Dissertations / Theses on the topic 'Metodi non invasivi'

L’elaborato espone sei diversi metodi contact-less per la rilevazione della frequenza respiratoria. Sono stati menzionati i vari studi che si sono occupati dell’acquisizione, l’elaborazione ed il confronto dei dati ricavati con quelli ottenuti tramite altre metodiche considerate gold standard. Le tecniche trattano: segnali di pressione quali OscP e KorS, fotocamere ToF, un sistema ibrido che utilizza il segnale PPGI e IRTI, un sensore capacitivo, uno a radiofrequenze ed un radar CW. Il confronto, prendendo in considerazione i segnali rilevati tramite cintura di pressione o polisonnigrafo, ha dimostrato una forte correlazione. Si è osservato che queste tecniche possono essere una valida alternativa con diversi vantaggi: analisi di pazienti dormienti, allettati o con ferite cutanee per cui sarebbe impossibile utilizzare le classiche tecniche esistenti che prevedono cinture o elettrodi a contatto con il corpo.

La misurazione della pressione arteriosa è molto comune nella pratica clinica poichè permette di avere una valutazione generale sullo stato di salute del paziente. La pressione arteriosa viene rilevata sia nei controlli di routine che nell'assistenza di un paziente in area critica. La misurazione può essere non invasiva oppure invasiva. La tecnica invasiva consiste nella rilevazione della pressione arteriosa tramite catetere. Il monitoraggio può avvenire tramite sensore extravascolare oppure intravascolare. I metodi non invasivi invece, permettono di valutare in maniera indiretta e ad intervalli regolari, i valori pressori, basondosi sulle intuizioni di Riva-Rocci e Korotkoff. La debolezza di queste tecniche non invasive risiede nell’impossibilità di tracciare la variabilità e la forma d’onda della pressione arteriosa. L’esigenza di avere una rilevazione non invasiva continua ha quindi spinto nel corso degli anni i ricercatori a sviluppare nuovi metodi di misura. Lo scopo delle nuove tecniche e dei miglioramenti di quelle più tradizionali resta comunque lo stesso: raggiungere l’accuratezza e la precisione della misurazione diretta, restando ovviamente non invasive.

Analisi delle più utilizzate tecnologie non invasive per la riduzione delle adiposità localizzate e per il miglioramento dell'aspetto della cellulite quali: LPG Endermologie, Radiofrequenza, Ultrasuoni focalizzati ad alta intesità (HIFU), Ultrasuoni cavitazionali, Terapia laser a basso livello energetico (LLLT), Criolipolisi, Terapia ad onde d'urto (ESWT)

The eyes are acoustically continuous with the brain and inner ear tissues in regard to matched impedances, based on tissue densities, thus, vibration of one site will be reflected in all sites. With this being the case, the vibrational energy response of the eye due to an external source can be used to determine a correlation or draw a conclusion concerning the vibrational energy response of the brain would be. And since there is a correlation between the vibrational energies, any changes in the acoustical energy in the eye can possibly be used to determine the changes in acoustical energy in the brain. Such an assertion was tested using the eye/balloon model, in which frequency specific tones can be used to analyze the vibrational response of the eye and the coupled brain. Changes in the intracranial pressure via the vibrational response induce changes in the intraocular pressure via the vibrational principle. Further, the model supports the observation that vibration delivered to the eye can be perceived as sound, if of sufficient intensity, resulting in an eye audiogram similar in degree to that obtained conventionally by bone conduction on the mastoid or forehead. The literature is suggestive that there is no positive correlation between IOP and ICP in terms of pressure, but there is a correlation when acoustical response is measured. This supports the possibility of measuring the changes in acoustical properties on the eye and within the cranium due to any external disruptions. The eye can therefore be considered an acoustical window to the brain and inner ear.

Background: NAFLD is one of the most common causes of liver disease worldwide. It is a spectrum of disease characterized by macrovesicular steatosis of the liver that ranges from simple fatty liver (steatosis), to non-alcoholic steatohepatitis (NASH). NASH may eventually evolve to cirrhosis and end stage complication. Liver biopsy has long been considered the gold standard of reference to diagnose NAFLD but it is costly and invasive. Recently, non-invasive methods have been proposed. Aims and methods: The aim of this study was to investigate the accuracy of non-invasive methods including (Ultrasound, computed tomography scan, Xenon-133 scan, Hepatic steatosis index, Fibroscan, NAFLD fibrosis score, APRI index, and FIB-4 index) and their combination to diagnose steatosis and to diagnose significant liver fibrosis (>F2) and cirrhosis (F4) as compared to liver biopsy. We conducted a retrospective study of 114 NASH patients (79 males, mean age 49.6±10.6). All had adequate liver histology. Results: The distribution of fibrosis stage was as follows: F0-F1= 50%, F2=16.8%, F3=19.2%, F4=14%. The distribution of steatosis grade was as follows: grade 0-1=16%, grade2=53.3%, grade3=30.7%. The following tests correlated with fibrosis: APRI index (r=0.554), FIB-4(r=0.555), NAFLD fibrosis score (r=0.473), Fibroscan(r=0.586) and Hepatic Steatosis Index (HSI) (r=0.245). The FIB-4 and APRI index showed the best diagnostic accuracy for significant fibrosis as indicated by an Area Under the Curve (AUC) of 0.801 and 0.782, respectively. The FIB-4 showed the best AUC= 0.886 for cirrhosis. None of the following tests US, CT, HSI, and xenon-133 scan were considered correlated significantly. The best combination algorithm for the detection of cirrhosis was gender and FIB-4 with an AUC of 0.8937. Conclusion: this study demonstrates that non-invasive methods for liver fibrosis are accurate to diagnose >F2 and F4. Severe steatosis cannot be reliably diagnosed by non-invasive methods. Notably, a combination of FIB-4 and gender significantly improves the performance of the single method for cirrhosis. These methods may help reducing the number of liver biopsies stratifying NASH patients that should start a screening program for HCC and esophageal varices.
Contexte : La stéatose hépatique non alcoolique (SHNA) est l'une des causes les plus répandues des maladies du foie à l'échelle mondiale. Il s'agit d'un spectre de maladies qui se caractérise par une stéatose hépatique macrovésiculaire allant de la stéatose hépatique simple (stéatose) à la stéatohépatite non alcoolique (NASH). La NASH peut éventuellement évoluer vers une cirrhose et des complications en phase terminale. La biopsie du foie a longtemps été considérée comme la norme de référence par excellence pour le diagnostic de la SHNA, mais elle est coûteuse et invasive. Des méthodes non invasives ont récemment été proposées. Objectifs et méthodes : La présente étude avait pour objectif d'évaluer la précision de certaines méthodes non invasives (notamment les ultrasons [US], la tomographie par ordinateur [TO], la scintigraphie au xénon 133, l'indice de stéatose hépatique (ISH), la technique Fibroscan, le score de fibrose de SHNA, l'indice de ratio entre l'aspartate aminotransférase et les plaquettes [APRI] et l'indice FIB-4) et de l'utilisation combinée de ces méthodes pour le diagnostic de la stéatose et pour le diagnostic d'une fibrose hépatique significative (> F2) et de la cirrhose (F4), par comparaison à la biopsie du foie. Nous avons réalisé une étude rétrospective sur 114 patients atteints de NASH (79 patients de sexe masculin, âge moyen de 49,6 ans ± 10,6). Tous ces patients présentaient une histologie hépatique adéquate.Résultats : La répartition des stades de fibrose était la suivante : F0 F1 = 50 %, F2 = 16,8%, F3 = 19,2 %, F4 = 14 %. La répartition des stades de stéatose était la suivante : stade 0-1 = 16 %, stade 2 = 53,3 %, stade 3 = 30,7 %. Les tests suivants ont été mis en corrélation avec la fibrose : l'indice APRI (r = 0,554), l'indice FIB-4 (r = 0,555), le score de fibrose de SHNA (r = 0,473), la technique Fibroscan (r = 0,586) et l'indice de stéatose hépatique (r = 0,245). L'indice FIB-4 et l'indice APRI ont offert la meilleure précision diagnostique en ce qui concerne la fibrose significative, comme l'indiquent la surface sous la courbe (SSC) de 0,801 et la SSC de 0,782 respectivement. L'indice FIB-4 a présenté la meilleure SSC, soit 0,886, pour ce qui est de la cirrhose. Aucun des tests suivants, c'est à dire les tests aux US, la TO, l'ISH, et la scintigraphie au xénon 133, n'était considéré comme étant corrélé significativement. Le meilleur algorithme de combinaison pour le dépistage de la cirrhose était le sexe et l'indice FIB-4 avec une surface sous la courbe de 0,8937. Conclusion: cette étude démontre que les méthodes non invasives de diagnostic de la fibrose hépatique sont précises en ce qui concerne les stades > F2 et F4. La Stéatose sévère ne peut être diagnostiqué de façon fiable par des méthodes non invasives Notamment, une combinaison de l'indice FIB-4 et du sexe améliore considérablement le rendement de la méthode unique en ce qui a trait à la cirrhose. Ces méthodes pourraient aider à réduire le nombre de biopsies du foie visant à stratifier les patients atteints de NASH qui devraient entreprendre un programme de dépistage du carcinome hépatocellulaire (CHC) et des varices œsophagiennes.

La tesis doctoral que presento es el resultado del trabajo realizado en el Servicio de Neumología del Hospital de la Santa Creu i Sant Pau de Barcelona y del Institut de Recerca Biomèdica de Sant Pau (IIB Sant Pau), siguiendo las normativas de la Universitat Autònoma de Barcelona para su presentación como compendio de publicaciones. El estudio de la inflamación bronquial en el asma, se ha convertido en una herramienta valiosa para el diagnóstico, control y predicción de respuestas terapéuticas. En los últimos años ha aumentado el interés en los métodos que permitan evaluar de una forma no invasiva la inflamación de la vía aérea. Entre los métodos no invasivos descritos usados en la práctica clínica para evaluar la inflamación de la vía aérea figuran: el recuento de células inflamatorias en el esputo inducido y la fracción exhalada de óxido nítrico (FeNO). La temperatura del aire exhalado y la nariz electrónica se plantean como nuevas herramientas de medición de la inflamación bronquial y del control del asma. La línea de investigación desarrollada tuvo como objetivo fundamental mejorar los conocimientos sobre los fenotipos inflamatorios del asma a través de métodos no invasivos. Está basada en tres proyectos. El primero, es un proyecto clínico cuyos resultados muestran que existen un alto porcentaje de pacientes con disociación entre los resultados de la FeNO y de los eosinófilos en el esputo inducido y que cursan con características clínicas e inflamatorias diferenciales. Los otros dos proyectos permiten conocer la utilidad en el asma de dos nuevos métodos no invasivos como lo son, la temperatura del aire exhalado (TAE) y el reconocimiento de patrones de compuestos orgánicos volátiles mediante la “nariz electrónica”. Estos trabajos aportaron como resultados principales que en el caso de la TAE, no parece que éste sea un método que proporcione una información clínica útil puesto que no se encontró ninguna correlación entre este método y el grado de control del asma, la gravedad de la enfermedad, la obstrucción bronquial, o la inflamación bronquial. Por otro lado, los resultados del tercer estudio sí que fueron alentadores, puesto que de manera significativa, el uso de la nariz electrónica en un entorno clínico habitual permitió discriminar con fiabilidad los diferentes fenotipos inflamatorios bronquiales en pacientes con asma. Así pues, los resultados de esta tesis sirven como fundamento del estudio y aplicabilidad de diversos métodos no invasivos en el asma.
This doctoral thesis is the result of the work done in the Service of Respiratory Medicine of the Hospital de la Santa Creu i Sant Pau in Barcelona and the Institute of Biomedical Research of Sant Pau (IIB Sant Pau), following the regulations of the Universitat Autònoma de Barcelona. The study of bronchial inflammation in asthma has become a valuable tool for its diagnosis, monitoring and prediction of therapeutic responses. In recent years, there has been an increased interest in methods of noninvasive evaluation of the airway inflammation. The described non-invasive methods used in the clinical practice to assess airway inflammation include the inflammatory cell counts in induced sputum and the fractional exhaled nitric oxide (FeNO). The exhaled breath temperature and the electronic nose device are considered to be new tools for measuring airway inflammation and control of asthma. The line of the developed research had as a main goal to improve the knowledge of inflammatory phenotypes of asthma through non-invasive methods. It is based on three projects. The first (1) is a clinical project that shows a high percentage of patients with dissociation between the results of the FeNO and eosinophils in induced sputum, presenting clinical and inflammatory differential characteristics. The other two projects provide an insight into the utility of two non-invasive diagnostic methods: 2) the exhaled breath temperature (EBT) and 3) the recognition of the patterns formed by organic volatile compounds using the electronic nose device. The second study does not support the usefulness of the EBT plateau, because no correlation was found between EBT and control of asthma, severity of disease, bronchial obstruction or bronchial inflammation. Furthermore, the results of the third study were encouraging since the using of an e-nose device in a regular clinical setting can reliably discriminate different inflammatory asthma phenotypes among patients with persistent asthma. Thus, the results of this thesis disclosed the applicability of various non-invasive methods performed in routine clinical practice.

This thesis investigates the feasibility of using a set of non-invasive biomedical signals to monitor respiration. The signals of interest being the electrocardiogram (EGG), photoplethysmography (PPG) and impedance plethysmography (IP) signals. The work has two main aims; the first being to estimate breathing rates from the signals, the second being to detect apnoeas from the signals. The fusion of information from different signals is used throughout in developing algorithms that give more accurate respiratory information than that obtained using one signal alone. Respiratory waveforms are derived from the signals, and the accuracy of detecting individual breaths from the waveforms is assessed and compared objectively. Results from evaluations on two separate databases show there is no waveform that gives sufficient accuracy to consider using it alone. A novel fusion method is developed which uses measurements from all three signals. This fusion method is based on weighting the estimates from each signal, according to the innovation from a Kalman filter model, applied to each respiratory waveform separately. The fused estimates give a higher overall correlation with respect to the reference breathing rate values than any of the breathing estimates derived from a single waveform. The detection of both central and obstructive sleep apnoea from the signals is investigated. It is shown that the accuracy of detecting central apnoeas from the IP signal using a timedomain method, often used in practice, can be improved by combining it with information from the frequency-domain. When discriminating between obstructive sleep apnoeic and non-apnoeic data it is seen that combining features from two signals results in a superior classification accuracy than is possible by using features from just one signal. The proposed classification system using just one of these signals, the EGG, is shown to give a performance accuracy comparable to that found in the literature. In conclusion this thesis shows that by fusing information from a number of non-invasive biomedical signals, estimations of breathing rates can be found with correlation 0.8. This is superior to estimation using only the impedance pneumography signal (correlation 0.64) which is currently used to monitor respiration. The fusion approach could potentially be applied to improve other non-invasive physiological monitoring systems.

Wild chimpanzee populations are considered to be under threat of extinction due to the damaging consequences of human impact into their natural habitat and illegal trade. Conservation genomics is an emerging field that has the potential to guide conservation efforts not only in the wild (in situ) but also outside their natural range (ex situ). In this thesis, we have explored to which extent target capture methods on specific genomic regions can provide insights into chimpanzee genetic diversity in captive and wild populations. Specifically, we have characterized the ancestry and inbreeding of 136 European captive chimpanzees to aid their management in captivity and inferred the origin of 31 confiscated individuals from illegal trade by sequencing ancestry informative SNPs. Also, we have examined molecular strategies to maximize the library complexity in target capture methods from fecal samples so they can be applied in large-scale genomic studies. Finally, we have captured the chromosome 21 from 828 fecal samples collected across the entire extant chimpanzee range. As a result of our high density sampling scheme, we have found strong evidence of population stratification in chimpanzee populations and we have discovered new local genetic diversity that is linked to its geographic origin. Finally, with this newly generated dataset and fine-grained geogenetic map, we have implemented a strategy for the geolocalization of chimpanzees which has a direct conservation application
Les poblacions salvatges de ximpanzés estan en perill d'extinció a causa de les dramàtiques conseqüències associades a l’impacte humà en el seu hàbitat natural i al tràfic il·legal. La genòmica de la conservació és un camp emergent que té el potencial de guiar esforços de conservació d’espècies en perill d’extinció no només en el seu hàbitat natural (in situ) sinó també en captivitat (ex situ). En aquesta tesi, hem analitzat fins a quin punt els mètodes de captura de regions específiques del genoma són una bona eina per explorar la diversitat genètica dels ximpanzés tant en poblacions captives com salvatges. Concretament, hem caracteritzat la subespècie i els nivells de consanguinitat de 136 ximpanzés de zoos europeus amb l'objectiu de guiar-ne la seva gestió en captivitat, i hem inferit l'origen de 31 individus confiscats del tràfic il·legal a través de la seqüenciació de SNPs informatius de llinatge. També hem posat en pràctica estratègies moleculars per maximitzat la complexitat de les llibreries en la captura de regions específiques a partir de mostres fecals i així poder ser aplicades en estudis genòmics a gran escala. Finalment, hem capturat el cromosoma 21 de 828 mostres fecals recollides per tota la distribució geogràfica dels ximpanzé. Arran de l’alta densitat de mostreig, hem trobat evidències que apunten a una alta estratificació poblacional en els ximpanzés i hem desxifrat nova diversitat genètica vinculada a l’origen geogràfic dels individus. Finalment, amb el conjunt de dades generat i el mapa geogenètic obtingut, hem implementat una estratègia per la geolocalització de ximpanzés amb aplicació directe per a la conservació.

The aim of this thesis was to design, develop and evaluate a Non-Contact Corneal Aesthesiometer (NCCA), using a controlled pulse of air, of a pre-determined pressure. First, the system design and alterations are described, then in a series of model experiments, the standardisation and characteristics of the air-pulse were examined. These studies revealed that the NCCA could produce a repeatable stimulus of known volume and rate of air-flow. Furthermore, the air-flow exiting the stimulus air jet was of a laminar shape, with minimal dispersion. The control of the air-flow dispersion was further enhanced by using a 0.5mm diameter air jet and a working distance of lcm. Varying the stimulus duration was not found to influence these qualities of the air-pulse. The air-pulse stimulus was shown to possess the ability to produce corneal nerve stimulation either by surface deformation, temperature change, or both. Using thermal imaging equipment, a temperature drop in the ocular tear film was demonstrated that was localised, and limited to the cornea. A second series of experiments investigated the ability of the NCCA to measure a corneal sensitivity threshold. These studies indicated that a forced-choice, doublestaircase, Method of Limits experimental technique produced an accurate threshold, with low variability in the results, over a minimum time period. Further studies showed that this threshold measurement was repeatable to within 0.1 mbars. A database of typical normal sensitivity thresholds, under a number of physiological variables - corneal location, gender, age and iris colour, was developed. The results from these studies compared well qualitatively with those using invasive stimuli. A third series of experiments examined the ability of the NCCA to assess corneal nerve function when it was under a number of external influences. The first situation was that of anaesthesia,p roduced by 0.4% benoxinate hydrochloride. Non-contact corneal sensitivity loss and recovery were shown to return to normal levels 60mins after instillation of the anaesthetic. The second situation was that of long-term contact lens wear (i.e. longer than three years). Non-contact sensitivity was shown to be reduced with both soft and gas-permeable lens wear, although the extent of loss did not differ between them, nor was it influenced by the length of wear. Thirdly,corneal sensitivity loss and recovery was assessed in subjects following excimer laser photorefractive keratectomy (PRK). Three laser trials were completed: a longitudinal myopic study, a transverse myopic study, and a longitudinal hyperopic study. The results indicated that non-contact corneal sensitivity loss/recovery was not related to the attempted depth of ablation, and that sensitivity had still not returned to normal levels one year post-op.

Thesis: S.M., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2014.
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Cataloged from PDF version of thesis.
Includes bibliographical references (pages 101-106).
This thesis presents a continuous and non-invasive arterial blood pressure (CNAP) monitoring technique using ultrasound. An arterial blood pressure (ABP) waveform provides valuable information in treating cardiovascular diseases. Although an invasive ABP measurement through arterial catheterization performed in an intensive care unit (ICU) is considered a gold standard, its invasive nature not only increases various patients' risks but makes its usage for cardiovascular studies expensive. Therefore, reliable non-invasive ABP waveform estimation has been desired for a long time by medical communities. This work details ABP waveform estimation based on a vessel cross-sectional area measurement combined with the elastic property of an arterial vessel, represented by a pulse wave velocity (PWV). Several ultrasound techniques including uniform insonation and echo-tracking are explored to measure the PWV using so-called QA method as well as the cross-sectional area. The physiological background of the arterial system and considerations for a clinical test are also presented. Experimental results validate the QA method and the proposed ABP waveform estimation method in a custom-designed experimental setup consisting of a diaphragm pump and a latex rubber tube using two commercially available single element ultrasonic transducers. The design of a portable CNAP monitoring device using ultrasound will fuel the exponential growth of a readily available, inexpensive but powerful cardiovascular diagnostic tool.
by Joohyun Seo.
S.M.

Thesis: S.B., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 39-40).
This study aims to explore a new method for analysis of muscle fiber type, using data collected from weightlifts on a leg press. A dynamic muscle model is developed, which utilizes the Descherevskii kinetic theory in combination with a muscle "matrix" model to predict net muscle contraction forces and velocities as a function of fiber type. These relationships are integrated into a dynamic model for lifting a weight, allowing for the derivation of joint trajectories in time, from the molecular properties of muscle. The model-predicted velocity trajectories for the lift are compared with curves obtained experimentally from weightlifting trials. Longer lifts with slower peak velocities indicate higher ratios of slow-twitch fibers, and shorter lifts with greater peak velocities indicate higher ratios of fast-twitch fibers. This idea is supported by both the model results and in experimental trends. With further refinement of experimental protocols, the leg press test has the potential to be a powerful training tool for athletes-both to compare their muscle makeup with other athletes, and to track their own progress over the course of their training.
by Laura Treers.
S.B.

The trustworthiness of the blood pressure (BP) readings acquired by oscillometric home-based monitoring systems is a challenging issue that requires patients to see the doctor for trusted measurements, especially those who are obese or have cardiovascular diseases such as hypertension or atrial fibrillation. Even with the most accurate monitors one may get different readings if BP is repeatedly measured. Trusted BP readings are those measured with accurate devices at proper measurement conditions. The accurate monitors need an indicator to assure the trustworthiness of the measured BP. In this work, a novel algorithm called the Dynamic Threshold Algorithm (DTA) is proposed that calculates trusted boundaries of the measured systolic and diastolic pressures from the recorded oscillometric waveforms. The DTA determines a threshold from the heart rate of subjects to locate the oscillometric pulse at the mean arterial pressure (PULSEMAP) and uses the peak, trough, and pressure of the located pulse to calculate the trusted boundaries. In terms of accuracy, a modeling approach is employed to estimate BP from the arterial lumen area oscillations model in the diastolic region (ALA-based). The model requires compliance parameter ‘c’ to estimate BP. To this end, a pre-developed linear regression model between ‘c’ and the corresponding amplitude ratio of the PULSEMAP is employed to evaluate ‘c’. The proposed method uses ‘c’ and estimates BP by minimizing differences between peak and trough amplitudes of the actual and corresponding simulated waveforms. The proposed DTA and ALA-based methods were tested on two datasets of healthy subjects and one dataset of sick subjects with cardiovascular diseases, and results were validated against corresponding references and compared with two popular maximum amplitude and maximum/minimum slope algorithms. Mean absolute error (MAE) and standard deviation of errors (STDE) are used to evaluate and compare the results. For healthy subjects, the MAE of the estimated systolic (SBP) and diastolic (DBP) blood pressures was improved up to 57% and 57% with an STDE of 55% and 62%, respectively. For sick subjects, the MAE was improved up to 40% and 29% with an STDE of 36% and 20% for SBP and DBP, respectively.

Questo lavoro di tesi nasce con l’obbiettivo di analizzare le ricerche effettuate da un gruppo di bioingegneri italiano, che per primo ha utilizzato il metodo non invasivo dell’espirazione prolungata per la stima della portata media cardiaca (CO) in pazienti post-chirurgici ventilati meccanicamente. In questo studio è stata comparata per la prima volta la tecnica dell’espirazione prolungata con quella della termodiluizione, considerata il gold standard clinico per la misura della portata media cardiaca, ma che richiede l’uso di cateteri. Per questo obbiettivo sono stati selettivamente reclutati venti pazienti che avevano affrontato un intervento chirurgico in anestesia generale e successivamente erano stati assistiti tramite ventilazione meccanica. La CO è stata calcolata attraverso una versione modificata della formula di Fick, in cui i valori della pressione parziale dell’anidride carbonica nel sangue arterioso e venoso sono stati stimati con gli algoritmi di Kim e Godfrey. I risultati sono confrontati con quelli ottenuti tramite termodiluizione. L’applicazione del primo algoritmo mostra una leggera sottostima (-6%) rispetto ai valori calcolati tramite termodiluizione e una deviazione standard di 0.72 L min-1, al contrario l’algoritmo di Godfrey mostra una sovrastima più marcata (+30%) e una deviazione standard di 1.07 L min-1. La standardizzazione e automazione della procedura proposta in pazienti ventilati meccanicamente, consente di ottenere una stima non invasiva della portata media cardiaca con una precisione confrontabile con quella di altri metodi minimamente invasivi.

The general purpose of this thesis was to investigate new cardiac resynchronization therapy (CRT) optimization techniques and to assess their reliability when compared to invasive measurements of left ventricular contractility (LV dP/dtmax).We first assessed whether cardiac output (CO) measured by trans-thoracic impedance cardiography could correctly identify the optimal interventricular (VV) pacing interval while using invasive measurements of LV dP/dtmax as reference. We did not find any significant statistical correlation between the two optimizing methods when their corresponding optimal VV intervals were compared. We also tested the hypothesis that measurements of right ventricular contractility (RV dP/dtmax) could be used to guide VV delay optimization in CRT. The comparison of optimal VV intervals obtained from the left and right ventricular dP/dtmax did not show a statistically significant correlation; however, a positive correlation was found when broader VV intervals were evaluated and we concluded that this finding deserves further investigation. An interesting alternative for CRT optimization is the use of device integrated algorithms or sensors capable to adapt the CRT settings to the current needs of the individual patient. In this respect we investigated the use of cardiogenic impedance (CI) measurements obtained through the CRT-D device as a method for CRT optimization with invasive measurements of LV dP/dtmax as a reference. Our results showed that CI could be measured through the device after implantation and that a patient-specific impedance-based prediction model was capable to accurately predict the optimal AV and VV delays. To follow up on these positive results we re-evaluated the patient-specific impedance-based prediction models 24 hours post implantation and investigated the possibility of calibrating them using parameters derived from non-invasive measurements of arterial pressure obtained by finger pelthysmography at implantation.The results showed that the patient-specific impedance-based prediction models did not perform as well on the follow-up data as they did on the data from implantation day and that they correlated poorly with plethysmographic parameters. Our studies suggest that novel methods for CRT optimization should be thoroughly evaluated and compared to established measures of left ventricular function prior to introduction into clinical practice.

El asma relacionado con el trabajo (ART) incluye el asma ocupacional (AO) y el asma exacerbado por el trabajo (AET), y representa un problema de salud importante con un negativo impacto socio-económico. El AO se refiere al asma causado de novo por exposición a un agente específico en el lugar de trabajo, y el AET se define como un empeoramiento de un asma preexistente o concomitante agravado por las condiciones de trabajo. Al igual que el asma bronquial, el ART es una enfermedad inflamatoria crónica heterogénea de las vías respiratorias. La inflamación bronquial es un reflejo directo de la enfermedad y su evaluación de forma no invasiva presenta un interés creciente para comprender los mecanismos fisiopatológicos implicados en las enfermedades inflamatorias respiratorias El objetivo de esta tesis fue establecer la utilidad de dos métodos no invasivos: esputo inducido (EI) y condensado de aire exhalado (CAE), en la evaluación de la inflamación en pacientes con sospecha de ART. Inicialmente se realizaron dos estudios, en pacientes asmáticos con asma estable y en una población adulta sana, para proporcionar datos de referencia para los respectivos estudios realizados posteriormente con muestras de EI y de CAE en sujetos con sospecha de ART. En pacientes controles con asma estable, se observó que la inflamación y la hiperrespuesta bronquial persisten en la mayoría de éstos a pesar del tratamiento, y que cuando la hiperrespuesta persiste, ésta es más grave en pacientes con una inflamación eosinofílica. El segundo estudio se realizó en adultos sanos estratificados según edad, y se observó que los valores de pH y los niveles de 8-isoprostano en el CAE presentaron relación con la edad, sugiriendo que los valores obtenidos en estudios con grupos controles deberían ser ajustados por este factor. La evaluación de la inflamación bronquial en el ART permitió mejorar nuestros conocimientos sobre los mecanismos fisiopatológicos implicados en los diferentes tipos de ART. Al realizar estudios de inflamación bronquial es necesario distinguir entre los diferentes tipos de agentes ocupacionales: de alto peso molecular (APM) y de bajo peso molecular (BPM). Se investigó el perfil inflamatorio de sujetos con sospecha de ART mediante contajes celulares diferenciales y biomarcadores inflamatorios en muestras de EI antes y después de una prueba de provocación bronquial específica (PPBE). Se encontró un incremento de eosinófilos y neutrófilos y de interleuquina (IL) -10, y una disminución de leucotrieno B4 (LTB4) en EI tras la exposición a agentes de APM. Estos resultados refuerzan la teoría de que la mayoría de los agentes de APM inducen AO a través de un mecanismo mediado por IgE, dando lugar a una respuesta alérgica tipo Th2. No se observaron diferencias significativas en los recuentos celulares diferenciales ni en los niveles de biomarcadores inflamatorios en muestras de EI de pacientes expuestos a agentes de BPM. Sin embargo, se observó que la exposición a agentes de BPM puede ocasionar un aumento de la inflamación neutrofílica en pacientes con enfermedades respiratorias previas, sugiriendo la existencia de diferentes mecanismos de acción en función de si el agente de BPM causa AO o bien provoca empeoramiento de una enfermedad respiratoria preexistente. Al investigar el perfil inflamatorio de sujetos con sospecha de ART mediante el análisis del CAE, se observó que tras la exposición al agente causal el pH del CAE mostró una sensibilidad del 79% y una especificidad del 100% para el diagnóstico del AET, lo que demuestra que este biomarcador conjuntamente con la PPBE puede ser útil para el diagnóstico del AET, y sugiere de nuevo que el mecanismo de acción de los agentes de BPM parece variar en función de si éstos causan AO o inducen AET.
Asthma is a chronic disorder of the airways characterized by reversible airway obstruction, airway inflammation and non-specific airway hyper-reactivity (AHR). Up to 25% of all asthma cases developing in adulthood are caused by occupational exposure. This condition is known as work-related asthma (WRA); it includes both occupational asthma (OA) and work-exacerbated asthma (WEA), and it presents a major health challenge with adverse socio-economic impact. OA refers to de novo asthma caused by exposure to an agent specific to a workplace, and WEA is defined as a worsening of pre-existing or concomitant asthma which is exacerbated by working conditions. Like bronchial asthma, WRA is a heterogeneous chronic inflammatory disorder of the airways. Airway inflammation is a direct reflection of the disease and its assessment in a non-invasive manner does not disturb the underlying disease process and allows its monitoring. Recently, this practice has aroused growing interest in the attempts to understand the pathophysiological mechanisms of inflammatory airway diseases. This thesis aimed to establish the usefulness of two non-invasive methods: induced sputum (IS) and exhaled breath condensate (EBC) for the assessment of airway inflammation in subjects with suspected WRA. Two studies were carried out in asthmatic patients with ell-controlled asthma and in a healthy adult sample as control groups in order to provide reference data for the respective studies performed later with IS and EBC samples in subjects with suspected WRA. Evaluating the type and degree of airway inflammation present in these control patients with well-controlled asthma we found that airway inflammation and AHR persist in most patients despite of treatment and that when AHR persists, it is more severe in patients with eosinophilic inflammation. The second study was carried out in healthy adults stratified into groups according to age, in order to establish reference values for certain biomarkers of airway inflammation and to determine whether there are age-associated differences. pH values and 8-isoprostane levels in EBC showed a relationship with age, suggesting that the values obtained in studies with control groups should be adjusted for this factor. Assessment of airway inflammation in WRA improved our understanding of the pathophysiological mechanisms implicated in the genesis of the different types of WRA. In this context, it seems necessary to distinguish between the different types of occupational agents: high-molecular-weight (HMW) and low-molecular-weight (LMW), when conducting airway inflammation studies. We investigated the inflammatory profile by evaluating sputum differential cell counts and several inflammatory biomarkers in sputum supernatants of subjects with suspected WRA preceding and following a specific inhalation challenge (SIC). Increases in sputum eosinophils and neutrophils and in interleukin (IL)-10 concentration and a decrease in leukotriene B4 (LTB4) after exposure to HMW agents have been reported. These findings support the notion that most HMW agents induce OA via an IgE-mediated mechanism inducing a Th2-mediated allergic response. No significant changes in sputum differential cell counts or inflammatory biomarkers were found after SIC in patients with OA due to exposure to LMW agents. However, exposure to LMW agents can result in increased neutrophilic inflammation in patients with airway diseases unrelated to OA, suggesting different mechanisms of action according to whether the LMW agent is the cause of OA or provokes aggravation of a pre-existing respiratory disease. Investigating the inflammatory profile by analysing EBC in subjects with suspected WRA, EBC pH after exposure to the offending agent had a sensitivity of 79% and specificity of 100% for the diagnosis of WEA, demonstrating that in conjunction with SIC this biomarker may be useful for diagnosing WEA, and suggesting again that the mechanism of action of LMW agents seems to differ according to whether they cause OA or induce WEA.

Non-invasive methods to investigate brain function have been used in research laboratories for many decades, however their popularity has increased in recent years given the ease of use and broad application. Such methods have proved valuable in improving our knowledge about numerous areas of basic brain function. Many non-invasive techniques have also been applied to patient groups to allow further identification of pathological mechanisms, but critically a new role has been found for some as biomarkers of disease. Neurodegenerative disease is fast becoming one of the biggest medical problems in the first world. An aging population has caused the relative incidence of many conditions to rise dramatically and studies suggest that this trend will continue. Although our knowledge surrounding these conditions has improved significantly, most remain notoriously difficult to diagnose and to treat. The recent introduction of neuroprotective drugs offers the potential to slow the progression of some diseases. However, to take full advantage of these disease-modifying treatments, administration must occur early in the disease course which fuels the demand for selective and specific diagnostic tests. There is currently a great need to enhance the clinical diagnostic repertoire with reliable, robust and specific biomarkers of neurodegenerative disease. However, careful, rigorous studies are required to validate the use of non-invasive techniques in this role. The same level of care should also be applied to techniques used in basic research; without a fundamental understanding of the mechanisms underpinning these techniques, their utility in the investigation of specific processes or pathways is questionable. This thesis aims to address specific cases to evaluate existing techniques and to screen potential new disease biomarkers.

The present study sets out to assess patterns of evolutionary diversification in central African duikers (subfamily Cephalophinae). The sampling strategy consisted of collecting geo-referenced duiker feces across 43 sites and seven countries. However, several challenges related to the use of non-invasive samples needed to be addressed prior to large scale DNA amplification. First, the best storage method for obtaining DNA from fecal samples needed to be established. Our study revealed that while silica is best for nuclear microsatellite analyses, RNAlater is the best storage medium for maximal mitochondrial amplification. Moreover, extracting DNA as early as possible always provided the best results. Second, since it is impossible to determine the species identity of duiker feces solely based on their morphology, a simple and reliable molecular method was needed. A tree-based approach based on ~650 base pairs of the control region amplified from reference samples was found to be the most reliable method to recover the identity of unknown samples. Third, for fine scale analyses of population genetic structure, a set of twelve nuclear microsatellites were assembled from existing bovid data. These microsatellites markers were chosen because they are very polymorphic, cross amplify among targeted taxa, co-amplify with combined markers of the same multiplex, and are powerful enough for individual identification. Patterns of mitochondrial and nuclear microsatellite variation were used to test two important hypotheses of diversification in the tropics: the Pleistocene refugia and the riverine barrier hypotheses. Analyses of historical and contemporary population genetic structure were carried out on the three most abundant species in our sampling area: the bay duiker (C. dorsalis), the Peter’s duiker (C. callipygus), and the blue duiker (P. monticola) using mitochondrial and nuclear markers described above. These data show that (1) southwest Nigeria and southwest Cameroon comprise genetically distinct populations in C. callipygus and P. monticola species, (2) signatures of demographic expansion for all three taxa are broadly coincident with the location of hypothesized upland refugia in Gabon and Equatorial Guinea and (3) the Sanaga, Ogooué, and Sangha rivers may constitute a partial riverine barrier and/or act as fluvial refugia for duikers.

Current methods for measuring energy flow rate in a pipe use a variety of invasive sensors, including temperature sensors, turbine flow meters, and vortex shedding devices. These systems are costly to buy and install. A new approach that uses non-invasive sensors that are easy to install and less expensive has been developed. A thermal interrogation method using heat flux and temperature measurements is used. A transient thermal model, lumped capacitance method LCM, before and during activation of an external heater provides estimates of the fluid heat transfer coefficient h and fluid temperature. The major components of the system are a thin-foil thermocouple, a heat flux sensor (PHFS), and a heater. To minimize the thermal contact resistance R" between the thermocouple thickness and the pipe surface, two thermocouples, welded and parallel, were tested together in the same set-up. Values of heat transfer coefficient h, thermal contact resistance R", time constant �[BULLET], and the water temperature �[BULLET][BULLET], were determined by using a parameter estimation code which depends on the minimum root mean square RMS error between the analytical and experimental sensor temperature values. The time for processing data to get the parameter estimation values is from three to four minutes. The experiments were done over a range of flow rates (1.5 gallon/minute to 14.5 gallon/minute). A correlation between the heat transfer coefficient h and the flow rate Q was done for both the parallel and the welded thermocouples. Overall, the parallel thermocouple is better than the welded thermocouple. The parallel thermocouple gives small average thermal contact resistance average R"=0.00001 (m2.�[BULLET][BULLET]/W), and consistence values of water temperature and heat transfer coefficient h, with good repeatability and sensitivity. Consequently, a non-invasive energy flow rate meter or (BTU) meter can be used to estimate the flow rate and the fluid temperature in real life.
MS

Les méthodes non invasives d'évaluation des lésions tissulaires hépatiques les plus utilisées et les mieux validées sont l'élastométrie et le FibroTest. La stéatopathie non-alcoolique (NAFLD) est devenue la forme la plus fréquente de maladie hépatique. Différentes études suggèrent que la NAFLD est associée à un risque accru de mortalité, en particulier d'origine cardiovasculaire. Les objectifs de cette thèse étaient 1) de mieux définir certaines limites des méthodes non invasives d'évaluation de la fibrose hépatique; 2) d'évaluer la valeur pronostique du FibroTest et d'un biomarqueur de stéatose, le SteatoTest chez les patients ayant un diabète et/ou une dyslipidémie. Le travail réalisé a permis de montrer une variabilité interobservateur notable de l'élastométrie entre deux opérateurs expérimentés dans l'hépatite chronique virale C. La stéatose du foie, estimée par le SteatoTest, a été identifiée comme un facteur indépendant associé à la surestimation de la fibrose du foie par l'élastométrie chez les sujets ayant un diabète de type 2. Nous avons également mis en évidence une variabilité du test APRI et l'impact de l'activité nécrotico-inflammatoire sur ce test dont la formule comprend l'aspartate transaminase exprimée en multiple de la normale dans l'hépatite chronique virale C. Chez des patients à haut risque de NAFLD, nous avons pu démontrer la valeur pronostique à 10 ans du FibroTest et du SteatoTest, pour prédire la mortalité globale indépendamment des facteurs métaboliques. Le FibroTest était également prédictif de la mortalité d'origine hépatique et de l'incidence des complications cardiovasculaires et le SteatoTest de la mortalité d'origine cardiovasculaire

Abstract Healthy subjects show wide interindividual variation in their heart rate behavior, but the factors affecting heart rate dynamics are not well known. This research was undertaken to evaluate heart rate variability (HRV) and baroreflex sensitivity (BRS) in a large random sample of subjects without evidence of heart disease, and to estimate the relation of heart rate behavior to age, sex and cardiovascular risk factors. Short-term HRV was analyzed from 15-minute periods of standardized recording in supine and upright positions using time and frequency domain measures, and BRS was calculated using the Valsalva maneuver in an original randomly selected population of 600 hypertensive and 600 control middle-aged subjects. In addition, HRV was analyzed from the same segments using new measures based on fractals and complexity (chaos theory) of R - R interval dynamics in the same random population, and from 24-hour period in 114 healthy subjects aged from 1 to 82 years. Large interindividual variation was observed in the measures of HRV and BRS in middle-aged subjects; coefficient of variation (CV) of the standard deviation of R - R intervals (SDNN) 39% (54 ± 21 ms) and CV of BRS 49% (9.9 ± 4.9 ms/mmHg). In healthy middle-aged men, SDNN was weakly related to age (r = -0.19, p < 0.01), HDL cholesterol (0.19, p < 0.01), serum insulin (-0.23, p < 0.001) and triglyceride (-0.25, p < 0.001) levels. In women, SDNN was only related to insulin levels (r = -0.23, p < 0.001). BRS was related to systolic blood pressure (r = -0.31 and -0.30, in men and women respectively, p < 0.001 for both) and blood glucose (r = -0.25, p < 0.01) and serum insulin levels (r = -0.34, p < 0.001) in women. Lesser intersubject variation was observed in the non-linear measures of HRV; CV 14% of short-term scaling exponent (a1), a measure of fractal-like correlation properties of HRV, (1.21 ± 0.17) and CV 12% of approximate entropy, a measure of complexity, (1.13 ± 0.14). Neither a1 or ApEn was related to any risk factors. Women had lower overall short-term HRV (p < 0.01) and BRS (p < 0.001), but a higher spectral high-frequency component of HRV, higher ApEn and lower a1 (p < 0.001 for all) compared to men. The impairment in overall HRV was confined to the hypertensive subjects with metabolic features of the insulin resistance syndrome (IRS, n = 69), but the BRS and spectral high-frequency component were also impaired in hypertensive subjects without IRS compared to normotensive subjects. The 24-hour cardiac interbeat interval dynamics changed markedly from childhood to old age. Children showed similar complexity and fractal correlation properties of R - R intervals as young adults. Healthy aging resulted in R - R interval dynamics with higher regularity and predictability and altered fractal scaling. The traditional measures of HRV and BRS are weakly related to many cardiovascular risk factors in subjects without heart disease, but the interindividual variation of HRV and BRS is only partly explained by these factors, suggesting a genetic background of the intersubject variation in cardiovascular autonomic regulation. The new dynamical measures of HRV show less interindividual variation than the conventional measures of HRV in healthy subjects and are not related to cardiovascular risk variables, suggesting that these dynamical measures quantify the "intrinsic" capacity of a healthy cardiovascular control system without the significant influence of life-style, metabolic or demographic variables. However, there are sex and age-related differences also in the fractal and complexity measures of heart rate behavior.

The functioning of the heart, which main role is pumping blood to the rest of the body, is the result of a complex combination of multi-scale physical processes from the molecular to the tissue level. The predominance of animal experiments to understand the cardiac function has a high cost and associated ethical burden. There is a growing interest for non-invasive ways of extracting measurements. Owing to improvements of numerical methods and computational infrastructure, cardiac models might provide complementary clinically-relevant information in a non-invasive way. The majority of cardiac models use mesh-based numerical techniques, whose performance depends on the construction of a well-defined mesh that represents the high complexity of anatomical structures such as the heart. This thesis presents a derivation of a fully coupled multi-physics meshless model of the heart as an alternative and provides robust evidence of its ability to simulate the heart's behavior as observed in experimental measurements.
El funcionament del cor, que té el paper principal de bombar sang a la resta del cos, és el resultat d’una complexa combinació de processos físics des del nivell molecular fins al teixit. El predomini d'experiments amb animals i humans per a la comprensió de la funció cardíaca tenen un alt cost i una càrrega ètica associada. Hi ha un creixent interès per maneres no invasives d’extreure mesures. A causa de les millores dels mètodes numèrics i de la infraestructura computacional, els models cardíacs poden proporcionar informació complementària clínicament rellevant de manera no invasiva. La majoria dels models cardíacs utilitzen tècniques numèriques basades en malla, el rendiment de les quals depèn de la construcció d’una malla bend efinida que representi l’alta complexitat de les estructures anatòmiques com el cor. Aquesta tesi presenta una derivació d’un model multi-físic sense malla totalment acoblat com a alternativa i proporciona proves robustes de la seva capacitat de simular el comportament del cor, tal com s’observa en les mesures experimentals.

Cardiac disease is one of the leading causes of death in the world, with an increase in cardiac arrhythmias in recent years. In addition, myocardial ischemia, which arises from the lack of blood in the cardiac tissue, can lead to cardiac arrhythmias and even sudden cardiac death. Cardiac arrhythmias, such as atrial fibrillation, are characterised by abnormal wave excitation and repolarization patterns in the myocardial tissue. These abnormal patterns are usually diagnosed through non-invasive electrical measurements on the surface of the body, i.e., the electrocardiogram (ECG). However, the most common lead configuration of the ECG, the 12-lead ECG, has its limitations in providing sufficient information to identify and locate the origin of cardiac arrhythmias. Therefore, there is an increasing need to develop novel methods to diagnose and find the origin of arrhythmic excitation, which will increase the efficacy of the treatment and diagnosis of cardiac arrhythmias. The objective of this research was to develop a family of multi-scale computational models of the human heart and thorax to simulate and investigate the effect of arrhythmic electrical activity in the heart on the electric and magnetic activities on the surface of the body. Based on these simulations, new theoretical algorithms were developed to non-invasively diagnose the origins of cardiac arrhythmias, such as the location of ectopic activities in the atria or ischemic regions within the ventricles, which are challenging to the clinician. These non-invasive diagnose methods were based on the implementation of multi-lead ECG systems, magnetocardiograms (MCGs) and electrocardiographic imaging.

Blood flow is an important measurement in the diagnosis of cardiovascular diseases – the main cause of death globally. Cardiovascular diseases are often associated with atherosclerosis, which is a condition that causes the narrowing of arteries due to a buildup of lipids on the wall of the arterial vessels. Atherosclerosis occurring in the upper or lower limbs (referred to as peripheral arterial diseases) may lead to heart attack, stroke or severe health complications. Early detection of peripheral arterial diseases will enable primary prevention, and thus a reduction in morbidity, mortality and associated resources and financial costs. Limitations and drawbacks in the current methods for peripheral arterial blood flow measurement were primary factors in directing this research, which focuses on developing a reliable, easy-to-use and low-cost, non-invasive blood flow metering method that can replace or be an alternative option to current methods. This thesis describes the design and development of a novel electromagnetic induction method that can be used for peripheral arterial blood flow measurement non-invasively. In general terms, an electromagnetic induction flow metering technique is desirable because it is linear and insensitive to viscosity, temperature, conductivity and pressure loss. Additionally, and unlike previous non-invasive electromagnetic blood flow meters, the proposed method can be calibrated offline and is insensitive to velocity profile. The latter is important in obtaining measurements with high accuracy as blood flow in mammals is asymmetric. A mathematical model was developed for the proposed electromagnetic induction method based on the theory of “weight functions” by Shercliff and the “virtual current” theory by Bevir. This model demonstrated that, for multiple flow channels within a cross-sectional area bounded by a multi-electrode array and across which a uniform magnetic field is applied, flow induced potentials, due to the flow interaction with the magnetic field, can be predicted. From these flow induced potentials, the total volumetric flow rate can be found, irrespective of the number, size and location of the flow channels within the area bounded by the electrode array using a technique based on the Discrete Fourier Transform method. This proposed method allows the venous and arterial blood flow in a limb to be found. Next, a finite element model was developed in COMSOL Multiphysics software to validate the theoretical work. This was achieved by modelling multiple flow channels within a cylindrical region and obtaining flow induced potentials, which were compared with the theoretical values. From these induced potentials, the volumetric flow rate was found, using the DFT method, and confirmed. Finally, a practical model was designed and built which consisted of a physical pipework model (simulating a human limb), an electromagnet and signal conditioning and processing systems. Flow induced potential difference measurements were made using this model and compared with the predicted theoretical values. Overall, a good agreement was found between the theoretical results, computer simulations and practical results. Based on this work and additional work that is suggested in thisresearch, a medical prototype non-invasive electromagnetic blood flow meter device can be developed for clinical trials.

Advances in technology have now made it possible to analyze cardiac output (Q) with only a single-breath, making measurements during exercise quicker and less invasive for the subject. Certain non-invasive techniques allow for measurement of the disappearance of a soluble inert gas as it diffuses across the blood-gas barrier in the lungs. The rate of disappearance of the gas is directly proportional to the flow of blood past the lungs and subsequently provides an estimate of pulmonary capillary blood flow (Qc), or Q. The SensorMedics® Corporation (Yorba Linda, CA) has developed a single-breath acetylene (C₂H₂) technique (SensorMedics Vmax 229TM), which includes a simple device to linearize expiratory flow rate by increasing the time by which the sensors can measure the disappearance of the marker gas and improve quantification. The purpose of this investigation was to determine the reproducibility of the C₂H₂ single-breath technique during ramping exercise testing with the addition of a starling resistor in 11 apparently healthy, sedentary volunteers (7 male and 4 female). Subjects performed three maximal ramping exercise test sessions over a 6-week period and Qc was measured at rest and at three time points during the exercise test. The C₂H₂ single-breath Qc measurement technique was shown to be repeatable when systematically related to VO₂ (Qc/VO₂ relation highly correlated r² = 0.72-.74), but slightly lower than previously reported. Means and 95% confidence intervals revealed the precision of the technique over repeated testing days. This method was able to capture Qc measurements at intensities greater than 75% VO₂pk in all subjects with the use of the Starling resistor. Bland-Altman plots reveal Qc measures to be about 50% more variable than highly reproducible measures such as VO₂ and HR. Intraclass reliability coefficients (r) found through repeated measures ANOVA were found to perform low (rx,x= -0.11-0.31) from rest throughout all intensities of exercise. This device is limited in the ability of the sensors to accurately analyze Qc with subjects who are unfamiliar and have difficulty with the single-breath maneuver. Such instances make it difficult for objective, accurate determinations to be made by the clinician. The C₂H₂ single-breath method was found to capture Qc at higher intensities and a high level of precision with the addition of the starling resistor. However, more evidence needs to be analyzed before use of this device can be put into clinical practice.
Master of Science

O estudo endócrino-reprodutivo com o uso da extração e dosagem de metabólitos de esteroides em excretas tem sido proposta como uma ferramenta extremamente útil por não ser invasiva e permitir estudos longitudinais com grande número de coletas de amostras sem produzir estresse, além de ser viável em psitacídeos. Assim, este estudo objetivou descrever e comparar as concentrações de metabólitos de glicocorticoides, testosterona, estrógeno e progesterona em excretas de ararajubas em diferentes categorias reprodutivas, com o uso de técnicas não invasivas, além de validar fisiologicamente os ensaios para dosagens desses metabólitos em excretas da espécie. Para isso, foram utilizadas 24 (vinte e quatro) ararajubas, das quais foram coletados excretas durante diferentes fases reprodutivas, sendo: sem atividade reprodutiva, em atividade de incubação de ovos e em atividade de postura de ovos. Além disso, foram feitos desafios com aplicação de ACTH e GnRH, para validação dos ensaios. Como resultados, obtivemos picos de concentração de metabólitos de glicocorticoides após aplicação de ACTH e picos de concentração de metabólitos de testosterona nos machos após aplicação do GnRH, validando fisiologicamente os ensaios para mensurar estes metabólitos hormonais; os ensaios para mensurar metabólitos de estrógeno e progesterona foram validados biologicamente. Foram observados valores semelhantes de metabólitos de glicocorticoides entre as diferentes categorias reprodutivas, porém diferentes nos metabólitos de testosterona, estrógeno e progesterona, com valores maiores durante postura (testosterona e estrógeno), e maiores na postura com relação aos animais sem atividade reprodutiva (progesterona).
The endocrine and reproductive study using the extraction and quantification of metabolites of steroids in excreta has been proposed as an extremely useful tool for being non-invasive and allow longitudinal studies with large numbers of samples collected without producing stress, and is feasible in parrots. Thus, this study aimed to describe and compare the concentrations of metabolites of glucocorticoids, testosterone, estrogen and progesterone in the excretes golden conures in different reproductive categories, with the use of non-invasive techniques, and validate physiologically assays for determination of these metabolites in the excreta species. For this, we used 24 (twenty four) golden conures, which excreta were collected during different reproductive phases, as follows: no reproductive activity, activity in the incubation of eggs and egg-laying activity. Additionally, challenges were performed with application of ACTH and GnRH for validation tests. We observed peak concentrations of glucocorticoid metabolites after administration of ACTH and peak concentrations of metabolites of testosterone in males after application of GnRH, physiologically validating assays to measure these hormone metabolites; tests to measure metabolites of estrogen and progesterone were biologically validated. Values of glucocorticoid metabolites were similar between different reproductive categories, but between metabolites of testosterone, estrogen and progesterone were different, with higher values during posture (testosterone and estrogen), and higher in posture toward animals without reproductive activity (progesterone) .

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005.
Includes bibliographical references.
Many brain tumors are localized deeply and are currently surgically inaccessible without causing severe damage to the overlying structures of the brain. The current spectrum of non-invasive methods for treating such tumors includes radiotherapy, which requires exposure to ionizing radiation, and chemotherapy, which is systemically toxic. However, these tumors may also potentially be attacked by focusing highly intense ultrasound onto them. Focused ultrasound surgery is without the side effects of radiotherapy and chemotherapy, and the therapeutic effect of ultrasound therapy can be monitored in real- time using the proton chemical shift MRI technique. However, in order for brain tumors to be treated non-invasively, the ultrasound must be focused onto the targeted brain tissue through the intact cranium. Transcranial focusing of ultrasound is a longstanding and difficult problem as skull is a highly heterogeneous material. As the ultrasound field propagates through the bones of the skull, it undergoes substantatial distortion due to the variations in density and speed of sound therein. There is substantial individual variation in skull size, thickness and composition. Furthermore, the acoustic attenuation coefficient in bone is high, so the skull may also be heated by the ultrasound propagating through it. This thesis contains novel simulation techniques for analyzing transcranial acoustic propagation and for analyzing the temperature changes so produced in the brain, skull and scalp. These techniques have also been applied to modeling non-invasive treatment of the liver, and to producing therapeutic ultrasound fields that harness non-linear acoustic effects advantageously.
(cont.) The thesis also contains unified models for the speed of sound and the acoustic attenuation coeffiecient in human skull. These models were generated by combining genetic optimization algorithms, acoustic propagation modeling and empirical measurement of intracranial ultrasound fields; they are valid across the full range of trabecular and cortical cranial bone.
by Christopher W. Connor.
Ph.D.

La portata media cardiaca, (cardiac output “CO”) è un parametro essenziale per una buona gestione dei pazienti o per il monitoraggio degli stessi durante la loro permanenza nell’unità di terapia intensiva. La stesura di questo elaborato prende spunto sull’articolo di Theodore G. Papaioannou, Orestis Vardoulis, and Nikos Stergiopulos dal titolo “ The “systolic volume balance” method for the non invasive estimation of cardiac output based on pressure wave analysis” pubblicato sulla rivista American Journal of Physiology-Heart and Circulatory Physiology nel Marzo 2012. Nel sopracitato articolo si propone un metodo per il monitoraggio potenzialmente non invasivo della portata media cardiaca, basato su principi fisici ed emodinamici, che usa l’analisi della forma d’onda di pressione e un metodo non invasivo di calibrazione e trova la sua espressione ultima nell’equazione Qsvb=(C*PPao)/(T-(Psm,aorta*ts)/Pm). Questa formula è stata validata dagli autori, con buoni risultati, solo su un modello distribuito della circolazione sistemica e non è ancora stato validato in vivo. Questo elaborato si pone come obiettivo quello di un’analisi critica di questa formula per la stima della portata media cardiaca Qsvb. La formula proposta nell'articolo verrà verificata nel caso in cui la circolazione sistemica sia approssimata con modelli di tipo windkessel. Dallo studio svolto emerge il fatto che la formula porta risultati con errori trascurabili solo se si approssima la circolazione sistemica con il modello windkessel classico a due elementi (WK2) e la portata aortica con un’onda rettangolare. Approssimando la circolazione sistemica con il modello windkessel a tre elementi (WK3), o descrivendo la portata aortica con un’onda triangolare si ottengono risultati con errori non più trascurabili che variano dal 7%-9% nel caso del WK2 con portata aortica approssimata con onda triangolare ad errori più ampi del 20% nei i casi del WK3 per entrambe le approssimazioni della portata aortica.

La còrnia és una estructura transparent ubicada a la part frontal de l’ull que permet la transmissió de la llum i protegeix globus ocular d’agressions externes. La principal característica de la còrnia és la seva transparència. Aquesta depèn del nivell de hidratació de l’estroma, que ha de mantenir-se en un constant estat de deshidratació. Aquest nivell de hidratació depèn d’un equilibri dinàmic entre els fluxos iònics que travessen les capes endotelials i epitelials. Per tant, la permeabilitat d’aquestes capes resulta un factor determinant per mantenir la homeòstasis corneal i conseqüentment, la transparència corneal. Malgrat això, no existeixen mètodes apropiats per avaluar la funció barrera corneal de forma no invasiva i que puguin ser utilitzats in vivo. Ja que la permeabilitat iònica té molta importància en les propietats elèctriques passives dels teixits vius, els mètodes basats en aquestes propietats són àmpliament utilitzats en estudis in vitro de la funcionalitat de les capes corneals. Aquesta tesis doctoral es centra en el desenvolupament i validació d’un mètode no invasiu per l’avaluació de l’estat funcional de les principals capes corneals que pugui ser utilitzat in vivo. Per avaluar la viabilitat del mètode proposat s’ha desenvolupat un model numèric basat en elements finits (FEM). Els resultats de les simulacions indiquen que les mesures obtingudes mitjançant elèctrodes col·locats sobre la superfície corneal són suficientment sensibles als canvis de les propietats elèctriques de l’endoteli i de l’epiteli. Una primera versió del sensor d’impedància s’ha fabricat utilitzant un substrat de Pyrex®. De forma que s’ha d’aplicar una certa pressió per tal d’aplanar la curvatura corneal i assegurar el contacte elèctric entre la superfície corneal i els elèctrodes. Malgrat la pressió exercida, sols es pot assegurar el contacte elèctric per la configuració d’elèctrodes més pròxima. Malgrat aquesta limitació, s’ha validat la capacitat del mètode per avaluar in vivo la funció barrera de la còrnia. Per tal de superar les limitacions del substrat rígid, s’ha desenvolupat un sensor de impedància flexible basat en un substrat polimèric de SU-8. D’aquesta forma, la facilitat d’ús i aplicabilitat del mètode proposat milloren notablement ja que no es requereix pressió per aplicar el sensor. La viabilitat del mètode ha estat avaluada incrementant farmacològicament la permeabilitat epitelial de conills i monitoritzant el procés de cicatrització de l’epiteli. Els resultats obtinguts s’han comparat satisfactòriament amb mesures de permeabilitat a la fluoresceïna, un mètode destructiu que es relaciona directament amb la permeabilitat. També s’ha observat que la resolució de les mesures realitzades està principalment limitada per variacions en el gruix de la llàgrima entre el sensor i la superfície corneal. De la mateixa forma, s’ha observat que la contribució de la llàgrima a la impedància mesurada es pot minimitzar augmentant la separació. En paral·lel amb el desenvolupament del sistema in vivo, s’ha estudiat la possibilitat d’aplicar el mètode a l’avaluació de la funció barrera de l’endoteli en còrnies extretes. Aquest nou desenvolupament podria ser molt útil per avaluar la funcionalitat corneal abans d’un transplantament. El mètode proposat permetrà la simplificació dels procediments experimentals utilitzats actualment, que requereixen de l’eliminació de l’epiteli abans de fer la mesura. Les mesures d’impedància obtingudes s’han comparat satisfactòriament amb tècniques microscòpiques de tinció immunològiques. El treball multidisciplinar presentat en aquesta tesis doctoral ha resultat en un nou mètode per a l’avaluació in vivo de la funció barrera corneal de forma no invasiva. Els excel·lents resultats obtingut han permès la transferència tecnològica del mètode proposat a la pràctica clínica. D’aquesta forma, el microsistema desenvolupat ha estat acceptat com a dispositiu mèdic per l’Agència Espanyola dels Medicaments i Productes Sanitaris (AEMPS) per ser utilitzat en humans. Actualment, el mètode desenvolupat es troba en fase d’assaig clínic.
The cornea is a hemispherical transparent structure located in front of the eye that allows the transmission of light and protects the ocular globe against external aggressions. The corneal transparency depends on the hydration of the stroma, which has to remain in a constant state of dehydration. This hydration level depends on a dynamic equilibrium between the ion fluxes through the endothelial and epithelial layer. Thus, the permeability of those layers plays the most important role to maintain the corneal homeostasis, and finally, the corneal transparency. However, there is a lack of proper non-invasive methods for assessing the corneal barrier function in in vivo conditions. Since ionic permeability has a fundamental impact on the passive electrical properties of living tissues, methods based on the study of those properties have consistently been used in in vitro studies of the corneal layers functionality. This dissertation is focused on the development and validation of a non-invasive method to assess the functional state of the main corneal layers in in vivo conditions. An electrical model of the cornea has been developed and analyzed by means of finite elements method (FEM). The simulation results indicate that the measurements performed by electrodes placed on the corneal surface are indeed sufficiently sensitive to the changes in the electrical properties of the epithelial and endothelial layers. The impedance sensor was firstly fabricated using a rigid Pyrex substrate. Consequently, in order to flatten the corneal curvature and ensure the electric contact between the electrodes and the corneal surface a reasonable pressure must be applied. However, the proper electric contact can only be achieved with the closest electrode configuration. Despite this limitation, the capability to in vivo assess the corneal barrier function was successfully evaluated. To overcome the limitations of the rigid substrate, a flexible impedance sensor has been developed using a polymeric SU-8 substrate. Therefore, the usability and performance of the proposed method is increased since no pressure is needed to place the sensor on the corneal surface. Its feasibility was evaluated in vivo by pharmacologically increasing the epithelial permeability and monitoring a corneal epithelium wound-healing process. The obtained impedance results were successfully compared to the measurements of permeability to sodium fluorescein, a well-known destructive method directly related with the permeability. It was also observed that the resolution of the performed measurements is mainly limited by variations in the tear film thickness between the sensor and the corneal surface. However, it was observed that the contribution of the tear film to the measured impedance can be minimized by increasing the separation between electrodes. In parallel with the development of the in vivo system, it has been studied the possibility to apply the method to assess the endothelium barrier function of excised corneas. This new development could be a helpful tool for evaluating the corneal functionality before grafting. The proposed method will allow the simplification of the currently used experimental procedures, which requires the remove of the epithelium to perform the measurement. The obtained impedance results were successfully compared with microscopy immunostaining techniques. The multidisciplinary work described in this dissertation has given rise to a novel method for in vivo assessment of the corneal barrier function in a non-invasive way. The excellent results obtained in the experimental field have allowed transferring the proposed method to the clinical practice. Thus, the developed microsystem has been accepted as a medical device by Spanish Agency of Medicines and Medical Devices(AEMPS)to be used in humans. Currently, the developed method is clinical assay phase.

While all mammals sleep, the functions and implications of sleep are not well understood, and are a strong area of investigation in the research community. Mice are utilized in many sleep studies, with electroencephalography (EEG) signals widely used for data acquisition and analysis. However, since EEG electrodes must be surgically implanted in the mice, the method is high cost and time intensive. This work presents an extension of a previously researched high throughput, low cost, non-invasive method for mouse behavior detection and classification. A novel hierarchical classifier is presented that classifies behavior states including NREM and REM sleep, as well as active behavior states, using data acquired from a Signal Solutions (Lexington, KY) piezoelectric cage floor system. The NREM/REM classification system presented an 81% agreement with human EEG scorers, indicating a useful, high throughput alternative to the widely used EEG acquisition method.

A non-invasive, in vitro method of estimating mean pulmonary artery pressure (PAP) was developed. This information was obtained by establishing a relationship between the pneumatic right drive pressure (RDP) and PAP waveforms. The RDP-PAP relationship was formalized into a series of multiple-linear regression equations for TAH cardiac cycles of known fill volume (FV). Correlation of computed estimates of PAP to actual measurements showed that these equations were greater than 92% accurate within 1.84 mmHg. In addition, while the RDP-PAP relationships were wholly dependent on FV, it was shown that they are independent of the manner in which FV was obtained. This method proved useful over the clinical operating range of the pneumatic heart driver, as well as over the normal physiological range of PAP in the human. Effectiveness of this method in vivo needs to be demonstrated.

Extracellular oxygen concentrations affect cellular metabolism and influence tissue function. Detection methods for these extracellular oxygen concentrations currently have poor spatial resolution and are frequently invasive. Fluorescence Lifetime Imaging Microscopy (FLIM) offers a non-invasive method for quantifying local oxygen concentrations. However, existing FLIM methods also show limited spatial resolution >1 μm and low time-resolved accuracy and precision, due to widefield time-gate. This study describes a new optimised approach using FLIM to quantity extracellular oxygen concentration with high accuracy (±7 μmol/kg) and spatial resolution ( ≅ 0.3 μm). An oxygen sensitive fluorescent dye, tris(2,2′-bipyridyl)ruthenium(II) chloride hexahydrate [Ru(bipy)3]+2, was excited with a multi-photon laser and fluorescence lifetime was measured using time-correlated single photon counting (TCSPC). The system was fully calibrated with optimised techniques developed for avoiding artefacts associated with photon pile-up and phototoxicity, whilst maximising spatial and temporal resolution. An extended imaging protocol (1800 sec) showed no phototoxic effects on cells at dye concentrations of <0.4 mM. Extracellular spatial oxygen gradients were identified around isolated chondrocytes, seeded in three-dimensional agarose gel. The technique was validated by regulating oxygen cellular consumption and thus confirming that the oxygen gradient was governed by cellular consumption. The technique identified a subpopulation of cells exhibiting statistically significant spatial oxygen gradients at the cell perihery. The subpopulation was shown to be significantly larger in cell diameter correlating with what that expected from chondrocytes in the deep zone. This technique provides an exciting opportunity to non-invasively quantify pericellular spatial oxygen gradients from within three-dimensional cellular constructs without prior manipulation of the cells. Thus by examining cellular metabolisms it will advance our understanding of the optimal cellular environment for tissue engineering and regenerative medicine.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2008.
Includes bibliographical references (p. 83-92).
Research on spine biomechanics is critical to understand pathology such as degenerative changes and low back pain. However, current study on in-vivo spine biomechanics is limited by the complex anatomy and invasive methodology. Modem clinical imaging techniques such as magnetic resonance and fluoroscope images, which are widely accessible nowadays, have the potential to study in-vivo spine biomechanics accurately and non-invasively. This research presents a new combined magnetic resonance and fluoroscope imaging matching method to study human lumbar vertebral kinematics and disc deformation during various physiologic functional activities. Validation and application of this method as well as discussion of its performance and applicability are detailed herein.
by Shaobai Wang.
S.M.

This work presents the development of a novel and non-invasive method that measures fluid flow rate and temperature in pipes. While current non-invasive flow meters are able to measure pipe flow rate, they cannot simultaneously measure the internal temperature of the fluid flow, which limits their widespread application. Moreover, devices that are able to determine flow temperature are primarily intrusive and require constant maintenance, which can shut down operation, resulting in downtime and economic loss. Consequently, non-invasive flow rate and temperature measurement systems are becoming increasingly attractive for a variety of operations, including for use in leak detection, energy metering, energy optimization, and oil and gas production, to name a few. In this work, a new solution method and parameter estimation scheme are developed and deployed to non-invasively determine fluid flow rate and temperature in a pipe. This new method is utilized in conjunction with a sensor-based apparatus--"namely, the Combined Heat Flux and Temperature Sensor (CHFT+), which employs simultaneous heat flux and temperature measurements for non-invasive thermal interrogation (NITI). In this work, the CHFT+ sensor embodiment is referred to as the British Thermal Unit (BTU) Meter. The fluid's flow rate and temperature are determined by estimating the fluid's convection heat transfer coefficient and the sensor-pipe thermal contact resistance. The new solution method and parameter estimation scheme were validated using both simulated and experimental data. The experimental data was validated for accuracy using a commercially available FR1118P10 Inline Flowmeter by Sotera Systems (Fort Wayne, IN) and a ThermaGate sensor by ThermaSENSE Corp. (Roanoke, VA). This study's experimental results displayed excellent agreement with values estimated from the aforementioned methods. Once tested in conjunction with the non-invasive BTU Meter, the proposed solution and parameter estimation scheme displayed an excellent level of validity and reliability in the results. Given the proposed BTU Meter's non-invasive design and experimental results, the developed solution and parameter estimation scheme shows promise for use in a variety of different residential, commercial, and industrial applications.
MS

Cette thèse vise à proposer des outils innovants pour le calcul de structures aéronautiques évoluant à haute température. En effet, les régimes de fonctionnement des moteurs actuels conduisent à des évolutions élasto-viscoplastiques généralisées dans les pièces métalliques et l’utilisation de modèles simplifiés (élastiques) n’est plus totalement satisfaisante en terme de précision, même en phase de préconception. De même, la géométrie complexe permettant le refroidissement continu des pièces (micro-perforations) doit être prise en compte de manière exacte. Les techniques de calcul standard pour ce genre de problème conduiraient à des simulations lentes et peu flexibles (la moindre modification entraînant une remise en œuvre complète de la chaîne de calcul). Plus précisément, cette thèse étend les méthodes de type global/local non-intrusives au cas de la viscoplasticité généralisée en utilisant deux échelles de temps et d'espace, chacune adaptée aux phénomènes locaux et globaux à capturer. La méthode est ensuite étendue au calcul de nombreux cycles complexes de chargement, par des techniques de saut de cycles. Le schéma de couplage en temps permet alors une adaptation locale du pas de temps par sous-domaine. Des techniques d’accélération de convergence sont proposées, à l’échelle d’un incrément puis à celle de la succession de cycles (sauts de cycles). Ces développements permettent d’obtenir rapidement et précisément une estimation du cycle limite qui alimente un modèle de durée de vie. Le couplage non-intrusif est réalisé dans un script de programmation pilotant un code commercial (dans notre cas le langage Python et Abaqus/Standard). La méthode a été appliquée sur des plateformes de calculs industrielles, en réutilisant directement des maillages et les mises en données issues de modèles intervenant plus tôt dans la chaîne de calcul. Un cas métier, issu d’un bureau d’études de Safran Aircraft Engines, a pu être traité
This thesis consists in developing innovating tools destined to the simulation of aeronautical structures evolving at high temperature. Indeed, working rates of current engines lead to an elasto-viscoplastic evolution generalized in metallic parts and the use of simplified models (linear elastic) are no longer totally satisfying in term of accuracy, even in initial design process. Likewise, the complex geometry allowing the continuous cool down process of parts (micro-perforations) has to be exactly taken into account. The standard computation techniques dedicated to this kind of models would lead to slow simulations with a lack of flexibility (the slightest modifications leading to restart the whole design process of the computation chain).More precisely, this thesis extends the noninvasive global/local methods to the framework of viscoplasticity generalized to the whole structure, using two scales in time and space, each one adapted to global and local phenomena to capture. The method is then extended to the computation of high number of complex load cycles, by skipped cycles techniques. The time coupling scheme lets then a local adaptation of time steps per subdomain. Convergence acceleration techniques are also set up, first for one time step and then through several load cycles (skipped cycles). These developments conduct to obtain quickly an evaluation of the limit cycle providing data to a lifetime expectancy model.The noninvasive coupling is realized in a programming language script managing the commercial software (respectively in our case Python and Abaqus/Standard). The method has been applied on industrial computational platforms, by reusing directly meshes and data from previous engineering tasks appearing earlier in the computational chain. A genuine test case from a Safran Aircraft Engines design office, was performed successfully

[EN] The behavior of the heart is governed by electrical currents generated in the myocardium, and therefore, the study of the cardiac electrical activity is essential for the diagnosis of cardiac diseases. The forward problem of the electrocardiography (FP) entails the calculation of the torso potentials from the electrical activity of the heart and the 3D body model, while the inverse problem (IP) resolution allows the noninvasive reconstruction of the electrical activity of the heart from surface potentials. The IP is of great importance in clinical applications since it allows estimating the electrical activity of the myocardium with only noninvasive recordings. However, IP resolution is still a big challenge in electrocardiography since it is ill-posed, very unstable and has multiple solutions. In this thesis different algorithms and strategies based on the IP resolution were developed and applied in the noninvasive diagnosis of ventricular and atrial arrhythmias and evaluated with mathematical cellular models and clinical data bases. The thesis focuses on the IP resolution for the noninvasive reconstruction of the myocardial electrical activity for different diseases and propagation patterns, implementing a novel system for complex propagation patterns. The obtained results and propagation patterns were evaluated and classified with the corresponding optimal resolution strategy that minimizes the error and increases the stability of the system, proving its advantages and disadvantages depending on the different diseases and their activation pattern. A novel iterative method was implemented for the IP dipolar resolution optimized for representing simple propagation patterns, achieving a high stability and robustness against noise by constraining the solution to a limited number of dipoles. However, propagation patterns not representable by few dipoles need to be computed with the IP in terms of epicardial solutions which provide a more detailed estimation of the myocardial activity. IP resolution in the voltage and phase domains showed a good accuracy for simple and organized propagation patterns. This method allowed the noninvasive diagnosis of the Brugada syndrome or the location of ectopic focus in atrial arrhythmias by performing a parametric analysis of the electrograms morphology or the activation map reconstruction. However, mathematical and patient results presented in this thesis proved that, for complex propagation patterns like atrial fibrillation (AF), inverse solutions in the voltage and phase domains are over-smoothed and over-optimistic, simplifying the complex AF activity, leading to non-physiological results that do not match with the complex intracardiac electrograms recorded in AF patients. In this thesis, we proposed a novel technique for the noninvasive identification and location of high dominant frequency AF sources, based on the assumption that in many cases atrial drivers present the highest activation rate with an intermittent propagation to the rest of the tissue that activates at a slower rate. Although, voltage and phase inverse solutions for AF complex propagation patterns were over smoothed and inaccurate, the noninvasive estimation of frequency maps was significantly more accurate, allowing the identification of the AF frequency gradient and location of high frequency sources. This technique may help in planning ablation procedures, avoiding unnecessary interseptal punctures for right-to-left frequency gradients cases and facilitating the targeting of the AF drivers, reducing risk and time of the clinical procedure.
[ES] El comportamiento del corazón se rige por corrientes eléctricas generadas en el miocardio y, por lo tanto, el estudio de su actividad eléctrica es esencial para el diagnóstico de enfermedades cardíacas. El problema directo (PD) de la electrocardiografía implica el cálculo de los potenciales del torso a partir de la actividad eléctrica del corazón y el modelo 3D del cuerpo, mientras que la resolución del problema inverso (PI) permite la reconstrucción no invasiva de la actividad eléctrica del corazón a partir de los potenciales de superficie, cobrando una gran importancia en la práctica clínica. Sin embargo, sigue siendo un gran desafío para la electrocardiografía ya que está mal planteado, es muy inestable y tiene múltiples soluciones. A lo largo de esta tesis se han desarrollado diferentes estrategias para la resolución del PI, aplicándolas en el diagnóstico no invasivo de arritmias ventriculares y auriculares, verificándolas mediante modelos celulares matemáticos y bases de datos clínicas. La tesis se centra en la resolución del PI para la reconstrucción no invasiva de la actividad eléctrica del miocardio para diferentes enfermedades cardiacas con diferentes patrones de propagación, implementando un novedoso sistema para patrones de propagación complejos. Además, se han validado los resultados obtenidos y se han clasificado los diferentes patrones de propagación con la estrategia de resolución del PI óptima que minimice el error y aumente la estabilidad del sistema. Un nuevo método iterativo fue implementado para la resolución del PI para fuentes dipolares, siendo óptimo para representar patrones de propagación simples, logrando una alta estabilidad e inmunidad al ruido al restringir la solución a un número limitado de dipolos. Sin embargo, los patrones de propagación que no pueden ser representados por un número limitado de dipolos deben calcularse mediante la resolución del PI en términos de potenciales epicárdicos, proporcionando una estimación más detallada de la actividad del miocardio. La resolución del PI en el dominio de la tensión y fase mostró ser muy preciso para patrones de propagación simples y organizados. Este método permite el diagnóstico no invasivo del síndrome de Brugada o la ubicación de focos ectópicos en arritmias auriculares mediante un análisis paramétrico de la morfología de los electrogramas o la reconstrucción de los mapas de activación. Sin embargo, los resultados matemáticos y clínicos presentados en esta tesis demostraron que, para patrones de propagación complejos como la fibrilación auricular (FA), los resultados obtenidos mediante la resolución del PI en el dominio de la tensión y fase son demasiado suaves y optimistas, simplificando enormemente la complejidad de la FA, llevando a resultados no fisiológicos que no coinciden con la actividad compleja de los electrogramas intracardiacos registrados en pacientes con FA. En esta tesis, se ha propuesto una novedosa técnica para la identificación y localización no invasiva de fuentes con una frecuencia dominante alta, basado en la suposición de que en muchos casos las fuentes eléctricas que generan y mantienen la FA presentan una tasa de activación más alta, con una propagación intermitente hacia el resto del tejido auricular cuya frecuencia de activación es más lenta. Aunque las soluciones en el dominio de la tensión y fase para patrones de propagación complejos fueron más suaves y menos precisas, la estimación no invasiva de los mapas de frecuencia fue significativamente más precisa, permitiendo la identificación del gradiente de frecuencia y ubicación de las fuentes de FA de alta frecuencia. Esta técnica puede ser de gran ayuda en la planificación de los procedimientos de ablación, evitando punciones interseptales innecesarias para casos con un gradiente de frecuencia de derecha a izquierda y facilitando la localización de las fuentes de alta frecuencia
[CAT] El comportament del cor es regeix per corrents elèctrics generades en el miocardi i, per tant, l'estudi de la seua activitat elèctrica és essencial per al diagnòstic de malalties cardíaques. El problema directe (PD) de l'electrocardiografia implica el càlcul dels potencials del tors a partir de l'activitat elèctrica del cor i el model 3D del cos, mentre que la resolució del problema invers (PI) permet la reconstrucció no invasiva de l'activitat elèctrica del cor a partir de els potencials de superfície. La resolució del PI de l'electrocardiografia té una gran importància en la pràctica clínica atès que fa possible una estimació de l'activitat elèctrica del miocardi únicament a partir de registres no invasius. No obstant això, la resolució del PI segueix sent un gran desafiament per a la electrocardiografia ja que està mal plantejat, és molt inestable i té múltiples solucions. Al llarg d'aquesta tesi s'han desenvolupat diferents estratègies basades en la resolució PI, aplicant-les en el diagnòstic no invasiu d'arítmies ventriculars i auriculars, verificant mitjançant models cel·lulars matemàtics i bases de dades clíniques. La tesi se centra en la resolució del PI per a la reconstrucció no invasiva de l'activitat elèctrica del miocardi per a diferents malalties cardíaques amb diferents patrons de propagació, implementant un nou sistema per a patrons de propagació complexos. A més se han validat els resultats obtinguts i se han classificat els diferents patrons de propagació amb l'estratègia de resolució del PI òptima que minimitze l'error i augmente l'estabilitat del sistema. Un nou mètode iteratiu va ser implementat per a la resolució del PI per fonts dipolars, sent òptim per representar patrons de propagació simples, aconseguint una alta estabilitat i immunitat al soroll en restringir la solució a un nombre limitat de dipols. No obstant això, els patrons de propagació que no poden ser representats per un nombre limitat de dipols s'han de calcular mitjançant la resolució del PI en termes de potencials epicàrdics, proporcionant una estimació més detallada de l'activitat del miocardi. La resolució del PI en el domini de la tensió i fase va mostrar ser molt precís per a patrons de propagació simples i organitzats. Aquest mètode permet el diagnòstic no invasiu de la síndrome de Brugada o la ubicació de focus ectòpics en arítmies auriculars mitjançant una anàlisi paramètric de la morfologia dels electrogrames o la reconstrucció dels mapes d'activació. No obstant això, els resultats matemàtics i clínics presentats en aquesta tesi van demostrar que, per patrons de propagació complexos com la fibril·lació auricular (FA), els resultats obtinguts mitjançant la resolució del PI en el domini de la tensió i fase són massa suaus i optimistes, simplificant enormement la complexitat de la FA, obtenint resultats no fisiològics que no coincideixen amb l'activitat complexa dels electrogrames intracardiacos registrats en pacients amb FA. En aquesta tesi, s'ha proposat una nova tècnica per a la identificació i localització no invasiva de fonts amb una freqüència dominant alta, basat en la suposició que en molts casos les fonts elèctriques que generen i mantenen la FA presenten una taxa d'activació més alta, amb una propagació intermitent cap a la resta del teixit auricular on la freqüència d'activació és més lenta. Encara que, les solucions en el domini de la tensió i fase per patrons de propagació complexos van ser més suaus i menys precises, l'estimació no invasiva dels mapes de freqüència va ser significativament més precisa, permetent la identificació del gradient de freqüència i ubicació de les fonts de FA d'alta freqüència. Aquesta tècnica pot ser de gran ajuda en la planificació dels procediments d'ablació, evitant puncions interseptales innecessaris per a casos amb un gradient de freqüència de dreta a esquerra i facilitant la
Pedrón Torrecilla, J. (2015). Non-invasive Reconstruction of the Myocardial Electrical Activity from Body Surface Potential Recordings [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/58268
TESIS

Grouting is used in underground construction to reduce the water flow into tunnels and caverns and to limit the lowering of the surrounding groundwater table. Due to their wide availability and low cost relative to other materials, cement based materials are commonly used as grouts and, in this context, the rheology of the cement grout is an important factor. Rheological properties of cement grout such as viscosity and yield stress are commonly measured off-line using laboratory instruments, and some simple tools are available to make field measurements. However, these methods often lack accuracy and reliability. Although the rheological properties of the grout used play a fundamental role in design and execution, no method has yet been developed to measure these properties in-line in field work.   In this work, for the first time, an in-line rheometry method combining the Ultrasound Velocity Profiling (UVP) technique with Pressure Difference (PD) measurements, known as “UVP+PD”, was successfully tested for continuous in-line measurements of concentrated micro cement based grouts. The feasibility of using the UVP+PD method depends on the in-line determination of the rheological properties and time dependent behaviour of the cement grouts. A test set-up consisting of a combination of an experimental “flow loop” and a conventional field grouting rig – UNIGROUT E22H – from AtlasCopco, was used to investigate the feasibility of determining the rheological properties of cement grout using the UVP+PD method under field conditions. A laboratory based test set-up was used to further investigate the rheological properties in a more controlled environment.   The velocity profiles were measured directly in-line. The shape of the velocity profiles was visualized, and the change in the shape of the profiles with concentration and time was observed. The viscosity and yield stress of the grout were determined using rheological models, e.g. Bingham and Herschel-Bulkley. In addition, rheological properties were determined using the non-model approach (gradient method) and the tube viscometry concept and were compared with results obtained using the rheological models. In addition, the obtained rheological properties were subsequently compared with off-line measurements using a conventional rotational rheometer.  The UVP+PD method was found to be capable of determining the true rheological behavior of cement grout regardless of the rheological model, providing the opportunity to visualize the change in the shape of the velocity profiles. Furthermore, it was possible to make an accurate determination of the velocity by ultrasound velocity profiling at a very flow rate (i.e. 1liter/min). The ultrasound velocity profiling was also found to be a reliable tool for determining the characteristics of the grout pump. In conclusion, the UVP+PD method was demonstrated to be a promising new in-line tool for determining the rheological properties of commonly used cement based grouts and the changes with concentration and time.

QC 20130530

Birds are commonly used as biomonitors of environmental pollution, with most tests involving invasive or destructive sampling techniques. The need to develop and validate non-invasive techniques has long been recognised. From blood, eggs, feathers or guano, the last shows most promise in this field. However it constitutes both faecal and urinary excretions. The faecal component has serious analytical drawbacks from digestive processes and being comprised of both bio-available and unabsorbed components. In contrast the typically white urine part of guano represents substances emanating entirely from within the bird. Despite the analysis of urine (urinalysis) being widely and successfully used in mammals, its limited application to date in birds is at best misguided because it disregards the nature of avian urine. This thesis endeavours to show how the analysis of the (normally discarded) solid component of avian urine may provide a quantifiable measure of both environmental pollutant exposure and endogenous stress hormone concentrations in birds. The literature is reviewed with regard to birds as biomonitors of the environment and the use of non invasive sampling techniques, especially excreta collected from wild animals including birds. Avian renal physiology and urine composition is described with specific reference to current avian urinalysis methods and how these compare with the proposed use of avian urate spheres (AUS) for biomonitoring. It is also shown how the biomineralisation process of AUS formation is relevant to their collection, extraction and chemical analysis from bird guano. To investigate if AUS contents could be used as a measure of a bird’s environmental pollution exposure, concentrations of lead, copper and zinc, were determined in urate spheres from domestic chickens (Gallus domesticus) exposed to a soil contaminated by these metals. Furthermore an attempt was made to compare metal concentrations in AUS with eggs, feathers and whole guano from the same birds. The results suggested AUS contained higher levels of the contaminating metals in exposed birds compared to control birds. However the aim to show the utility of AUS for biomonitoring the birds’ metal exposure was not achieved because of experimental design limitations. A similar investigation was carried out into the suspected exposure of nestling seabirds to elevated metal concentrations in their fish diet. Metal concentrations in urate spheres from the seabirds were measured along with those in various body tissues of their young. This metal analysis, although limited by small sample size, provided no evidence of an elevated exposure when compared with values reported in the literature. Subsequent reanalysis of earlier tested fish samples showed normal metal concentrations, suggesting the earlier reported fish data had been incorrect. To determine if AUS can be used to measure biologically relevant levels of the avian stress hormone corticosterone, a series of experiments is described using captive great tits (Parus major). These involved the ELISA detection of excreted corticosterone in AUS extracts. The suppressive response to dexamethasone administration was measurable in AUS from these birds, suggesting a physiological validation. However many issues have still to be resolved concerning this method of measuring corticosterone levels in birds. The overall finding of this thesis is that the analysis of AUS may have potential value as a noninvasive sampling method to biomonitor environmental pollution and stress in birds.