety of detectable immune responses in blood and urine to establish if there were differences between responders and non-responders to BCG treatment. We evaluated whether there were detectable immunological differences in blood or urine that could explain or predict outcome.

This work investigates whether in vivo magnetic resonance spectroscopy (MRS) and diffusion-weighted magnetic resonance imaging (DW-MRI) can be used for non-invasive monitoring of treatment response in an experimental tumor model. Twenty-nine nude mice with colorectal adenocarcinoma HT29 xenografts on each flank were included into 2 separate experiments. In the first experiment control tumors were compared to tumors irradiated with 15 Gy at Day 2. MR baseline values were established at Day 1 followed by 4 post-treatment MR examinations. Mice were sacrificed for histological response evaluation and high-resolution ex vivo magic angle spinning (HR-MAS) MRS of tumor tissue samples for correlation with in vivo MR data. The second experiment included 3 groups recieving combined chemoradiation therapy; Control group, Capecitabine (359 mg/kg daily Day 1 - Day 5) group and Capecitabine (359 mg/kg daily Day 1 - Day 5) + Oxaliplatin (10 mg/kg at Day 2) group. All left-sided tumors were irradiated with 15 Gy at Day 2. Three repeated MR examinations were compared to the MR baseline values established at Day 1. After MR examinations the mice were sacrificed for histological response evaluation. The choice of chemoterapy was based on a clinical patient study currently running at Rikshospitalet-Radiumhospitalet HF, the LARC-RRP (Locally Advanced Rectal Cancer - Radiation Response Prediction) study. In Experiment 1, localized 1H MR spectra were acquired at short (35 ms) and long (144 ms) echo times (TEs) using a single-voxel technique. The metabolite choline is related to tumor growth. The choline peak area relative to the unsuppressed 35 ms TE water area in the same voxel, i.e. the normalized choline ratio, was assessed in all MRS examinations. For both TEs, the choline ratio increased after irradiation, followed by a decrease and a renewed increase 12 days after irradiation. In Experiment 1, statistically significant differences at the 0.1 level were observed between the choline ratios at Day 5 and Day 12 (p = 0.068) for short TE and between the ratios at Day 3 and Day 8 (p = 0.05) for long TE. The change in choline ratio was in accordance with the tumor necrotic fraction (NF) found in histological analyses. Principal component analysis (PCA) revealed a correlation between the score values of ex vivo HR-MAS MR spectra and necrosis. This suggests a correlation between ex vivo and in vivo MRS. In both experiments, the diffusion in the HT29 xenografts varied during treatment. There was a correlation between the amount of necrosis in tumor and the calculated apparent diffusion coefficient (ADC) obtained from DW-MRI examinations. In Experiment 1, statistically significant differences at the 0.1 level were observed between the ADCs at Day 3 and Day 5 (p = 0.05), between Day 5 and Day 12 (p = 0.068), and between Day 8 and Day 12 (p = 0.068). The HT29 xenografts responded to treatment with an initial increase of necrosis due to the short-term effect of treatment, stimulating development of fibrosis. In accordance to the change in choline and ADC, the level of necrosis increased 8 - 12 days after start of treatment, which might correspond to the long-term effect of treatment. The findings in this work shows that in vivo MRS and DW-MRI can be used for non-invasive monitoring of treatment response in an experimental tumor model. This suggests that in vivo MRS and DW-MRI could yield important information about a tumors response to therapy.

Irreversible electroporation is a minimally invasive technique for the non-thermal destruction of cells in a targeted volume of tissue, using brief electric pulses, (~100 µs long) delivered through electrodes placed into or around the targeted region. These electric pulses destabilize the integrity of the cell membrane, resulting in the creation of nanoscale defects that increase a cell’s permeability to exchange with its environment. When the energy of the pulses is high enough, the cell cannot recover from these effects and dies in a non-thermal manner that does not damage neighboring structures, including the extracellular matrix. IRE has been shown to spare the major vasculature, myelin sheaths, and other supporting tissues, permitting its use in proximity to these vital structures. This technique has been proposed to be harnessed as an advantageous non-thermal focal ablation technique for diseased tissues, including tumors. IRE electric pulses may be delivered through small (ø ≈ 1 mm) needle electrodes, making treatments minimally invasive and easy to apply. There is sub-millimeter demarcation between treated and unaffected cells, which may be correlated with the electric field to which the tissue is exposed, enabling numerical predictions to facilitate treatment planning. Immediate changes in the cellular and tissue structure allow real-time monitoring of affected volumes with imaging techniques such as computed tomography, magnetic resonance imaging, electrical impedance tomography, or ultrasound. The ability to kill tumor cells has been shown to be independent of a functioning immune system, though an immune response seems to be promoted by the ablation. Treatments are unaltered by blood flow and the electric pulses may be administered quickly (~ 5 min). Recently, safety and case studies using IRE for tumor therapy in animal and human patients have shown promising results. Apart from these new studies, previous work with IRE has involved studies in healthy tissues and small cutaneous experimental tumors. As a result, there remain significant differences that must be considered when translating this ablation technique towards a successful and reliable therapeutic option for patients. The dissertation work presented here is designed to develop irreversible electroporation into a robust, clinically viable treatment modality for targeted regions of diseased tissue, with an emphasis on tumors. This includes examining and creating proving the efficacy for IRE therapy when presented with the many complexities that present themselves in real-world clinical patient therapies, including heterogeneous environments, large and irregular tumor geometries, and dynamic tissue properties resulting from treatment. The impact of these factors were theoretically tested using preliminary in vitro work and numerical modeling to determine the feasibility of IRE therapy in heterogeneous systems. The feasibility of use was validated in vivo with the successful treatment of human mammary carcinomas orthotopically implanted in the mammary fat pad of mice using a simple, single needle electrode design easily translatable to clinical environments. Following preliminary theoretical and experimental work, this dissertation considers the most effective and accurate treatment planning strategies for developing optimal therapeutic outcomes. It also experimentally characterizes the dynamic changes in tissue properties that result from the effects of IRE therapy using ex vivo porcine renal cortical tissue and incorporates these into a revised treatment planning model. The ability to use the developments from this earlier work is empirically tested in the treatment of a large sarcoma in a canine patient that was surgically unresectable due to its proximity to critical arteries and the sciatic nerve. The tumor was a large and irregular shape, located in a heterogeneous environment. Treatment planning was performed and the therapy carried out, ultimately resulting in the patient being in complete remission for 14 months at the time of composing this work. The work presented in this dissertation finishes by examining potential supplements to enhance IRE therapy, including the presence of an inherent tumor-specific patient immune response and the addition of adjuvant therapeutic modalities.
Ph. D.

Le trouble obsessionnel compulsif (TOC) est une pathologie psychiatrique fréquente dont la chronicité et la sévérité constituent un véritable problème de santé publique. Son traitement pharmacologique repose sur une prescription empirique d’antidépresseurs sérotoninergiques dont l’efficacité est incertaine puisque 40 à 60% des patients répondent partiellement à ce traitement et peuvent développer des effets indésirables. Les données de la littérature prospectives sur la spécification neurobiologique, clinique et thérapeutique des patients résistants sont limitées. Ceci nous a amenés à effectuer quatre études cliniques et une méta-analyse. L’objectif était de caractériser cliniquement et génétiquement les patients présentant un TOC résistant et de proposer une prise en charge spécifique et personnalisée à ces patients par différentes techniques de neuro-modulation non invasives.La première étude a consisté à identifier des facteurs cliniques et génétiques prédictifs de la réponse à l’escitalopram après 12 semaines de traitement chez 69 patients souffrant d’un TOC. Nous avons identifié sur le plan clinique un lien entre l’aspect dimensionnelle du TOC et la réponse. Dans cette étude, 70 % des patients ont présenté une amélioration partielle des symptômes. Pour ces patients résistants, nous avons proposé trois techniques de neurostimulation non invasives et avons choisi comme cible l’aire motrice supplémentaire (SMA) du fait de son impact fonctionnel associé à son hyperexcitabilité dans le TOC et de sa localisation. Dans une seconde étude, nous avons testé l’efficacité d’une prise en charge par stimulation magnétique transcranienne répétitive (rTMS) basse fréquence au niveau de la SMA dans le cadre d’un essai clinique contrôlé randomisé en double aveugle. Les résultats négatifs de cette approche nous ont amené à réaliser une méta-analyse ayant pour objectif d’évaluer particulièrement l’intérêt de la rTMS chez les patients atteints de TOC résistant. Les données de cette méta-analyse sont en faveur de la rTMS active. Nous avons ensuite testé un nouveau paradigme : la stimulation par Theta Burst continue au niveau de la SMA. Cette troisième étude contrôlée randomisée en double aveugle n’a pas montré son efficacité dans la prise en charge du TOC résistant. Enfin, dans une quatrième étude, nous avons testé l’efficacité d’une prise en charge par stimulation transcranienne directe à courant continu avec la cathode au niveau de la SMA et l’anode au niveau du cortex orbitofrontal droit. Les résultats de cette étude pilote sont encourageants mais nécessitent d’être confirmés.Les résultats de ce travail ont été confrontés aux données de la littérature afin d’orienter les recherches futures sur la détermination des facteurs cliniques (principalement au travers de l’aspect dimensionnel) et génétiques prédictifs de la réponse. Il s’agira également de proposer des alternatives méthodologiques et neurophysiologiques dans l’utilisation des techniques de neurostimulations non invasives afin d’améliorer leur usage plus particulièrement chez les patients résistants
Obsessive compulsive disorder (OCD) is a common psychiatric condition whose chronicity and severity are a real public health problem. Its pharmacological treatment is based on an empirical prescription of serotonergic antidepressants, the efficacy of which is uncertain since 40 to 60% of patients partially respond to this treatment and may develop adverse effects. Prospective data available in the literature on the neurobiological, clinical and therapeutic specification of resistant patients are limited. This has led us to conduct four clinical studies and one meta-analysis. The objective was to clinically and genetically characterize patients with resistant OCD and to propose a specific and personalized management to these patients by different non-invasive neuro-modulation techniques.The first study consisted of identifying clinical and genetic factors predictive of response to escitalopram after 12 weeks of treatment in 69 patients with OCD. We have identified a clinical link between the dimensional aspect of OCD and response. At the end of this study, 70% of patients showed a partial symptoms improvement. For these resistant patients, we proposed three non-invasive neurostimulation techniques and chose as a target the supplementary motor area (SMA) based on its functional impact associated with its hyperexcitability in OCD and its location. In a second study, we tested the efficacy of low-frequency, repetitive transcranial magnetic stimulation (rTMS) over the SMA in a double-blind, randomized, controlled clinical trial. The negative results of this approach led us to carry out a meta-analysis to specifically evaluate the value of rTMS in patients with resistant OCD. The data from this meta-analysis support active rTMS. We then tested a new paradigm: continues Theta Burst stimulation over the SMA. This third double-blind, randomized controlled trial did not show efficacy in the management of resistant OCD. Finally, in a fouth trial, we tested the efficacy of direct transcranial current stimulation with the cathode over the SMA and the anode over the right orbitofrontal cortex. The results of this pilot study are encouraging but need to be confirmed.The results of this work were compared with data from the literature in order to guide future research on the determination of clinical (mainly through the dimensional aspect) and genetic predictive factors of response. We also propose methodological and neurophysiological alternatives in the use of non-invasive neurostimulation techniques in order to improve their use, particularly in resistant patients

La peri-implantite (PI) è una grave patologia che interessa tessuti peri-implantari molli e duri. Ad oggi, la prevenzione è l’unico mezzo per contrastarla. Recentemente, è stata sperimentata una terapia basata sulla somministrazione di corrente elettrica a radio frequenza (successo: 81%). Il trattamento è stato simulato numericamente, fornendo le distribuzioni di corrente (EC) e campo elettrico (EF) nei tessuti: l’effetto anti-infiammatorio è attribuibile alla EC, quello di rigenerazione ossea al EF. Sono state considerate le misure di bioimpedenza (BM) per individuare le infiammazioni; numericamente si sono osservati cambiamenti nel modulo di impedenza del 4-20% (secondo diversi parametri), anche più alti sperimentalmente (35% infiammazione, 56% PI). Le BM permettono quindi di identificare il tessuto da trattare. Per la ripetibilità, sono state considerate radici di denti naturali, numericamente e sperimentalmente; l’ordine di grandezza è lo stesso (qualche kΩ), anche se ci sono differenze legate alle condizioni di misura. La variabilità intra-soggetto è il 10% in uno stesso giorno, fino al 26% in giorni diversi; quella inter-soggetto è più alta. La sicurezza elettrica è stata attentamente esaminata e si sono individuate le direttive applicabili (IEC 60601-1, 60601-1-2 and 60601-2-2). Sono stati fatti test in vitro per valutare l’effetto della terapia sulla vitalità cellulare: non c’è un significativo aumento della necrosi (vitalità: 85% test, 94% controlli), l’effetto negativo principale è l’apoptosi. Sono stati numericamente indagati possibili effetti termici: non sono stati individuati riscaldamenti nocivi dei tessuti. Si è progettato un nuovo dispositivo (PeriCare®) per trattare la PI, con parti diagnostica (BM) e terapeutica. Si stanno progettando elettrodi specifici e realizzando il prototipo. Si sta compilando il fascicolo tecnico e pianificando i test di conformità, in vista della certificazione. Il dispositivo medico dovrebbe entrare nel mercato entro l’anno.
Peri-implantitis is a severe disease affecting hard and soft peri-implant tissues. At present, prevention is the only means to contrast it. Recently, a therapy based on the administration of radio frequency electric current was experimented (success rate: 81%). The treatment was numerically simulated, providing the electric current (EC) and field (EF) distributions in peri-implant tissues: the anti-inflammatory effect can be associated to EC, the bone regeneration to the EF. Bioimpedance measurements (BM) were investigated to detect inflammation; changes in the measured impedance modulus are equal to 4-20% (depending on different parameters) from numerical results, also more evident experimentally (35% inflammation, 56% peri-implantitis). So, BM could allow to detect the tissue to be treated. To evaluate the repeatability, natural tooth roots were numerically and experimentally measured; the order of magnitude is the same (some kΩ), even if there are differences probably due to the measurement conditions. Intra-subject variability was of 10% in the same day, but up to 26% in different days; inter-subject variability was higher. The electrical safety was accurately taken into account. The applicable directives were individuated (IEC 60601-1, 60601-1-2 and 60601-2-2). In vitro tests were carried out to evaluate the effect of the therapy on cell vitality: there is not a significant increase in necrosis (vitality: 85% tests, 94% controls), the main negative effect is apoptosis. Possible thermal effects were numerically investigated: no dangerous tissue heating was observed. A new device for the peri-implantitis treatment, PeriCare®, was designed, with diagnostic (BM) and therapeutic parts. Proper electrodes are being designed and the prototype is being realized. The technical file is being compiled and the conformity verification tests are being planned towards the certification process. Hopefully, the medical device will be placed into the market within this year.

Les ultrasons focalisés de haute intensité (HIFU) sont reconnus et couramment utilisés dans le domaine médical pour le traitement des tumeurs solides. Cette technique permet une destruction localisée des tissus biologiques par élévation de la température. Ce manuscrit décrit la conception et l’utilisation d’un système thérapeutique et d’une nouvelle solution de focalisation brevetée, ayant pour objectif principal le traitement non invasif des adénocarcinomes mammaires. Dans un premier temps, un dispositif existant destiné au traitement surfacique des métastases hépatiques et en cours d’évaluation clinique a été utilisé. Une étude ex vivo sur échantillons humains de tissu mammaire a permis de montrer la possibilité de déposer de la pression en profondeur de façon non invasive. Basé sur cette étude, le développement d’une nouvelle modalité de focalisation a été entrepris dans le but d’élargir le volume traité sans impliquer des temps de traitement supérieur à la minute et des déplacements mécaniques du dispositif. Cette modalité a permis d’augmenter de 30 % le volume traité par le dispositif existant sans augmenter le temps de traitement. Compte tenu des limites du dispositif existant et de la nouvelle solution à intégrer, un nouveau dispositif a été conçu et fabriqué dans le but de répondre aux besoins des traitements des adénocarcinomes mammaires. La focalisation naturelle de ce transducteur permet de déposer de la pression en profondeur. Si la nouvelle modalité de focalisation électronique est utilisée, un champ de pression élargi est émis, permettant ainsi d’augmenter le volume de traitement. Les performances de cette sonde de traitement ont été évaluées numériquement puis validées lors d’expérimentations préliminaires in vitro sur des tissus hépatiques et lors d’une étude ex vivo sur des échantillons humains de tissu mammaire. Ces travaux représentent la première étape de l’élaboration d’un traitement HIFU pour traiter les adénocarcinomes mammaires avec un dispositif HIFU non-invasif, guidé par échographie et utilisable manuellement
High Intensity Focused Ultrasound (HIFU) is a technique commonly used in the medical field for the treatment of solid tumors. This therapeutic strategy allows for the localized destruction of biological tissue by temperature elevation. This manuscript describes the design and utilization of a therapeutic system and a novel, patented focalization technique for non-invasive treatment of mammary adenocarcinomas. In a first instance, an existing device that has been previously used for intraoperative treatment of hepatic metastases, and one that is currently undergoing clinical trials, was used. An ex vivo study on human mammary samples demonstrated the possibility of applying pressures on deep tissue layers in a non-invasive manner. Based on this study, the development of a new focalization modality was developed to provide larger treated volumes while yielding treatment times under a minute and eliminating the need for mechanical steering of the device. This new modality provided treated volumes 30% larger than those produced by the existing device with no changes to treatment time. Given the limitations of the existing device, in addition to the need of integrating the new focalization strategy, a new device was designed and specifically fabricated to meet the demands for treating mammary adenocarcinomas. The natural focalization of this novel transducer allows for depositing pressure deep in tissue. When the new focalization modality is used, a larger pressure field produces increased treated volumes. The performance provided by the novel probe was first characterized through modeling studies. These results were then validated through preliminary in vitro studies on hepatic tissues as well as in ex vivo studies on human mammary tissue samples. This work represents the first stage of development of a HIFU treatment for mammary adenocarcinomas using a novel, non-invasive and image-guided HIFU device that can be used manually

Non Alcoholic Fatty Liver Disease (NAFLD) is a worldwide increasing disease but still many questions about its evolution, the need of a screening and the availability of effective specific treatments are open. Aims of this PhD project were: 1) the evaluation of NAFLD natural history in a subgroup of NAFLD affected diabetic patients enrolled during the daily clinical activity of a splenohepatology ecoDoppler laboratory in order to identify, if present, predictive factors of “evolutive NAFLD”; 2) the experimental evaluation, in High Fat Diet (HFD) fed rats, of the potential therapeutic effect of 3 molecules targeting respectively: a) lipid metabolism (Apolipoprotein A analogue compound -L4F), b) insulin sensitivity (peroxisome proliferator activated receptor delta agonist –PPARd agonist) c) endothelial function (EET Analog). We developed two studies: a clinical observational study and an experimental study. Clinical study: 100 patients with type 2 diabetes were evaluated as far as steatosis is concerned. Among them, 80 had sonographic signs of steatosis. There was no difference in the prevalence between male and female patients. 21 type 2 diabetic patients with liver steatosis were reevaluated after 6 years without any specific treatment. Liver steatosis increases only in less than 1/3 of non-obese diabetic patients and demonstrates that in the majority of them sonographic degree of steatosis improves or recovers concurrently with biohumoral parameters. The presence of increased levels of serum AST and ferritin and lower pulsatility index of haepatic artery seems to be correlated to a worse prognosis and may be used to identify those patients who deserve a higher surveillance. Experimental study: 30 male Wistar rats (4-5 weeks old, 150 grams body weight) were purchased from Charles River Laboratories. 24 rats have been fed with HFD for 8 weeks. After 8 weeks of diet animals have been divided in 4 groups: 7 untreated (HFD); 7 treated with L4F (L4F), 7 treated with PPARd agonist (PPARd) and 3 treated with EET Analog (EET). Treatments lasted 6 weeks. We demonstrate that HFD induced NAFLD reproduces splanchnic haemodynamic alteration of liver steatosis in humans and shows an activation of innate immune system also at early degree of steatosis without hepatic inflammation and fibrosis. The activation of innate immune system can be evaluated by the analysis of lipopolysaccharide (LPS) stimulated/unstimulated CC motif chemockine ligand 2 (CCL2) production in cultured peripheral blood mononuclear cells (PBMCs). PPARd agonist and L4F improved HFD induced liver steatosis and reduced CCL2 production in PBMCs but preserved the ability of PBMCs to react to LPS stimulation EETA administration didn’t improved liver steatosis and further decreased portal vein velocity and reduced the ability of PBMCs to react to LPS stimulation.

Background: Although the negative impact of sleep apnea on the clinical course of acute ischemic stroke (AIS) is well known, data regarding non-invasive ventilation in acute patients are scarce. Several studies have shown its tolerability and safety, yet no controlled randomized sequential phase studies exist that aim to establish the efficacy of early non-invasive ventilation in AIS patients. Methods/design: We decided to examine our hypothesis that early non-invasive ventilation with auto-titrating bilevel positive airway pressure (auto-BPAP) positively affects short-term clinical outcomes in AIS patients. We perform a multicenter, prospective, randomized, controlled, third rater- blinded, parallel-group trial. Patients with AIS with proximal arterial obstruction and clinically suspected sleep apnea will be randomized to standard stroke care alone or standard stroke care plus auto-BPAP. Auto-BPAP will be initiated within 24 hours of stroke onset and performed for a maximum of 48 hours during diurnal and nocturnal sleep. Patients will undergo unattended cardiorespiratory polygraphy between days three and five to assess sleep apnea. Our primary endpoint will be any early neurological improvement on the NIHSS at 72 hours from randomization. Safety, tolerability, short-term and three-months functional outcomes will be assessed as secondary endpoints by un-blinded and blinded observers respectively. Discussion: We expect that this study will advance our understanding of how early treatment with non-invasive ventilation can counterbalance, or possibly reverse, the deleterious effects of sleep apnea in the acute phase of ischemic stroke. The study will provide preliminary data to power a subsequent phase III study.

Background: Although the negative impact of sleep apnea on the clinical course of acute ischemic stroke (AIS) is well known, data regarding non-invasive ventilation in acute patients are scarce. Several studies have shown its tolerability and safety, yet no controlled randomized sequential phase studies exist that aim to establish the efficacy of early non-invasive ventilation in AIS patients. Methods/design: We decided to examine our hypothesis that early non-invasive ventilation with auto-titrating bilevel positive airway pressure (auto-BPAP) positively affects short-term clinical outcomes in AIS patients. We perform a multicenter, prospective, randomized, controlled, third rater- blinded, parallel-group trial. Patients with AIS with proximal arterial obstruction and clinically suspected sleep apnea will be randomized to standard stroke care alone or standard stroke care plus auto-BPAP. Auto-BPAP will be initiated within 24 hours of stroke onset and performed for a maximum of 48 hours during diurnal and nocturnal sleep. Patients will undergo unattended cardiorespiratory polygraphy between days three and five to assess sleep apnea. Our primary endpoint will be any early neurological improvement on the NIHSS at 72 hours from randomization. Safety, tolerability, short-term and three-months functional outcomes will be assessed as secondary endpoints by un-blinded and blinded observers respectively. Discussion: We expect that this study will advance our understanding of how early treatment with non-invasive ventilation can counterbalance, or possibly reverse, the deleterious effects of sleep apnea in the acute phase of ischemic stroke. The study will provide preliminary data to power a subsequent phase III study.

Pas de résumé en français
Primary central nervous system lymphomas (PCNSL) are very aggressive malignancies with poor survival rate even with treatments (survival median is 44 months). This disease affects immune cells (lymphocytes) and forms diffuse and non-surgically removable tumor in the central nervous system. High-dose chemotherapy and radiotherapy are the common treatments with severe side effects. New therapeutic approaches are required for increasing treatment efficiency. We focused on primary intraocular lymphomas (PIOL) and primary cerebral lymphomas (PCL), which are subtypes of PCNSL. PIOL and PCL cells have a high propensity to migrate and form metastases in the brain and in the controlateral eye in the case of PIOL, and in the eye in the PCL case. However, metastatic dissemation mechanisms remain unclear. The objective of the present work was to study the effects of innovative treatments of B-cell lymphoma on primary tumor, on metastases, and on circulating tumor cells in PIOL and PCL immunocompetent syngeneic murine models of lymphomas using non-invasive in vivo imaging methods. We studied the effects of Ublituximab, a glycoengineered anti-CD20 monoclonal antibody (mAb), and CpG-ODN, a TLR-9 agonist, in mouse models. We showed that Ublituximab exhibits significant anti-tumor effect in PIOL and PCL, while CpG showed significant anti-tumor effect in PCL. We monitored the tumor burden and metastases using innovating non-invasive optical imaging or cell detection methods: bioluminescence imaging (BLI) and in vivo flow cytometer (IVFC). BLI was used to locate metastasis and to quantify tumor burden. We indeed developed a bioluminescence-based tumor burden quantification method that reduces user-dependence, allows comparisons between experiments, reveals statistical relevance, and which is easy to use. An IVFC device was set up to investigate the role of circulating tumor cells (CTCs) in PIOL and PCL. This fluorescence-based technique allows detection of CTCs by analyzing the cells flowing in blood vessels. However we had to overcome the problem of autofluorescence and tissue absorption. Two approaches were studied in parallel: a elaborating new cell line expressing far red fluorescent proteins, modulating the excitation light of an IVFC device to give the cell a unique signature therefore enhancing sensitivity, increasing signal to noise ratio. The modulated excitation IVFC allowed us to calculate the velocity of cells, and infer their position in blood vessel phantoms. The analysis of treatment effects on tumor burden, metastases and CTCs in PIOL and PCL could help understanding lymphoma metastatic dissemination and contribute to treatment follow-up, thus allowing design of new therapeutic approaches with increased efficacy

Les levures du genre Candida figurent parmi les pathogènes majeurs isolés chez les patients en soins intensifs et sont responsables d'infections systémiques : les candidoses invasives. Le retard et le manque de fiabilité du diagnostic sont susceptibles d'aggraver l'état du patient et d'augmenter le risque de décès à court terme. Pour respecter les objectifs de traitement, les experts recommandent de traiter le plus précocement possible les patients à haut risque de candidose invasive. Cette attitude permet de proposer un traitement précoce aux malades atteints, mais peut entraîner un traitement inutile et coûteux et favoriser l'émergence de souches de moindre sensibilité aux antifongiques utilisés.Ce travail applique des méthodes statistiques modernes à des données observationnelles longitudinales. Il étudie l'impact des traitements antifongiques systémiques sur la répartition des quatre principales espèces de Candida dans les différents prélèvements de patients en réanimation médicale, sur leur sensibilité à ces antifongiques, sur le diagnostic des candidémies ainsi que sur le pronostic des patients. Les analyses de séries de données temporelles à l'aide de modèles ARIMA (moyenne mobile autorégressive intégrée) ont confirmé l'impact négatif de l'utilisation des antifongiques sur la sensibilité des principales espèces de Candida ainsi que la modification de leur répartition sur une période de dix ans. L'utilisation de modèles hiérarchiques sur données répétées a montré que le traitement influence négativement la détection des levures et augmente le délai de positivité des hémocultures dans le diagnostic des candidémies. Enfin, l'utilisation des méthodes d'inférence causale a montré qu'un traitement antifongique préventif n'a pas d'impact sur le pronostic des patients non neutropéniques, non transplantés et qu'il est possible de commencer une désescalade précoce du traitement antifongique entre le premier et le cinquième jour après son initiation sans aggraver le pronostic
Candida species are among the main pathogens isolated from patients in intensive care units (ICUs) and are responsible for a serious systemic infection: invasive candidiasis. A late and unreliable diagnosis of invasive candidiasis aggravates the patient's status and increases the risk of short-term death. The current guidelines recommend an early treatment of patients with high risks of invasive candidiasis, even in absence of documented fungal infection. However, increased antifungal drug consumption is correlated with increased costs and the emergence of drug resistance whereas there is yet no consensus about the benefits of the probabilistic antifungal treatment.The present work used modern statistical methods on longitudinal observational data. It investigated the impact of systemic antifungal treatment (SAT) on the distribution of the four Candida species most frequently isolated from ICU patients', their susceptibilities to SATs, the diagnosis of candidemia, and the prognosis of ICU patients. The use of autoregressive integrated moving average (ARIMA) models for time series confirmed the negative impact of SAT use on the susceptibilities of the four Candida species and on their relative distribution over a ten-year period. Hierarchical models for repeated measures showed that SAT has a negative impact on the diagnosis of candidemia: it decreases the rate of positive blood cultures and increases the time to positivity of these cultures. Finally, the use of causal inference models showed that early SAT has no impact on non-neutropenic, non-transplanted patient prognosis and that SAT de-escalation within 5 days after its initiation in critically ill patients is safe and does not influence the prognosis

Laser e Braquiterapia Vaginal apresentaram uma Taxa de Cura (TC) máxima de 93% e 100%, respetivamente, com uma Taxa de Persistência (TP) significativa até 100% e uma Taxa de Recorrência (TR) de 0-59%. Laser tem poucas complicações e é indicado para mulheres sexualmente ativas. Braquiterapia, devido à sua toxicidade, deve ser reservada para lesões de alto grau e refratárias. Imiquimod e 5-Flouorouracil revelaram uma TC de 25-82%, TP 26-75%, TR de 6-94% e são indicados em lesões multifocais. O tratamento conservador tem uma TC de 44-60% com uma TP e TR até 50%. Ao contrário das lesões de baixo grau, as lesões de alto grau requerem tratamento que deve ser selecionado de acordo com as caraterísticas das lesões e dos pacientes.
Laser and Vaginal Brachytherapy showed a maximum 93% and 100% Cure Rate (CR), respectively, with a significant Persistence Rate (PR) up to 100% and 0-59% Recurrence Rate (RR). Laser has few complications and is indicated for sexually active women. Brachytherapy, due to toxicity, should be reserved for high-grade and refractory lesions. Imiquimod and 5-Flouorouracil revealed a 25-82% CR, 26-75% PR, 6-94% RR and are indicated in multifocal lesions. Expectant management has 44-60% CR with PR and RR up to 50%. In contrast to low-grade lesions, high-grade lesions require treatment which should be selected depending on its characteristics and the patient's.

Laser e Braquiterapia Vaginal apresentaram uma Taxa de Cura (TC) máxima de 93% e 100%, respetivamente, com uma Taxa de Persistência (TP) significativa até 100% e uma Taxa de Recorrência (TR) de 0-59%. Laser tem poucas complicações e é indicado para mulheres sexualmente ativas. Braquiterapia, devido à sua toxicidade, deve ser reservada para lesões de alto grau e refratárias. Imiquimod e 5-Flouorouracil revelaram uma TC de 25-82%, TP 26-75%, TR de 6-94% e são indicados em lesões multifocais. O tratamento conservador tem uma TC de 44-60% com uma TP e TR até 50%. Ao contrário das lesões de baixo grau, as lesões de alto grau requerem tratamento que deve ser selecionado de acordo com as caraterísticas das lesões e dos pacientes.
Laser and Vaginal Brachytherapy showed a maximum 93% and 100% Cure Rate (CR), respectively, with a significant Persistence Rate (PR) up to 100% and 0-59% Recurrence Rate (RR). Laser has few complications and is indicated for sexually active women. Brachytherapy, due to toxicity, should be reserved for high-grade and refractory lesions. Imiquimod and 5-Flouorouracil revealed a 25-82% CR, 26-75% PR, 6-94% RR and are indicated in multifocal lesions. Expectant management has 44-60% CR with PR and RR up to 50%. In contrast to low-grade lesions, high-grade lesions require treatment which should be selected depending on its characteristics and the patient's.

The research project, Generative Soundscapes for Enhanced Engagement in Non-Invasive Neurorehabilitation, focuses on the incorporation of multimedia technologies in the form of a generative soundscape in a traditional restorative treatment method for cognitive impairments to improve engagement rate, well-being and user experience of the patients. It utilizes the currently developed engagement framework and protocols to create a sound based intervention and expand the effectiveness of neurorehabilitation treatment. The associated experiment will contrast the fundamental treatment method with a mirrored experience strengthened through added multimedia technology to analyze how engaged the patient was and how the additional sound based multimedia element improved their willingness to participate. Ultimately, the research aims to assess the impact of a possibly heightened engagement rate in patients through the incorporation of multimedia technologies as an adjunction to traditional treatment methods and promote a more comfortable experience during treatment.

The research project, Generative Soundscapes for Enhanced Engagement in Non-Invasive Neurorehabilitation, focuses on the incorporation of multimedia technologies in the form of a generative soundscape in a traditional restorative treatment method for cognitive impairments to improve engagement rate, well-being and user experience of the patients. It utilizes the currently developed engagement framework and protocols to create a sound based intervention and expand the effectiveness of neurorehabilitation treatment. The associated experiment will contrast the fundamental treatment method with a mirrored experience strengthened through added multimedia technology to analyze how engaged the patient was and how the additional sound based multimedia element improved their willingness to participate. Ultimately, the research aims to assess the impact of a possibly heightened engagement rate in patients through the incorporation of multimedia technologies as an adjunction to traditional treatment methods and promote a more comfortable experience during treatment.

Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library.
Mucositis is a common side-effect of chemotherapy, which is characterised by ulceration to the epithelium lining of the gastrointestinal tract. Recently, a non-invasive breath test, the ¹³C-sucrose breath test (SBT), has been developed and applied as a biomarker to detect small intestinal damage associated with methotexate (MTX)-induced mucositis in rats. This thesis extended this work, and concluded that the non-invasive SBT is a biomarker of small intestinal function that can be applied easily and cost-effectively, in both animals and humans, to monitor gut function in relation to chemotherapy agents and/or potential anti-mucositis treatments. This thesis has illustrated the important application of the SBT in the arena of supportive cancer care, where new chemotherapy and anti-mucositis agents can be assessed in relation to small intestinal toxicity.
http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1277572
Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

One treatment modality for atrial fibrillation, the most common cardiac arrhythmia, is radiofrequency catheter ablation in which fibrotic tissue is created around the pulmonary veins. The procedure has major drawbacks, hence a new treatment modality would be beneficial. This is the first in silico study for the feasibility of a non-invasive treatment of atrial fibrillation with scanned ion beams, which are successfully used in cancer radiotherapy. In collaboration with the Mayo Clinic (Rochester, Minnesota, USA) the first comparison between different irradiation techniques to cardiac target volumes was carried out in this work. In the presented results it was shown that the dose deposition to organs at risk could be drastically reduced compared to a potential non-invasive treatment of atrial fibrillation with photons. As a result of the actively applied ion beam, interference effects were observed when irradiating the moving cardiac volumes. The motion influences of respiration and heartbeat were studied individually and the resulting displacement was examined. To achieve a homogenous dose deposition in the moving target volumes, motion mitigation techniques (gating and rescanning) were successfully applied. The results will be validated in animal experiments at GSI in 2014.

Submitted in partial compliance with the requirements for the Master’s Degree in Technology: Chiropractic, Durban University of Technology, 2014.
Background: Myofascial Pain and Dysfunction (MPD) is a diagnosis commonly encountered by practitioners, hence, there are several treatment approaches employed by various practicing physicians. Practitioners are required to perform evidence-based protocols on patients; however, such intervention becomes increasingly difficult with the increasing volume of evidence available with regards to treatment of MPD. A systematic review provides a well-structured, critical analysis of the available protocols, and as such, provides practitioners with an evidence-based summary of the available modalities and the effectiveness of these modalities. Thus, the aim of the study was to systematically review and evaluate the literature to determine the effects of various non-invasive modalities on MPD. Objectives: Studies investigating various non-invasive modalities were identified, evaluated against the inclusion criteria and then reviewed against PEDro criteria to present current available evidence regarding their effectiveness as a source of treatment for MPD. Methods: A literature search was conducted, based on key terms including: active and latent myofascial trigger points, manual therapy, manipulation, acupressure, massage, muscle stretching, ultrasound, transcutaneous electric nerve stimulation, electric stimulation therapy, magnetic field therapy, and exercise therapy. Databases searched were: PubMed, EBSCOhost, Medline, CINAL, Proquest, Health Source, Sport Discus, Science Direct, Springer Link, Google Scholar and Summons. The articles were screened according to inclusion and exclusion criteria, after which a secondary hand and reference searches were performed. Thereafter, the articles were reviewed by four independent reviewers and the researcher. The PEDro Scale was used to determine methodological rigor of the included studies. The results were then analysed and ranked. Results: Following the screening process during data collection for this study, a total of 25 studies were identified and included. The review and ranking of these studies revealed a moderate level of evidence present for the effectiveness of Topical Agents. A limited level of evidence was noted for TENS, Ischemic Compression, Ultrasound, Laser and Other Modalities. Approximately 25% of the reviewed studies involved combination therapies; hence their outcomes cannot be applied to the effectiveness of individual modalities. Conclusion: Upon comparison of the quality of evidence available for the various types of modalities present for the treatment of MPD, it was noted that Topical Agents were supported by a stronger level of evidence than TENS, Ischeamic Compression, Ultrasound, Laser and Other Modalities. However, due to a lack of strong overall evidence for any of these modalities it has been concluded that more research is required to establish which modality is in fact the most effective.

Han, Jinghao.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2007.
Includes bibliographical references (p. 182-204).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.

Tese de mestrado, Ciência Cognitiva, Universidade de Lisboa, Faculdade de Ciências, Faculdade de Letras, Faculdade de Medicina, Faculdade de Psicologia, 2010
Esta dissertação foi desenvolvida no contexto do estudo científico da emoção, e foca a modulação de estados afectivos através de estímulos perceptuais. O progresso deste trabalho foi guiado por dois objectivos principais: primeiro, o desenvolvimento do sistema Affective Multimodal Data Base (AMDB), uma ferramenta para indução de estados afectivos; e segundo, a realização de um estudo empírico, utilizando o AMDB, com o objectivo de examinar a modulação de padrões de respostas afectivas em pessoas que sofrem de enxaqueca com aura. O sistema AMDB é uma plataforma de software para a geração de estímulos afectivos através da combinação de sons, imagens estáticas e vídeos a ser utilizados em contextos de indução de estados afectivos. Contribuições deste mestrado para o desenvolvimento do AMDB incluem a adição de um interface gráfico para o utilizador, a implementação de apresentação de estímulos e gravação de respostas fisiológicas de forma sincronizada, melhoramentos na implementação modular do sistema, e por fim, a realização de um primeiro caso de teste do AMDB. A decisão de focar o estudo empírico, desenvolvido dentro do âmbito deste trabalho, na patologia da enxaqueca foi motivada pelo facto desta ser muito difundida e apresentar relações claras com os mecanismos de emoção. Os resultados deste estudo sugerem um perfil afectivo específico às pessoas que sofrem de enxaqueca com aura caracterizado por susceptibilidade intensificada a estímulos desagradáveis, potenciação de estados afectivos negativos em situações de repetida exposição a estímulos neutros ou desagradáveis, e disposição aumentada para a interrupção de estados afectivos positivos na presença de estímulos ambientais de cariz emocional neutro ou desagradável. Este estudo espera contribuir para a compreensão dos padrões de respostas afectivas específicos na patologia da enxaqueca, servindo como ponto de partida para o design de abordagens terapêuticas baseadas na modulação de estados afectivos.
This thesis was developed in the context of the scientific study of emotion, and focuses on the modulation of affective states through perceptual stimuli. Two goals were pursued during the course of this master project. Firstly, the development of the Affective Multimodal Data Base (AMDB) system, a tool for multimodal emotion induction, and secondly, to conduct an empirical study, using the AMDB, that aimed at probing the modulation of affective response patterns in migraineurs. The AMDB system is a software platform for generating affective stimuli by combining sounds, pictures and videos, available in normalized affective stimuli libraries, into multimodal stimuli sequences to be used in emotion induction scenarios. Contributions of this master project to the development of the AMDB system include the addition of a graphical-user-interface, implementation of synchronized stimuli presentation and physiology response recording, improvement in the modular implementation of the system, and finally, realization of the first test-case of the AMDB system. It was decided to focus the empirical study on migraine, because it is a widespread pathology that presents a clear link with emotion mechanisms. The empirical study aimed at investigating dynamic patterns of affective responsiveness and modulation in migraineurs with aura. The findings from this study suggest an affective profile specific to migraineurs with aura characterized by an enhanced impact of unpleasant stimuli, potentiation of negative affective states when repeatedly exposed to non-pleasant stimuli, and high susceptibility to disrupt positive affective states in the presence of unpleasant and neutral environmental stimuli. This study hopes to contribute to the understanding of affective response patterns specific to migraine, and to provide insights for the design of therapy approaches to migraine based on emotion modulation, that could in the future help migraine sufferers ease the disease burden through the use of accessible media technologies.

This thesis is on non-invasive elastic property measurement of tissue or tissue-mimicking materials through vibro-acoustography and ultrasound assisted diffusing wave spectroscopy (UA-DWS). Towards this, a known force is applied by focused ultrasound beams and the novel measurement is the set of natural frequencies of vibration of the object defined by the focal volume, also called the region-of-interest (ROI). In the first investigation, vibrio-acoustic (VA) secondary waves from the ROI, carrying its resonant modes, reaching the surface of the object, are made use of. A new physical model which explains the transport of local shear waves by modulating the VA wave and using it as a carrier is suggested and demonstrated. Through an eigenvalue analysis of the vibrating ROI (VROI) connection is established between the material properties of the ROI, including Young’s and shear modulus, and the measured resonant modes. The measured first natural frequencies from phantoms made of agar are inverted for their storage moduli, which are verified by simulation and independent measurement using a rheometer. The shift of the natural frequency with temperature is used to calibrate temperature at the ROI in tissue-mimicking objects. Through this, a remote temperature sensor for application in an ultrasound hyperthermia system is demonstrated. In the second investigation, ultrasound-assisted diffusing wave spectroscopy (UA-DWS) is adapted to measure many resonant modes of the ROI. The evolution of mean-squared displacement (MSD) obtained through DWS displays a plateau which becomes noisy with the introduction of ultrasound forcing. It is observed that the power spectrum of the fluctuations contains peaks at locations corresponding to many of the natural frequencies of the VROI. With this measurement of a number of resonant modes, recovery of the anisotropic elastic tensor of the material in the ROI is demonstrated in pork fat. This opens up the possibility of imaging progress of malignancy in soft-tissue organs through the components of this tensor. In the final part of the work, rotational diffusion micro-rheology is demonstrated by doing UA-DWS in agar phantoms using non-spherical scattering centres. The main findings of this study is the sharper rise in the transient part of the MSD curve and in the intensity of noise in its plateau leading to a scaling of the complex modulus of elasticity spectrum when compared those from spherical particles. The reason for these differences is owing to the ability of non-spherical particles to capture phase fluctuations arising of both translation and rotation. The modelling of the dynamics of the ROI was done through a generalized Langevin equation (GLE) for a single predominant translational degree of freedom (DOF) system particle representing the ROI. The fluctuations in the plateau are correctly recovered through a multiplicative, internal noise, constructed using micro-polar theory, in the stiffness term. Possibility of morphological characterization of biological cells and their internal constituents is demonstrated through laboratory experiments in phantoms.

Tese de mestrado integrado em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2017
De acordo com os dados de 2017 da Organização Mundial da Saúde, as doenças cardiovasculares são a principal causa de morte a nível mundial. Se estes tipos de doenças não forem diagnosticadas e tratadas atempadamente, podem levar a insuficiências cardíacas ou outras complicações irreversíveis. As duas doenças cardiovasculares congénitas estudadas neste trabalho são a coarctação aórtica (CoA), caracterizada por uma estenose, habitualmente, na zona do arco da artéria aorta, e a doença da válvula aórtica (AvD), uma malformação ao nível da válvula aórtica. Estas doenças são responsáveis por cerca de 50,000 intervenções por ano. Deste modo, a melhoria métodos de diagnóstico e de intervenção adequados e eficientes é uma prioridade e pode levar ao decréscimo no número das intervenções, bem como reduzir a morbilidade e a mortalidade. A área de imagiologia médica de diagnóstico tem tido uma evolução significativa ao longo dos anos e é de extrema importância nas tentativas de substituição de métodos de diagnóstico invasivos. As imagens médicas são adquiridas e posteriormente processadas e analisadas, com recurso a programas adequados. Atualmente, é possível obter os valores de gradientes de pressão relativa a partir de Ecocardiografia Doppler e Ressonância Magnética. Contudo, os gradientes de pressão medidos no cateterismo cardíaco, o método gold standard para o diagnóstico de CoA e AvD, são gradientes de pressão absoluta. Nesta dissertação desenvolveu-se um método de diagnóstico de CoA e AvD, a partir dos mapas de pressão relativa no estreitamento da aorta e na válvula aórtica, respectivamente. O método matemático desenvolvido tem por base as equações de Poisson, resolvida com a condição de fronteira de Neumann utilizando os métodos de elementos finitos, e a de Navier Stokes para a conservação do momento. O método desenvolvido também tem em conta a informação proveniente da função de Windkessel da artéria aorta, uma artéria distensível. Esta função dá-nos o comportamento da propagação do pulso de pressão com uma velocidade de pulso de propagação. Deste modo, é observado um desfasamento temporal entre as curvas de fluxo da pressão e da velocidade, entre as duas regiões de interesse escolhidas. Deste modo, o método, denominado de Time-shift Corrected Pressure Maps (TCPM, sigla em inglês), permite obter os mapas de pressão absoluta, isto é, mapas de pressão que têm em conta o intervalo de tempo entre os picos de pressão na aorta descendente e ascendente, no caso do primeiro estudo, e antes e depois da válvula aórtica, no caso do segundo estudo. Os pacientes de ambos os estudos tinham indicação clínica para cateterismo cardíaco e foram submetidos a ressonância magnética cardiovascular de contraste de fase em tempo real (4D PC MRI, em inglês), para recolher as imagens ao nível da aorta e da válvula aórtica e os respectivos campos de velocidade da corrente sanguínea. O primeiro estudo tem como objetivo a aplicação do método TCPM a 27 pacientes de CoA (n=16 masculinos, n=11 femininos, faixa etária de 4 a 52 anos, idade média de 20±15 anos). Após aquisição das imagens, estas foram processadas usando programas específicos. Em primeiro lugar foi necessário segmentar a aorta, seguiu-se a seleção das regiões de interesse e, finalmente, a obtenção dos campos de velocidade e dos mapas de pressão relativa entre as duas regiões de interesse selecionadas. Após aplicação do método TCPM, foram aplicados testes estatísticos (correlação, teste t e Bland-Altman) para comparar os valores obtidos a partir de TCPM com os valores obtidos no cateterismo cardíaco. Após processamento das imagens dos 27 pacientes, 6 pacientes foram retirados do estudo. N=3 pacientes foram retirados porque a percentagem de fluxo que passa pelo estreitamento é insuficiente para calcular o gradiente de pressão a partir de TCPM e N=3 pacientes foram retirados porque a aorta não estava inserida por completo no FOV. As medições obtidas a partir de TPCM e cateterismo cardíaco têm uma correlação linear significante (R²=0,90; p<0,001). A partir dos gráficos Bland-Altman é possível verificar uma boa concordância entre as medições de ambos os métodos, com bias de -2,69 mmHg e os limites de concordância de ±4,74 mmHg. O teste de equivalência mostrou uma relação significante entre os métodos (p=0,007). O segundo estudo tem como objetivo a aplicação do método TPCM e o método da Área de Gorlin a 4 pacientes de AvD (n=4 masculinos, faixa etária 17 a 36 anos, idade média 27±7 anos). O método da Área de Gorlin permite obter o gradiente de pressão absoluta a partir da área geométrica da válvula e do fluxo total que passa nessa área. Após a aquisição das imagens, foi feito o processamento das mesmas. Numa primeira fase, as imagens foram segmentadas na região da válvula aórtica. Depois, as imagens segmentadas foram analisadas em dois programas distintos. O primeiro foi utilizado de forma a obter os campos de velocidade e os mapas de pressão relativa entre dois pontos antes e depois da válvula aórtica. O segundo permitiu definir a região da válvula como região de interesse e exportar os valores de velocidade, área, pressão relativa e fluxo absoluto nessa região. Os resultados mostram uma correlação linear significativa entre os valores de cateterismo cardíaco e de TCPM (R²=0,99; p<0,001). Os gráficos de Bland-Altman mostram uma boa concordância entre os valores de TCPM (24,75±22,50 mmHg) e de cateterismo (20,88±19,51 mmHg), com um bias de -3,87 mmHg e limites de concordância de ±3,64 mmHg. Os resultados também sugeriram uma ligeira subestimação dos valores do cateterismo cardíaco a partir do método da Área de Gorlin (14,47±13,00 mmHg), com um bias de 6,41 mmHg e limites de concordância de ±7,15 mmHg. Este estudo foi feito com uma amostra diminuta de 4 pacientes, o que não é suficiente para retirar conclusões com significância. Contudo, foi uma primeira abordagem positiva, que mostra a potencialidade que este método pode vir a apresentar. O método TCPM proposto neste projeto permite a medição não invasiva de gradientes de pressão absoluta a partir de mapas de pressão relativa em pacientes de CoA e AvD. Vários aspectos têm que ser tidos em conta de forma a garantir a eficácia deste método. Por exemplo, as regiões de interesse escolhidas têm que se cuidadosamente selecionadas de forma a serem perpendicular à direção do fluxo naquele local. Só desta maneira é possível obter o fluxo, os campos de velocidade e as pressões relativas corretas. Também, se o raio da estenose for menor que 2 voxéis, a relação sinal-ruído aumenta substancialmente, e a resolução especial da aquisição é insuficiente. Contudo, a aplicação do método TPCM a casos de grande estreitamento não é necessária visto que estes casos já são tipicamente identificados em imagens anatómicas de ressonância magnética e que o paciente segue automaticamente para intervenção quando a área do estreitamente representa cerca de 50% do valor de área típico da aorta. O método não invasivo TCPM apresenta uma boa concordância com o cateterismo cardíaco em termos da medição dos gradientes de pressão em CoA e AvD. Os bias e os limites de concordância entre cateterismo e TCPM foram substancialmente mais pequenos que os bias e os limites de concordância entre cateterismo e ecocardiografia Doppler e entre o cateterismo e o método da Área de Gorlin. Com os resultados apresentados já é possível ver o potencial desta técnica no processo de diagnóstico e decisão de intervenção em casos de CoA e AvD. Contudo, estudos com populações maiores será extremamente benéfico para validar clinicamente este método.
This dissertation aims to validate MRI-based time-shift corrected pressure mapping (TCPM) against cardiac catheterization in CoA and AvD patients. Also, in AvD patients, catheterization will be compared against Gorlin Area method. This project is divided in two independent studies: the first one for CoA patients and the second one for AvD patients, all with clinical indication for cardiac catheterization. In both CoA and AvD, clinical guidelines recommend treatment in the presence of a relevant pressure gradient. While reliable non-invasive measurement approaches would be crucial, the accuracy of currently available methods has been limited. In both studies, 4D PC-MRI was performed to compute relative pressure maps via Pressure-Poisson equation. To consider the patient-specific peak pressure time-shift from the ascending to the descending aorta and before and after the aortic valve, relative pressure gradient maps were corrected by the inertial term. Comparison between TCPM and invasive peak-to-peak measurements was performed using correlation, Bland-Altman plots and mean-equivalence t-test. In the first study, with a cohort of 21 patients with CoA, TCPM and catheter measurements showed significant linear correlation (R²=0.90; p<0.001). Bland-Altman plots demonstrated good agreement between TCPM and catheter derived pressure gradients with mean differences of -2.69 mmHg and 95% limits of agreement between -6.38 and 1.00 mmHg between methods. The mean-equivalence test was significant (p=0.007). In the second study, with a cohort of 4 patients with AvD, the catheterization measurements were compared against TPCM measurements. The results showed significant linear correlation (R²=0.99; p<0.001). Bland Altman plots showed a good agreement between TCPM (24.75±22.50 mmHg) and catheter derived peak-to-peak pressure gradients (20.88±19.51 mmHg), and suggested slight underestimation of the pressure gradients by the Gorlin Area method (14.47±13.00 mmHg). Non-invasive TCPM showed equivalence to pressure gradients from invasive heart catheterization in patients with CoA and AvD. However, in the AvD study, they were obtained for a very small cohort of patients and do not have sufficient statistical significance to validate the method for AvD patients.

碩士
國立臺灣大學
企業管理碩士專班
97
Medical aesthetic treatments have been sought-after increasingly in the past few years due to both the aging of baby boomers and the improved economic status. Among all the medical aesthetic treatments, non-surgical , minimally invasive cosmetic treatments become more and more popular for its advantages of low risk, low down-time and natural looks after treatment immediately. In this study, the author is trying to analyze factors influencing customers’ revisiting intention after receiving non-surgical cosmetic procedures. Four factors influencing customers’ revisiting intention are proposed, including independent factors such as customers’ satisfaction, doctor characteristics, recovery service and one moderating factor of value-added activities. Using regression analysis, we found that revisiting intentions was significantly related to satisfaction ；doctors’ characteristics and service recovery were positively related to satisfaction. However, in medical aesthetics, value-added activities don’t have positively moderating effect to relationship between satisfaction and revisiting intention. Keywords：medical aesthetic treatments, non-surgical cosmetic procedures, consumer behavior, customer satisfaction, customers’ defection, physician choice, customer loyalty