Dissertations / Theses on the topic 'Non-invasive'

The ability to measure and quantify myocardial motion and deformation provides a useful tool to assist in the diagnosis, prognosis and management of heart disease. Myocardial motion can be measured by means of several different types of data acquisition. The earliest myocardial motion tracking technique was invasive, based on implanting radiopaque markers into the myocardium around the left ventricle, and recording the marker positions during the cardiac cycle by biplane cineradiography. Until recently, this was the only method with high enough spatial resolution of three-dimensional (3D) myocardial displacements to resolve transmural behaviors. However, the recent development of magnetic resonance imaging techniques, such as displacement encoding with stimulated echoes (DENSE), make detailed non-invasive 3D transmural kinematic analyses of human myocardium possible in the clinic and for research purposes. Diastolic left ventricular filling is a highly dynamic process with early and late transmitral inflows and it is determined by a complex sequence of many interrelated events and parameters. Extensive research has been performed to describe myocardial kinematics during the systolic phase of the cardiac cycle, but not by far the same amount of research has been accomplished during diastole. Measures of global and regional left ventricular kinematics during diastole are important when attempting to understand left ventricular filling characteristics in health and disease. This thesis presents methods for invasive and non-invasive quantification of cardiac kinematics, with focus on diastole. The project started by quantification of changes in global left ventricular kinematics during diastolic filling. The helical myocardial fiber architecture of the left ventricle produces both long- and short-axis motion as well as torsional deformation. The longitudinal excursion of the mitral annular plane is an important component of left ventricular filling and ejection. This was studied by analyzing the contribution of mitral annular dynamics to left ventricular filling volume in the ovine heart. In order to quantify strains for a specific body undergoing deformation, displacements for a set of internal points at a deformed configuration relative to a reference configuration are needed. A new method for strain quantification from measured myocardial displacements is presented in this thesis. The method is accurate and robust and delivers analytical expressions of the strain components. The developed strain quantification method is simple in nature which aids to bridge a possible gap in understanding between different disciplines and is well suited for sparse arrays of displacement data. Analyses of myocardial kinematics at the level of myocardial fibers require knowledge of cardiac tissue architecture. Temporal changes in myofiber directions during the cardiac cycle have been analyzed in the ovine heart by combining histological measurements of transmural myocardial architecture and local transmural strains. Rapid early diastolic filling is an essential component of the left ventricular function. Such filling requires a highly compliant chamber immediately after systole, allowing inflow at low driving pressures. Failure of this process can lead to exercise intolerance and ultimately to heart failure. A thorough analysis of the relation between global left ventricular kinematics and local myocardial strain at the level of myocardial fibers during early diastole in the ovine heart was performed by applying the method for strain quantification and the technique for computing temporal changes in myocardial architecture on measures of myocardial displacements and tissue architecture in the ovine heart. As data acquisition technologies develop, quantification methods for cardiac kinematics need to be adapted and validated on the new types of data. Recent improvements of DENSE magnetic resonance imaging enable non-invasive transmural strain analyses in the human heart. The strain quantification method was first tailored to displacement data from a surgically implanted bead array but has been extended to applications on non-invasive DENSE data measured in two and three dimensions. Validation against an analytical standard reveals accurate results and in vivo strains agree with values for normal human hearts from other studies. The method has in this thesis been used with displacement data from invasive marker technology and non-invasive DENSE magnetic resonance imaging, but can equally well be applied on any type of displacement data provided that the spatial resolution is high enough to resolve local strain variations.

Recent guidelines for the management of stable coronary artery disease (CAD) and myocardial revascularisation emphasise the importance of the presence of ischaemia for guiding revascularisation. Cardiovascular Magnetic Resonance (CMR) perfusion imaging and fractional flow reserve (FFR) are two methods of physiological ischaemia assessment, one invasive and the other non-invasive. In order that the results are interpreted accurately, it is important to be aware of the limitations and advantages of each technique. These techniques measure different parameters so it is not uncommon that the two tests may lead to differing results in one patient. In addition, the extent and not just the presence of ischaemia are increasingly considered to be an important variable that needs to be considered. The aim of this thesis is to assess the similarities and differences in ischaemia assessment between the two tests, in particular in the assessment of ischaemic burden and also on specific clinical scenarios such as microvascular and multivessel disease. Firstly, a close correlation between the extent of ischaemia measured by CMR and the FFR value itself is demonstrated. FFR measurement has previously been used as an indicator of the presence of ischaemia alone and the relationship with ischaemic extent has never been proven. It is an interesting finding, which lends weight to the strategy of targeted revascularisation aiming for the greatest reduction in ischaemic burden. The FFR value itself as an indicator of ischaemic burden is also useful in centres that do not have access to sophisticated imaging techniques such as CMR. Secondly, another simple method of invasive estimation of ischaemic burden is demonstrated via the use of a functional jeopardy score. This is validated against CMR but is limited by a tendency to overestimate the extent of ischaemia. The use of the FFR value itself, as demonstrated in chapter 4, therefore offers better potential as a marker of ischaemic extent. Two examples of areas where there may be discrepant results are in patients with multivessel disease and patients with microvascular disease. A comparative analysis of the diagnostic accuracy of these two tests in multivessel disease demonstrates reasonable concordance but does lead us to question which test is the diagnostic reference standard. In the discrepant cases, it is unclear whether CMR underestimates or FFR overestimates the number of perfusion territories. Finally, a novel method of non invasively differentiating between multivessel disease and microvascular disease is demonstrated, providing a feasible solution to this diagnostic dilemma. Multivessel CAD and microvascular disease can be accurately distinguished using the novel concept of perfusion dephasing analysis, which analyses the spatio-temporal variability in the distribution of myocardial perfusion to the LV myocardium. An improved diagnostic algorithm of CMR is therefore proposed, including the analysis of the variance of time to peak signal intensity, the most accurate index for perfusion dephasing. This has the potential for patient benefit in the reduction of unnecessary invasive angiography procedures.

Most sarcomas of the bone occur in patients of a relatively young age including skeletally immature patients. Approximately 50 child sarcomas are treated with limb salvage surgery per year in the United Kingdom. These children need an extendible implant that can be lengthened periodically to keep pace with the growth in the opposite limb. Surgically, invasive devices have been used for the past thirty years with intrinsic problems of infection and long-term recurrent trauma to the patient. To eliminate problems associated with the invasive device I have attempted to develop a non invasive extendible prosthesis by utilising a magnetically coupled drive. The aims of this study were to ascertain the clinical requirements of an electro-mechanical design, evaluate the performance of the proposed design, validate the design by in vitro tests and conclude its effectiveness by conducting an in vivo clinical trial. The final aim was to develop a similar concept for the distraction of juvenile spinal scoliosis. The drive technology used in this device is an induction motor with a gear driven telescoping prosthesis. In very young patients the potential loss of growth in the resected bone usually exceeds the amount of extension that could be built into the prosthesis. Therefore, maximisation of the growth potential was the prime objective of the prospective design. A previously designed two-stage epicyclic gearbox was tested and improvements were made to provide a load carrying capacity identified by in vivo measurements conducted in over 30 patients. In this design the motor configuration is in two parts: a rotor which fits inside the prosthesis and a stator which is an external device used to extend the prosthesis remotely. A compact external drive was developed with focused magnetic flux which required no cooling and operated on a single-phase power supply. The effect of the magnetic rotor on the diagnostic imaging was tested and the findings are reported in this thesis. A number of patients were treated with this new device and the clinical outcome is presented. A different version of the device for use with a spinal rod system was developed for the treatment of juvenile scoliosis.

Presented in this thesis are the following theoretical investigations carried out on the non-invasive microwave hyperthermia of malignant tumours in the human body: Fundamental concepts of electromagnetic wave propagation through a biomass and its interaction with it, are discussed. Various types of applicators used for producing hyperthermia in a biomass, are also discussed. Propagation of a uniform plane electromagnetic wave through a human body is investigated for the general case of oblique incidence. Various models used for the human body have been discussed and the planar multilayer model has been chosen for this study. Reflection and transmission coefficients for both the parallel and perpendicular linear polarisations of the wave, have been determined. For normal incidence, power transfer ratio at the muscle has been defined and calculated at 433, 915 and 2450 MHz (ISM frequencies). Efects of skin thickness and also of fat thickness, on the power transfer ratio at muscle, have been studied. Effects of the thickness and dielectric constant of a bolus, and also of the dielectric constant of an initial layer, on the power transfer ratio, have been studied and their optimum values obtained at the ISM frequencies. For microwave hyperthermia, 915 MHz is recommended as the frequency of operation. Steady-state solution of the bioheat transfer equation has been obtained, assuming the biomass to be a semi-infinite homogeneous medium. Effects of various physical parameters on the temperature profile in the biomass, have been studied. Also studied is the effect of the surface temperature on the magnitude, location and the width of the temperature peak attained in the biomass. A method to determine the microwave power and the surface temperature required to produce a prescribed temperature profile in the biomass, has been developed. The transient-state solution of the bioheat transfer equation has been obtained to study the building up of the temperature profile. Procedures for the design of an open-ended rectangular metal waveguide applicator and for estimating the total microwave power requirement to produce hyperthermia in the human body, have been developed. Performance of the applicators employing linear as well as planar arrays of open-ended rectangular metal waveguide antennas, has also been studied. In order to reduce the overall physical size of the applicators, filling up of the feed waveguide with a high dielectric constant but low loss material is suggested. A simple method of obtaining the elements of the array by partitioning a large aperture by using metal walls has been adopted. Calculation of the total microwave power required by various applicators for producing hyperthermia at various depths in a biomas, have been made and a comparison of the performance of various applicators, has been presented.

Presented in this thesis are the following theoretical investigations carried out on the non-invasive microwave hyperthermia of malignant tumours in the human body: Fundamental concepts of electromagnetic wave propagation through a biomass and its interaction with it, are discussed. Various types of applicators used for producing hyperthermia in a biomass, are also discussed. Propagation of a uniform plane electromagnetic wave through a human body is investigated for the general case of oblique incidence. Various models used for the human body have been discussed and the planar multilayer model has been chosen for this study. Reflection and transmission coefficients for both the parallel and perpendicular linear polarisations of the wave, have been determined. For normal incidence, power transfer ratio at the muscle has been defined and calculated at 433, 915 and 2450 MHz (ISM frequencies). Efects of skin thickness and also of fat thickness, on the power transfer ratio at muscle, have been studied. Effects of the thickness and dielectric constant of a bolus, and also of the dielectric constant of an initial layer, on the power transfer ratio, have been studied and their optimum values obtained at the ISM frequencies. For microwave hyperthermia, 915 MHz is recommended as the frequency of operation. Steady-state solution of the bioheat transfer equation has been obtained, assuming the biomass to be a semi-infinite homogeneous medium. Effects of various physical parameters on the temperature profile in the biomass, have been studied. Also studied is the effect of the surface temperature on the magnitude, location and the width of the temperature peak attained in the biomass. A method to determine the microwave power and the surface temperature required to produce a prescribed temperature profile in the biomass, has been developed. The transient-state solution of the bioheat transfer equation has been obtained to study the building up of the temperature profile. Procedures for the design of an open-ended rectangular metal waveguide applicator and for estimating the total microwave power requirement to produce hyperthermia in the human body, have been developed. Performance of the applicators employing linear as well as planar arrays of open-ended rectangular metal waveguide antennas, has also been studied. In order to reduce the overall physical size of the applicators, filling up of the feed waveguide with a high dielectric constant but low loss material is suggested. A simple method of obtaining the elements of the array by partitioning a large aperture by using metal walls has been adopted. Calculation of the total microwave power required by various applicators for producing hyperthermia at various depths in a biomas, have been made and a comparison of the performance of various applicators, has been presented.

Invasive and non-invasive methods of BTI monitoring and wearout preemption have been proposed. We propose a novel, simple to use, test structure for NBTI /PBTI monitoring. The proposed structure has an AC and a DC stress mode. Although during stress mode, both PMOS and NMOS devices are stressed, the proposed structure isolates the PBTI and NBTI degradation during test mode. A methodology of converting any data-path into ring oscillator (DPRO) is also presented. To avoid the performance overhead of attaching monitoring circuitry to functional block, a non-invasive scheme for BTI monitoring is presented for sleep transistor based logic families. Since, BTI is a critical issue for memories, a scheme for BTI monitoring of 6T SRAM cell based memories is also presented. We make use of the concept of a DPRO and show how a memory system can be made to oscillate in test mode. The frequency of oscillation is a function of the devices in the cell. After validation of the proposed schemes using extensive simulations, we have also validated the results on silicon. We also introduce the concept of wearout mitigation at the compiler level. Using an example of a register file, we present a preemptive method of wearout mitigation using a compiler directed scheme.

This Thesis covers the investigation into the feasibility of monitoring blood glucose non-invasively. The work carried out involved the development of an in-vitro instrument through a series of four stages, each stage of development being an improvement on the previous one. Using these instruments it was shown that by using an appropriate wavelength, glucose could be detected down to 156 mg/dL repeatedly in distilled water, saline and a non-opaque blood analogue. It was also demonstrated that this wavelength could be used to detect the difference between blood samples with different glucose levels. The instruments were also used to demonstrate that a appropriate wavelength could be used as a reference wavelength. In addition to the in-vitro instrument, a basic in-vivo instrument was developed so that physiological data could be taken from either a person's ear or little finger non-invasively. It was clearly demonstrated that the instrument could detect a physiological change in a person whilst the person carried out a 75 g oral glucose to tolerance test.

Thesis advisor: Robert Signorile
It has long been known that as neurons fire within the brain they produce measurable electrical activity. Electroencephalography (EEG) is the measurement and recording of these electrical signals using sensors arrayed across the scalp. Though there is copious research in using EEG technology in the fields of neuroscience and cognitive psychology, it is only recently that the possibility of utilizing EEG measurements as inputs in the control of computers has emerged. The idea of Brain-Computer Interfaces (BCIs) which allow the control of devices using brain signals evolved from the realm of science fiction to simple devices that currently exist. BCIs naturally present themselves to many extremely useful applications including prosthetic devices, restoring or aiding in communication and hearing, military applications, video gaming and virtual reality, and robotic control, and have the possibility of significantly improving the quality of life of many disabled individuals. However, current BCIs suffer from many problems including inaccuracies, delays between thought, detection, and action, exorbitant costs, and invasive surgeries. The purpose of this research is to examine the Emotiv EPOC© System as a cost-effective gateway to non-invasive portable EEG measurements and utilize it to build a thought-based BCI to control the Parallax Scribbler® robot. This research furthers the analysis of the current pros and cons of EEG technology as it pertains to BCIs and offers a glimpse of the future potential capabilities of BCI systems
Thesis (BA) — Boston College, 2010
Submitted to: Boston College. College of Arts and Sciences
Discipline: Computer Science Honors Program
Discipline: Computer Science

Heart disease has been responsible for a significant number of morbidities and mortalities over the last century. As lifestyles and cultures change, so does the approach of management of the disease. With the advent of new technology over the last 6-7 decades the approach towards diagnosing heart diseases has changed a lot. Tools like electrocardiogram, two-dimensional echocardiography, cardiac stress test, Holter monitoring, etc. have become essential in the primary and secondary prevention of heart disease, and also in its management. This clinic is an effort to make these tests easily accessible, affordable and reliable to the patients and potential patients residing in the Orange County area who are at risk for heart diseases.

This thesis is concerned with non-invasive ultrasonic flow measurement, using the transit time principle. The errors associated with the transit-time flowmeter are investigated and a design of flowmeter is suggested. A theoretical and experimental study of the transmission of sound through pipe walls is carried out where it is shown that advantage can be taken of the excitation of Lamb modes. A design of transducer arrangement is made from the results of the work. A solution to the difficult problem of measuring very small times is provided in the form of a novel vernier timing system. The benefits and disadvantages of this timing system are discussed along with the design aspects of other electronic circuits required in the construction of the flowmeter. The flawmeter has been built and tested in the laboratory and is shown to be highly repeatable and accurate. The results of testing the flowmeter compare favourably with tests conducted on a commercial instrument. Improvements to the design and construction and suggestions for further work are given.

Gene expression divergence between populations has been linked to adaptive morphological evolution and is thought to be a factor in the invasive success of certain weedy plants. Understanding the genetic basis of these regulatory changes can identify genes that have been under selection during adaptation to a new environment or new species interactions. A high-throughput sequencing approach was used to study the regulatory basis (cis and/or trans) of gene expression differences between native and invasive populations of Cirsium arvense (Canada thistle) by exploring patterns of differential gene expression and sequence variation. Parent and hybrid allele-specific expression ratios were compared to infer the relative effects of cis- and trans-regulatory change. Genes differentially regulated in cis are considered candidate genes involved in adaptation or weediness because there is evidence for selection acting primarily on cis-regulatory variation. Illumina sequencing of cDNA libraries derived from parents and hybrid pools resulted in a total of 82,713,256 paired-end (2x100bp) reads and 83.4% of these were mapped to a reference C. arvense transcriptome of 88,374 unigene sequences. Expression analysis and variant (SNPs and Indel) calling was performed to score the nature of regulatory divergence for the first 900 contigs, representing ~1% of the total dataset. Of the 40 high-confidence cases, 7 showed cis-effects, 6 showed trans-effects, 9 had varying degrees of both cis and trans, and 18 showed non-intermediate hybrid effects. A set of contigs that had high similarity to 63 known or confirmed stress-related genes, previously identified in studies of sunflower and Canada thistle, was also assayed for allelic imbalance. Of these, 2 cases showed a cis-effect, 2 showed both cis- and trans-effects, and 2 revealed hybrid effects. Contig 23614, an auxin-response transcription factor, was differentially regulated due to cis-effects and has been previously confirmed as drought-stress gene in both sunflower and C. arvense. This research identifies changes in gene expression that are driven by differential selective pressures in native and invasive populations. It also advances our understanding of the nature of genetic changes that drive gene expression evolution.

Antenatal fetal surveillance is a field of increasing importance in modern obstetrics. Measurements extracted (such as fetal heart rate) from antenatal fetal monitoring techniques have the potential to reduce the social, personal and financial burdens of fetal death on families, health care systems and the community. Techniques to monitor the fetus through pregnancy have been developed with the aim of providing information to enable the clinician to diagnose fetal wellbeing, characterise development and detect abnormality. An early diagnosis before delivery may increase the effectiveness of the appropriate treatment. Over the years, various research efforts have been carried out in the field of fetal electrocardiography by attaching surface electrodes to the maternal body. Unfortunately the desired fetal heartbeat signals at the electrode output are buried in an additive mixture of undesired interference disturbances. In this thesis, a non-invasive fetal electrocardiogram machine has been designed, constructed and implemented. This machine is composed of three modified electrocardiogram circuits and an external soundcard. Data was acquired from four surface electrodes placed on the maternal body. Eleven pregnant subjects, with a gestation age between the 30th and 40th weeks of pregnancy, were used to investigate the validity of this machine. Fetal R-waves were detected in 72.7 percent of subjects. The development of a non-invasive machine, capable of detecting and recording valuable anatomic and electrophysiological information of a fetus, represents an important tool in clinical and investigative obstetrics.

This thesis is concerned with non-invasive ultrasonic flow measurement, using the transit time principle. The errors associated with the transit-time flowmeter are investigated and a design of flowmeter is suggested. A theoretical and experimental study of the transmission of sound through pipe walls is carried out where it is shown that advantage can be taken of the excitation of Lamb modes. A design of transducer arrangement is made from the results of the work. A solution to the difficult problem of measuring very small times is provided in the form of a novel vernier timing system. The benefits and disadvantages of this timing system are discussed along with the design aspects of other electronic circuits required in the construction of the flowmeter. The flawmeter has been built and tested in the laboratory and is shown to be highly repeatable and accurate. The results of testing the flowmeter compare favourably with tests conducted on a commercial instrument. Improvements to the design and construction and suggestions for further work are given.

84 pp. / First Edition Published 2001
The noxious weed problem in the western United States has been described as, a biological forest fire racing beyond control because no one wants to be fire boss. Indeed, when small weed infestations are left unchecked, they can grow exponentially and spread across the land much like a slow-moving biological wildfire. However, land consumed by fire usually recovers and is often more productive than before the fire occurred. On the other hand, land consumed by noxious weeds may be irreversibly changed and never again reach its full biological potential. Reviewed 12/2016, First Edition Published 2001

84 pp.
First Edition Published, 2001
The noxious weed problem in the western United States has been described as, a biological forest fire racing beyond control because no one wants to be fire boss. Indeed, when small weed infestations are left unchecked, they can grow exponentially and spread across the land much like a slow-moving biological wildfire. However, land consumed by fire usually recovers and is often more productive than before the fire occurred. On the other hand, land consumed by noxious weeds may be irreversibly changed and never again reach its full biological potential.

Photoplethysmography (PPG) has become widely accepted as a valuable clinical tool for performing non-invasive biomedical monitoring. The dominant clinical application of PPG has been pulse oximetry, which uses spectral analysis of the peripheral blood supply to establish haemoglobin saturation. PPG has also found success in screening for venous dysfunction, though to a limited degree. Arterial Disease (AD) is a condition where blood flow in the arteries of the body is reduced,a condition known as ischaernia. Ischaernia can result in pain in the affected areas, such as chest pain for an ischearnic heart, but does not always produce symptoms. The most common form of AD is arteriosclerosis, which affects around 5% of the population over 50 years old. Arteriosclerosis, more commonly known as 'hardening of the arteries' is a condition that results in a gradual thickening, hardening and loss of elasticity in the walls of the arteries, reducing overall blood flow. This thesis investigates the possibility of employing PPG to perform vascular assessment, specifically arterial assessment, in two ways. PPG based perfusion monitoring may allow identification of ischaernia in the periphery. To further investigate this premise, prospective experimental trials are performed, firstly to assess the viability of PPG based perfusion monitoring and culminating in the development of a more objective method for determining ABPI using PPG based vascular assessment. A complex interaction between the heart and the connective vasculature, detected at the measuring site, generates the PPG signal. The haemodynamic properties of the vasculature will affect the shape of the PPG waveform, characterising the PPG signal with the properties of the intermediary vasculature. This thesis investigates the feasibility of deriving quantitative vascular parameters from the PPG signal. A quantitative approach allows direct identification of pathology, simplifying vascular assessment. Both forward and inverse models are developed in order to investigate this topic. Application of the models in prospective experimental trials with both normal subjects and subjects suffering PVD have shown encouraging results. It is concluded that the PPG signal contains information on the connective vasculature of the subject. PPG may be used to perform vascular assessment using either perfusion based techniques, where the magnitude of the PPG signal is of interest, or by directly assessing the connective vasculature using PPG, where the shape of the PPG signal is of interest. it is argued that PPG perfusion based techniques for performing the ABPI diagnosis protocol can offer greater sensitivity to the onset of PAD, compared to more conventional methods. It is speculated that the PPG based ABPI diagnosis protocol could provide enhanced PAD diagnosis, detecting the onset of the disease and allowing a treatmenpt lan to be formed soonert han was possible previously. The determination of quantitative vascular parameters using PPG shape could allow direct vascular diagnosis, reducing subjectivity due to interpretation. The prospective trials investigating PPG shape analysis concentrated on PVD diagnosis, but it is speculated that quantitative PPG shaped based vascular assessment could be a powerful tool in the diagnosis of many vascular based pathological conditions.

Intracranial pressure (ICP) is an important monitoring modality in the clinical management of several neurological diseases carrying the intrinsic risk of potentially lethal intracranial hypertension (ICH). Considering that the brain is in an enclosed compartment, ICH leads to brain hypoperfusion and eventually ischaemia followed by irreversible neuronal damage. Traumatic brain injury (TBI), for instance, is a condition in which ICH is strongly associated with unfavourable outcome and death. Although ICP can guide patient management in neurocritical care settings, this parameter is not commonly monitored in many clinical conditions outside this environment. The invasive character of the standard methods for ICP assessment and their associated risks to the patient (like infections, brain tissue lesions, haemorrhage) contribute to this scenario. Such risks have prevented ICP assessment in a broad range of diseases like in patients with risk of coagulopathy, as well as in other conditions in which invasive assessment is not considered or outweighed by the risks of the procedure. Provided that knowledge of ICP can be crucial for the successful management of patients in many sub-critical conditions, non-invasive estimation of ICP (nICP) may be helpful when indications for invasive ICP assessment are not met and when it is not immediately available or even contraindicated. Several methods for non-invasive assessment of ICP (nICP) have been described so far. Transcranial Doppler (TCD), for instance, is primarily a technique for diagnosing various intracranial vascular disorders such as emboli, stenosis, or vasospasm, but has been broadly utilised for non-invasive ICP monitoring due to its ability to detect changes in cerebral blood flow velocity derived from ICP variations. Moreover, TCD allows monitoring of these parameters as they may change in time. Optic nerve sheath diameter ultrasonography (ONSD) is another non-invasive tool which gained interest in the last years. The optic nerve sheath is in continuous with the subarachnoid space, and when ICP increased, the diameter of ONSD enlarges proportionally to ICP. The focus of this thesis is on the assessment, applications and development of ultrasoundbased for nICP assessment in different clinical conditions where this parameter is relevant but in many circumstances not considered, including TBI and other neurological diseases ULTRASOUND BASED NON-INVASIVE INTRACRANIAL PRESSURE 17 associated with impairment of cerebral blood flow circulation. As main results, ONSD and TCD-based non-invasive methods could replicate changes in direct ICP across time confidently, and could provide reasonable accuracy in comparison to the standard invasive techniques. These findings support the use of ultrasound based non-invasive ICP methods in a variety of clinical conditions requiring management of intracranial pressure and brain perfusion. More importantly, the low costs associated with nICP methods, ultrasound machines are widely available medical devices, could contribute to its widespread use as a reliable alternative for ICP monitoring in everyday clinical practice.

Al fine di migliorare le conoscenze riguardo la fisiologia perinatale nel cane e nel tentativo di fornire dei potenziali markers diagnostici e/o prognostici per la gestione dei neonati poco vitali o patologici, il progetto di dottorato si è concentrato su due aspetti principali: a) la definizione di alcune caratteristiche dei fluidi fetali nel cane in condizioni di normalità; b) il possibile uso di pelo e unghie come matrici per lo studio retrospettivo sulla concentrazione di deidroepiandrosterone (DHEA) e deidroepiandrosterone solfato (DHEAS), coinvolti nelle fasi finali della maturazione fetale e nell’adattamento neonatale. Per quanto riguarda il primo argomento un primo studio ha indagato la concentrazione di cortisolo nei fluidi fetali del cane alla nascita, indagando il possibile effetto del cortisolo sulla sopravvivenza dei neonati a 24 ore di età, indagando inoltre l’effetto di alcuni parametri materni e fetali sulla concentrazione di cortisolo nei fluidi fetali. Lo studio ha dimostrato una concentrazione maggiore di cortisolo nel fluido allantoideo rispetto al fluido amniotico, con una correlazione positiva nelle concentrazioni tra i due fluidi, è stato riscontrato infine un effetto della cucciolata sulle concentrazioni del cortisolo nei fluidi amniotico e allantoideo. La concentrazione di cortisolo nel fluido amniotico dei cuccioli morti nelle 24 ore dopo la nascita è risultata maggiore rispetto al fluido amniotico dei neonati normali. Un secondo studio ha indagato le concentrazioni di acido urico, lattato, glucosio e creatinina nel fluido amniotico appartenente a cuccioli di taglia piccola nati da taglio cesareo elettivo al termine di gravidanze normali, valutando la possibile influenza della parità materna e del sesso dei neonati sulla concentrazione di questi metaboliti, così come sull’effetto di questi metaboliti sull’outcome neonatale. Da questo studio non sono emerse differenze significative sulla concentrazione di acido urico e creatinina in relazione a parità materna e sesso dei neonati. Per quanto riguarda il glucosio è stata riscontrata un’influenza del sesso dei neonati ma non della parità materna sulla concentrazione nel liquido amniotico. La concentrazione del lattato nel fluido amniotico è risultata statisticamente più elevata nelle cagne multipare rispetto alle primipare. Un terzo studio ha indagato la composizione biochimica dei fluidi fetali del cane a termine di gravidanza. È stata effettuata una comparazione tra i fluidi di soggetti normali e patologici ma l’analisi statistica non è stata in grado di evidenziare differenze significative tra i due gruppi, probabilmente anche per la scarsa numerosità dei soggetti patologici rispetto ai sani. Per quanto riguarda le possibili differenze tra i fluidi nei soggetti sani, sono state evidenziate differenze significative nelle concentrazioni di alcuni dei parametri analizzati, suggerendo un diverso meccanismo di produzione e accumulo per i due fluidi nel cane. Lo studio ha rivelato inoltre l’influenza di taglia materna e parità, così come del sesso dei neonati, su alcuni dei parametri indagati. Altri studi sono necessari per meglio indagare le possibili differenze nella composizione dei fluidi fetali tra soggetti sani e patologici al fine di individuare possibili markers per la rapida individuazione dei soggetti patologici che richiedono una pronta assistenza nelle prime ore di vita. In relazione al secondo aspetto indagato è emerso che il DHEA, prodotto dai surreni fetali, presenta una concentrazione maggiore nel pelo dei neonati prematuri rispetto ai neonati morti tra 1 e 30 giorni di vita, concentrazione che risulta tuttavia simile a quella dei neonati morti nelle prime 24 ore di vita, questi risultati suggeriscono una possibile produzione di questo ormone da parte del feto stesso durante l’ultima fase di sviluppo intrauterino. Sebbene il pelo si sia rivelato una matrice utile per gli studi sulle concentrazioni del DHEA nei neonati, tuttavia il suo uso in vivo è limitato dal quantitativo richiesto per le analisi; è stata quindi indagata la concentrazione del DHEA e della sua forma di trasporto, DHEAS, anche nelle unghie dei cuccioli neonati. I risultati di questo studio hanno rivelato che le unghie sono una matrice ottimale per la determinazione di DHEA e DHEAS e che questa matrice potrebbe essere usata efficacemente anche per studi seriali in vivo. Le concentrazioni di DHEA e DHEAS nelle unghie sono risultate significativamente differenti ma fortemente e positivamente correlate. La concentrazione di DHEAS e non di DHEA è risultata statisticamente maggiore nei cani di tagli piccola rispetto ai soggetti di taglia grande, inoltre la concentrazione di DHEAS è risultata maggiore nei cuccioli prematuri rispetto ai nati morti o ai cuccioli morti tra 11 e 20 giorni di vita.
In order to improve knowledge about perinatal physiology in dogs, and in the attempt to provide some potential diagnostic/prognostic markers for a better management of diseased and less viable newborn puppies, the PhD project was focused on two main topics: a) the definition of some fetal fluids characteristics under normal condition; b) the investigations of suitability of hair and nail single collection for the retrospective analysis of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), involved in the fetal final maturation and neonatal adaptation. In relation to the first topic a first study was aimed to measure the fetal fluids cortisol concentrations in puppies at birth, and to assess the possible effect of cortisol on newborn survival at 24 hours of age, and the effect of some neonatal or maternal parameters on fetal fluids cortisol concentrations. A significant higher cortisol concentration in the allantoic than in the amniotic fluid was found, but with significant high positive correlation between amniotic and allantoic cortisol concentrations. Significant higher amniotic cortisol concentrations were found in puppies dead at 24 hours, as well a significant effect of the litter on fetal fluids cortisol concentrations. The second study investigated the concentrations of uric acid, lactate, glucose and creatinine in amniotic fluid of small sized purebred newborn dogs born by elective cesarean section at term of normal pregnancies, in relation to newborn outcome and the possible effect played by maternal parity and newborn gender on uric acid, glucose, lactate and creatinine concentrations. When the statistical analysis was performed on fetal fluids belonging to normal puppies no significant difference on uric acid concentration were found in relation to maternal parity or newborn gender. Regarding amniotic glucose concentration a significant influence of newborn gender, but not of maternal parity, was found. Amniotic lactate concentration was higher in multiparous in comparison to primiparous bitches. Regarding creatinine no significant differences were found in relation to maternal parity or newborn gender. The third study investigated the biochemical composition of fetal fluids at term pregnancy in dogs. A comparison between fetal fluids characteristics of normal and pathologic puppies was done, but, the statistical analysis did not show significant results, due to the small number of pathologic puppies. When the statistical analysis was applied to the normal puppies, differences between the two fluids were found for many parameters, suggesting a different source and mechanism of production and accumulation of the two fluids in dogs. The study showed also the possible influence of breed body size and of maternal parity and newborn gender on some parameters. Further studies are needed in order to better investigate possible differences between fetal fluids belonging to normal and to pathological puppies, and therefore to detect potential markers of fetal/neonatal diseases or for a quick identification of newborns at risk, that need special surveillance and cares, immediately after birth. In relation to the second topic the present thesis highlighted that DHEA, recognized to be produced by the adrenals of offspring, is higher in the hair of premature as compared to puppies 1-30 days old, although not different from stillborn puppies, suggesting the possible production of this hormone by the fetus itself in the last period of intrauterine development. Although the hair is suitable for perinatal DHEA analysis in dead puppies, the hair necessary for the analysis still limits the use of this matrix for in vivo studies in newborn puppies. Therefore, the measurement of DHEA and of its transport form DHEAS, also in the nails of newborn puppies was assessed. The results showed that nails were suitable for DHEA and DHEAS measurement, allowing the use of this matrix for serial studies on alive newborn puppies. DHEA and DHEAS concentrations were significantly different in the overall concentration in nails of newborn puppies, with a high correlation between the concentrations of DHEA and DHEAS; DHEAS and not DHEA concentrations were significantly higher in small size breeds in comparison with large size breeds, while DHEAS was higher in premature puppies when compared to puppies born-dead or dead between 11 and 20 days of age. When the usefulness of these non-invasive matrices for the study of the dog perinatology was considered, the nails resulted more suitable in comparison to the hairs. In fact, in the perspective of using these matrices in alive newborn puppies, at present the relatively large amount of hair necessary for the analysis prevent its use on alive newborns.

The use of hyperthermia as an adjuvant treatment to existing cancer therapies such as radiation therapy or chemotherapy is well established. A problem common to all clinical hyperthermia applications is the lack of temperature information available during treatment. To lend understanding to these treatments, computational modelling of the electromagnetic interactions inducing heat within the tissues has been undertaken. The work carried out in this thesis develops predictive models for the power deposition from two hyperthermia techniques: an invasive method using interstitial microwave antenna arrays; and a non-invasive method employing surface current sheet applicators, incorporating the capabilities of existing electromagnetic models and the new approaches developed in this thesis. Such models not only provide understanding of the power deposition during treatment, and hence a measure of the heating produced, but also provide analysis for the improvement of antenna/applicator design, thus improving clinical treatment methodologies. The thesis initially considers the interstitial antenna arrays, developing a model capable of solving the power deposition from an array of symmetric/asymmetric insulated antennas with arbitrary orientations and positions. An improved efficiency solution method is derived and evaluated. The scattering and absorption effects produced by insertion of such arrays within an inhomogeneous biological environment is incorporated using a conjugate gradient FFT solver, based on a spectral iterative technique. Investigations into arbitrary array orientations are carried out and new methods of power deposition control are subsequently proposed. The non-invasive current sheet applicators are approached in the same manner producing a model capable of simulating the power deposition from an array of arbitrarily orientated applicators overlying a highly inhomogeneous treatment volume.

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 tesi descrive la stimolazione magnetica transcranica, un metodo di indagine non invasivo. Nel primo capitolo ci si è soffermati sull’ anatomia e funzionalità del sistema nervoso sia centrale che periferico e sulle caratteristiche principali delle cellule neuronali. Nel secondo capitolo vengono descritte inizialmente le basi fisico-tecnologiche della strumentazione stessa, dando particolare attenzione ai circuiti che costituiscono gli stimolatori magnetici ed alle tipologie di bobine più utilizzate. Successivamente si sono definiti i principali protocolli di stimolazione evidenziandone le caratteristiche principali come, ampiezza, durata e frequenza dell’impulso. Nel terzo capitolo vengono descritti i possibili impieghi della stimolazione in ambito sperimentale e terapeutico. Nel quarto ed ultimo capitolo si evidenziano i limiti, della strumentazione e dell’analisi che la stessa permette, andando a definire i parametri di sicurezza, i possibili effetti indesiderati, il costo dell’apparecchiatura e l’uso combinato con altre tecniche specifiche

The present thesis proposes new methods for obtaining objective and accurate diagnoses in modern healthcare. Non-invasive techniques have been used to examine or diagnose three different medical conditions, namely neuropathy among diabetics, radiotherapy induced erythema (skin redness) among breast cancer patients and diagnoses of cutaneous malignant melanoma. The techniques used were Near-InfraRed spectroscopy (NIR), Multi Frequency Bio Impedance Analysis of whole body (MFBIA-body), Laser Doppler Imaging (LDI) and Digital Colour Photography (DCP).

The neuropathy for diabetics was studied in papers I and II. The first study was performed on diabetics and control subjects of both genders. A separation was seen between males and females and therefore the data had to be divided in order to obtain good models. NIR spectroscopy was shown to be a viable technique for measuring neuropathy once the division according to gender was made. The second study on diabetics, where MFBIA-body was added to the analysis, was performed on males exclusively. Principal component analysis showed that healthy reference subjects tend to separate from diabetics. Also, diabetics with severe neuropathy separate from persons less affected.

The preliminary study presented in paper III was performed on breast cancer patients in order to investigate if NIR, LDI and DCP were able to detect radiotherapy induced erythema. The promising results in the preliminary study motivated a new and larger study. This study, presented in papers IV and V, intended to investigate the measurement techniques further but also to examine the effect that two different skin lotions, Essex and Aloe vera have on the development of erythema. The Wilcoxon signed rank sum test showed that DCP and NIR could detect erythema, which is developed during one week of radiation treatment. LDI was able to detect erythema developed during two weeks of treatment. None of the techniques could detect any differences between the two lotions regarding the development of erythema.

The use of NIR to diagnose cutaneous malignant melanoma is presented as unpublished results in this thesis. This study gave promising but inconclusive results. NIR could be of interest for future development of instrumentation for diagnosis of skin cancer.

The production of antibodies for analytical purposes using invasive procedures on small mammals is common practice in biomedical research. The aim of this study was to develop an efficient method for non-invasive antibody production in the chicken. This thesis presents an alternative method that eliminates the discomfort, pain and distress invoked by traditional immunization procedures on mammals by instead harvesting antibodies (IgY) from the yolk of eggs laid by orally immunized hens. An efficient oral immunization regime was developed by first trying out a suitable non-aggressive oral adjuvant with Bovine Serum Albumine (BSA) as the model antigen. It was found that the pegylated mono/diglyceride RhinoVax® (Softigen®) at a concentration of 20% (v/v) produced a good humoral antibody response in chickens as well as development of IgY antibodies in the egg yolk. The age of the chicken is important in order to have a proper humoral immune response. We found that chicken older than 22 days produced circulating immunospecific anti BSA-antibodies of of IgG, IgM and IgA class when orally immunized with BSA alone, whereas chickens 15 days old only produced IgM and IgA antibodies. This is the first report of oral immunizations with a high dose (250–300mg) of BSA in 20% RhinoVax® consisting of 3 or 5 consecutive daily doses resulting in high concentrations of immunospecific IgY antibodies in the yolk. Using this technique of three consecutive daily doses repeated after 7 weeks and after 18 weeks, a booster effect was induced after the third immunization. This is the first demonstration of a clear anamnestic immune response in orally immunized chickens. The results suggest that it may be possible to further increase the concentration of immunospecific IgY antibodies by modifying the immunization regime. It seems plausible to develop a procedure where the immunogen can be fed to the chickens as in an ordinary egg producing farm thus making antibody production not classified as an animal experiment.

COLORECTAL CANCER SCREENING: A NON-INVASIVE APPROACH Amy Frazier May, 2004 58 Pages Directed by: Dr. Donna Blackburn, Dr. Patricia Bailey, and Dr. Thomas Nicholson Department of Nursing Western Kentucky University Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide and is expected to affect six percent of Americans within their lifetime (National Cancer Institute, 2003). Clinicians worldwide struggle with selecting the most accurate, cost-effective CRC screening tool. Could a noninvasive screening tool be the answer or part of the answer to the dilemmas surrounding CRC screening? The purpose of this correlational, replication study was to determine whether symptoms such as rectal bleeding, change in bowel habit, and weight loss are associated with symptomatic colorectal cancer using a sample of individuals scheduled for a routine colonoscopy. This study can be considered a pilot study since it has never been replicated in the United States (U.S). Data obtained from 47 Bowel Symptom Assessment Questionnaires (BSAQs) given to patients undergoing routine colonoscopy at Greenview Regional Hospital in Bowling Green, Kentucky were analyzed to address the research objectives of the study. None of the patients had colorectal cancer, but 15 of the 47 patients had polyps. None of the symptoms showed a significant correlation with polyps according to chi-square analysis. T-tests of the means of the polyp group versus the no polyp group showed no difference between the population means for each of the examined variables. Selva scores generated from the BSAQ did not show a 8 significant relationship with the presence or absence of polyps. Additional findings, limitations, and implications for future research are discussed.

Capillary Vascular Malformations (CMs) or Port Wine Stains are a congenital abnormality of the dermal vasculature that results in the skin having a pink to purple colouration. This thesis examines the development of the videomicroscopy as a non-invasive tool to examine the vessel structure of CMs in vivo. A number of studies have been undertaken including: 1. the use of colour filtering as an adjunct to videomicroscopy; 2. the development and validation through a biopsy study of a Depth Measuring Videomicroscope (DMV); 3. the description of vessel change following a single laser treatment using DMV; 4. the relationship between location and colour of a CM and vessel structure; 5. the effect of prolonged laser treatment on vessel structure; and 6. the effect of using new generation Pulsed dye lasers on CM vessel structure and their efficacy. Colour filtering appears to reduce the artefact from the reflection of light from the skin surface. The development of the Depth Measuring Videomicroscope (DMV), however, reduces this reflection and colour filtering is not required. The DMV can be used to measure the diameter and depth of Capillary Vascular Malformations (CM) in vivo and this has been validated against biopsy measurements using a Bland and Altman Test. Following laser treatment the larger and more superficial capillaries are successfully treated leaving the deeper (p<0.02) and smaller vessels (p<0.001).This occurs both after a single laser treatment and prolonged treatment. To improve the treatment of CMs resistance to standard pulsed dye laser treatment the capillary characteristics of resistant CMs were studied prior to treatment were newer generation pulsed dye lasers. Although, the optimum treatment parameters for a particular malformation could not be predicted from this study, 595nm wavelength, 1.5 ms pulse duration and 14 j/sqcm fluence appeared to be the most successful settings.

[Truncated abstract] The cost of managing osteoporotic fractures places a significant financial burden on the health-care system. To reduce the fracture burden, early identification of fracture risk is essential to allow early intervention. The limitations associated with dual-energy X-ray absorptiometry (DXA), such as limited sensitivity and specificity, cost, ionising radiation and accessibility, have resulted in the emergence of other technologies for assessing bone fragility. An example is the portable and non-ionising quantitative ultrasound (QUS) technology. The discriminatory power of quantitative ultrasonometry in fracture risk identification, either independently or in combination with other established risk factors, currently remains contentious. It is recommended that fracture risk assessment should not only focus on bone status, but also on the risk of falls. Additionally, it has been noted that disability arising from osteoporotic fractures, even when these fractures are not identified clinically, can translate into psychosocial symptoms and a poorer perception of health-related quality of life (HRQoL). The primary aim of the present study was to investigate if a composite model comprising: calcaneal QUS, falls risk and HRQoL assessments, can identify a group of elderly women at high risk of osteoporotic fracture from those at lower risk. One hundred and four community-dwelling women (mean age 71.3 ±5.8 years) were recruited for this study. These women underwent a series of tests that included: DXA bone mineral density (BMD) evaluation of the proximal femur and lumbar spine (L1 L4); calcaneal QUS measurement; spinal radiography; rasterstereographic back surface curvature (BSC) examination; and performance-based assessment of strength, mobility and balance. The women were classified into a `High Risk’group or a `Low Risk’ group using three separate classification criteria: i) low BMD, based on the World Health Organisation (WHO) recommended T-score of < -2.5, and⁄or a history of fragility fracture (Osteoporotic [OP] group versus Non-Osteoporotic [NOP] group); ii) presence of at least one radiographically identified prevalent vertebral fracture (Vertebral Fracture [VF] group versus Non-Vertebral Fracture [NVF] group); or iii) a history of either forearm or wrist fracture (Forearm/Wrist Fracture [WF] group versus Non-Forearm/Wrist Fracture [NWF] group)

Non-invasive electrical imaging of the heart aims to quantitatively reconstruct information about the electrical activity of the heart from multiple thoracic ECG signals. The computational framework required to produce such electrical images of the heart from non-invasive torso surface signals is presented. It is shown reliable electrical images of the heart can be obtained under a controlled environment. This has been demonstrated using an anatomically realistic boundary element porcine torso model. The procedures required to create a subject specific model using a small number of control points and to create a specific heart model from three-dimensional ultrasound images using a linear fitting procedure are presented. From discrete ECG electrodes a continuous representation of the potential field over the entire torso surface can also be produced using this linear fitting procedure. The construction of the transfer matrices for the two predominant electrocardiographic sources (epicardial potentials and myocardial activation times) are described in detail. The transfer matrices are used to compute activation times within the heart and epicardial potentials on the heart surface. Myocardial activation times are computed using an algorithm based on the Critical Point Theorem while epicardial potentials are computed using standard Tikhonov and Truncated SVD spatially regularised methods as well as Greensite's spatial and temporal regularisation method. The regularisation parameters for the epicardial potentials are determined using a variety of methods (e.g., CRESO criterion, L-curve, zero-crossing). The potential and activation based formulations are compared in a comprehensive inverse simulation study. To try and capture the dynamic and variable nature of cardiac electrical activity, the study is performed with three different types of cardiac sources with a realistic porcine model. These simulations investigate the effect on the computed solutions of individual and combinations of modelling errors. These errors include corruption in the torso surface signals, changes in material properties and geometric distortion. In general, the activation based formulation is preferred over the epicardial potential formulations, with Greensite's method found to be the best method for reconstructing epicardial potentials. Under optimal conditions, the activation approach could reconstruct the activation times to within RMS. Both potential and activation based formulations were found to be relatively insensitive to changes in material properties such as lung conductivities and activation function shapes. When examining individual errors, the geometry and positions of the torso and heart had the greatest effects on the inverse solutions. The relative heart position needed to be determined to within to obtain results within of the solutions obtained under control conditions. When the modelling errors are combined to produce errors which can be expected in a clinical or experimental situation the activation based solutions were consistently more accurate than potential based solutions. The next necessary step in this project is the detailed validation of the results against in-vivo data. This step is necessary before such algorithms can be reliably used to aid in the assessment of heart function in a clinical environment.

Blood pressure is one of the fundamental clinical measures. For more than 100 years, clinicians and researchers have used the mercury sphygmomanometer for blood pressure measurement. Environmental concern about mercury contamination has highlighted the need to find a replacement for traditional mercury sphygmomanometers. A number of currently used non-invasive blood pressure measurement methods have been studied in this research. The most commonly used automatic pressure monitoring method nowadays is the Oscillometric method. Height-based and Slope-based criteria are the two general means used to determine the systolic and diastolic pressures. However, these two criteria have many disputed points, making them debatable as a good standard for blood pressure measurement. For this reason, the auscultatory method continues to be the gold-standard for non-invasive blood pressure measurement. Current research uses a newly developed cuff with three different lengths of piezo film sensors and a pressure sensor to collect signals from the brachial artery. The objectives of the research are to process the measured signal from the sensors and develop a blood pressure measurement algorithm that will accurately determine the blood pressure noninvasively. Signal processing and heart beat / heart rate detection software have been developed. The best algorithm has been selected from three developed algorithms for further modification and validation. The final algorithm used two feed-forward Neural Networks to classify the acquired pressure signals into various regions of the pressure signals. The final algorithm has been tested on 258 measurements from 86 subjects. The testing result showed that the algorithm achieved grade A for both systolic and diastolic pressures according to the British Hypertension Society protocol. The mean differences (SD) between the observers and the developed algorithm were 1.44 (5.27) mmHg and 1.77 (6.17) mmHg for systolic and diastolic pressures, respectively, which also fulfilled the Association for the Advancement of Medical Instrumentation protocol. In conclusion, this algorithm was successfully developed and it is recommended for further clinical trial in a wider adult population. Further development of this algorithm also includes extending to other subgroups such as pregnant women, arrhythmia, diabetics and other subjects with diseases.

Lung cancer is the leading cause of cancer death and a priority research area. There is an unmet need to develop biomarkers to enable patient selection and stratification in future lung cancer trials. This thesis aimed to validate non-invasive therapeutic lung cancer biomarkers. The investigated biomarkers were derived from imaging techniques used in routine healthcare (computed tomography and [18F]fludeoxyglucose (FDG) positron emission tomography (PET)) and research-domain imaging methods of hypoxia (multi-parametric magnetic resonance imaging (MRI) and [18F]fluoroazomycin arabinoside (FAZA) PET) and proliferation ([18F]fluorothymidine (FLT) PET), along with circulating biomarkers. These biomarkers were derived from one randomized controlled trial and 3 prospective pilot studies. I report for the first time the outcome of early limited stage (LS)- small cell lung cancer (SCLC), staged using the tumour, node and metastasis (TNM) staging system, within a randomized controlled trial. Early (TNM stage I-II) LS-SCLC patients achieve long-term survival with minimal acute side-effects following chemoradiotherapy and prophylactic cranial irradiation. This study guides patient management and benchmarks achievable outcomes in the era of modern radiotherapy. I report on the effects of different [18F]FAZA PET acquisition and analysis procedures on image parameters, comparing hypoxic volumes and fractions using fixed (>1.4, >1.2) and image-derived thresholds in non-small cell lung cancer (NSCLC) patients. I also investigate, for the first time, image repeatability and compare findings with a tissue-based hypoxia assessment in a patient subset, thus providing new [18F]FAZA PET validation data for the optimal application of this modality to derive potential hypoxia biomarkers. I present the world first oxygen-enhanced (OE) MRI clinical study to evaluate repeatability and show pharmacodynamic treatment effect, providing new technical and biological validation data for OE-MRI NSCLC hypoxia biomarkers. These results suggest that OE-MRI is feasible, well-tolerated, repeatable and has potential clinical utility as a biomarker in future NSCLC hypoxia-targeted therapy trials and radiotherapy dose painting studies. I present a pilot study that evaluated, to my knowledge, the largest blood biomarker panel in lung cancer patients. I show that baseline IL-1b and neutrophil count and early-treatment CYFRA 21-1 predict lung cancer radiotherapy response. CYFRA 21-1 and VCAM-1 correlated with [18F]FLT PET, highlighting for the first time a potential role of blood biomarkers as imaging surrogates. A trial proposal to investigate nimorazole (a hypoxic radiosensitizer) in TNM stage II-III NSCLC patients is presented. One of the trial aims is to validate (and ultimately qualify) [18F]FAZA PET, building on the thesis results. In summary, this thesis presents important new validation data for a range of therapeutic lung cancer biomarkers.

Pulmonary hypertension (PH), a disease state affecting the pulmonary circulation, was first recognised in the 1950s. Obliteration of pulmonary capillary beds and vasoconstriction lead to elevated pulmonary vascular resistance (PVR) and increased right ventricular afterload. The direct consequence is impaired cardiac output (CO) response to exercise, resulting in progressive exercise limitation, and ultimately premature death from right heart failure. Despite the considerable expansion in pulmonary vasodilatory therapy in recent years, PH remains an incurable disease associated with high morbidity and mortality. Exercise CO is an important outcome measure in PH as it is directly linked to the consequences of disease. Cardiac output is conventionally measured at right heart catheterisation (RHC). The invasive nature of this procedure does not permit serial measurements to be made readily during follow-up to assess disease progression or treatment response. As a result, six-minute walk distance (6MWD), a simple measure of submaximal exercise capacity, has been used as a surrogate of exercise CO and the primary end-point in most randomised controlled trials of pulmonary vasodilatory agents to date. However, there are recognised limitations to the ability of 6MWD to predict outcome, and this necessitates the development of alternative outcome measures which are non-invasive, reproducible and responsive to change. Measurement of CO using the inert gas rebreathing method (IGR) may be such an alternative to 6MWD. It is a direct measure of right heart function and hence disease-specific. It can be combined with submaximal constant-load exercise to provide an objective assessment independent of patient effort. This form of exercise would also allow isotime comparison of metabolic variables which were shown to be more sensitive than variables measured at peak exercise in demonstrating improved exercise capacity from therapeutic interventions in chronic obstructive pulmonary disease (COPD). Another potential alternative outcome measure is end-tidal carbon dioxide partial pressure (PETCO2). It is a marker of ventilatory inefficiency and was shown to correlate with disease severity in PH. Accurate prognostication is central to PH management as it would inform treatment planning and patient counselling. Different strategies could be adopted to optimise the performance of existing prognostic factors. The predictive value of 6MWD may be improved by using % predicted 6MWD which adjusts for age, gender and anthropometric factors, and hence would give a more accurate representation of disease severity. A composite scoring system, combining key prognostic variables, would be more discriminatory than individual variables in predicting survival. Such prognostic equations have been derived from contemporary PH cohorts in France and the United States. Validation data published so far support their predictive value, but these equations may not perform as well in the United Kingdom (UK) as a locally derived risk score, due to differences in patient demographics and healthcare systems. The aims of this thesis were to investigate the use of novel non-invasive exercise variables and prognostic algorithms as outcome measures in PH. 1. The first two studies evaluate the ability of IGR haemodynamic measurements and isotime metabolic variables during submaximal constant-load exercise, and PETCO2 during the six-minute walk test (6MWT) to predict treatment response. 2. The last two studies explore the prognostic value of % predicted 6MWD and a novel UK-based composite risk score. The reproducibility and clinical correlates of IGR pulmonary blood flow (PBF) and stroke volume (SV) were determined. Changes in IGR PBF and SV and isotime metabolic variables, at rest and during submaximal constant-load exercise, were assessed after three months of new or modified disease-targeted therapy in patients with precapillary PH. IGR measurements were found to have good intersession reproducibility and correlate with conventional outcome measures including World Health Organisation functional class (WHO FC), 6MWD, N-terminal pro-brain natriuretic peptide (NT-proBNP) and Cambridge Pulmonary Hypertension Outcome Review (CAMHPOR) score. Resting and submaximal exercise IGR PBF and SV were able to detect treatment response, and may be more sensitive than 6MWD in detecting the effects of therapy in fitter patients. In comparison, isotime metabolic variables were less useful in detecting a treatment effect. The metabolic response during the 6MWT was determined and changes in PETCO2 were assessed after 3 months of new or modified disease-targeted therapy. Therapy-induced changes in the nadir of PETCO2 (PETCO2 nadir) correlated with changes in 6MWD, but resting, end-of-walk or PETCO2 nadir did not improve significantly at follow-up. Post-hoc analysis demonstrated that the study was under-powered to detect a change in PETCO2 with therapy. The prognostic performance of % predicted 6MWD, calculated using four different published reference equations, was compared with that of absolute 6MWD, at baseline and on treatment. Despite adjusting for physiological inter-subject variance, % predicted 6MWD is not superior to absolute 6MWD in predicting all-cause mortality. This may be related to limitations of existing reference equations or the use of all-cause rather than disease-specific mortality as the end-point. Baseline mortality predictors were identified from a Scottish cohort of incident and treatment-naive PH patients, and used to derive a simple scoring system for survival prediction over time. When validated in an independent UK PH cohort, the Scottish Composite Score (SCS) was predictive of survival and able to provide further risk stratification in WHO FC III patients. It may perform better in UK populations than other published equations derived from PH cohorts in France and the United States. In conclusion, IGR haemodynamic measurements may be useful as alternative outcome measures to 6MWD, and the SCS shows promise as the first UK-based composite risk score in PH. Further studies in larger cohorts are warranted to confirm their clinical utility.

Three techniques are investigated in order to assess their applicability for use in landfill design, construction and monitoring. Firstly, an assessment is made of QA procedures during liner construction through the detailed evaluation of two case studies. Construction QA procedures on-site are compared to available guidelines. The research illustrates the requirement for standardised, regulated QA procedures on landfill sites in order to provide a recognised framework for construction control. The Moisture Condition Value Test (MCV) is evaluated for use as a method of monitoring the placement of compacted clay landfill liners. London Clay and Mercia Mudstone, collected from the QA case study sites, are tested in terms of their suitability as engineered clay liners. Although, London Clay is the most acceptable it is this material which exhibits the poorest results in the MCV testing. This is due to seepage from the apparatus at high moisture contents. The research highlights the problems with the interpretation of the protocol for the testing and the differences between the Scottish and English Road Research Laboratory guidelines (Green & Hawkins, 1987). Thirdly, two airborne remote sensing techniques (ATM and CASI) are appraised as methods of monitoring landfill gas, or possibly leachate migration, from two case study landfill sites in South West England. Vegetation stress can be linked to landfill gas migration (Flower et al., 1981) and this stress can be detected as a deviation from normal spectral reflectances in vegetation (Honer et a!., 1983a). Anomalies are identified on-site through remote sensing but they cannot be directly attributed to the landfills. This research emphasises the effects of contamination from other sources. It also requires the use of a simultaneous ground survey to collate data from boreholes with measurements of soil and vegetation types. Essentially, the QA case studies and the remote sensing show potential for future use and suggestions are made in this thesis for further research. The MCV technique provides a method for assessing the controlling parameters of compaction. With further development of aspects outlined in this investigation there is the potential for specified use of these techniques In landfill engineering and monitoring.

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. Nowadays the fibrillatory process is known to be provoked by the high-frequency reentrant activity of certain atrial regions that propagates the fibrillatory activity to the rest of the atrial tissue, and the electrical isolation of these key regions has demonstrated its effectiveness in terminating the fibrillatory process. The location of the dominant regions represents a major challenge in the diagnosis and treatment of this arrhythmia. With the aim to detect and locate the fibrillatory sources prior to surgical procedure, non-invasive methods have been developed such as body surface electrical mapping (BSPM) which allows to record with high spatial resolution the electrical activity on the torso surface or the electrocardiographic imaging (ECGI) which allows to non-invasively reconstruct the electrical activity in the atrial surface. Given the novelty of these systems, both technologies suffer from a lack of scientific knowledge about the physical and technical mechanisms that support their operation. Therefore, the aim of this thesis is to increase that knowledge, as well as studying the effectiveness of these technologies for the localization of dominant regions in patients with AF. First, it has been shown that BSPM systems are able to noninvasively identify atrial rotors by recognizing surface rotors after band-pass filtering. Furthermore, the position of such surface rotors is related to the atrial rotor location, allowing the distinction between left or right atrial rotors. Moreover, it has been found that the surface electrical maps in AF suffer a spatial smoothing effect by the torso conductor volume, so the surface electrical activity can be studied with a relatively small number of electrodes. Specifically, it has been seen that 12 uniformly distributed electrodes are sufficient for the correct identification of atrial dominant frequencies, while at least 32 leads are needed for non-invasive identification of atrial rotors. Secondly, the effect of narrowband filtering on the effectiveness of the location of reentrant patterns was studied. It has been found that this procedure allows isolating the reentrant electrical activity caused by the rotor, increasing the detection rate for both invasive and surface maps. However, the spatial smoothing caused by the regularization of the ECGI added to the temporal filtering causes a large increase in the spurious reentrant activity, making it difficult to detect real reentrant patterns. However, it has been found that maps provided by the ECGI without temporal filtering allow the correct detection of reentrant activity, so narrowband filtering should be applied for intracavitary or surface signal only. Finally, we studied the stability of the markers used to detect dominant regions in ECGI, such as frequency maps or the rotor presence. It has been found that in the presence of alterations in the conditions of the inverse problem, such as electrical or geometrical noise, these markers are significantly more stable than the ECGI signal morphology from which they are extracted. In addition, a new methodology for error reduction in the atrial spatial location based on the curvature of the curve L has been proposed. The results presented in this thesis showed that BSPM and ECGI systems allows to non-invasively locate the presence of high-frequency rotors, responsible for the maintenance of AF. This detection has been proven to be unambiguous and robust, and the physical and technical mechanisms that support this behavior have been studied. These results indicate that both non-invasive systems provide information of great clinical value in the treatment of AF, so their use can be helpful for selecting and planning atrial ablation procedures.
La fibrilación auricular (FA) es una de las arritmias cardiacas más frecuentes. Hoy en día se sabe que el proceso fibrilatorio está provocado por la actividad reentrante a alta frecuencia de ciertas regiones auriculares que propagan la actividad fibrilatoria en el resto del tejido auricular, y se ha demostrado que el aislamiento eléctrico de estas regiones dominantes permite detener el proceso fibrilatorio. La localización de las regiones dominantes supone un gran reto en el diagnóstico y tratamiento de la FA. Con el objetivo de poder localizar las fuentes fibrilatorias con anterioridad al procedimiento quirúrgico, se han desarrollado métodos no invasivos como la cartografía eléctrica de superficie (CES) que registra con gran resolución espacial la actividad eléctrica en la superficie del torso o la electrocardiografía por imagen (ECGI) que permite reconstruir la actividad eléctrica en la superficie auricular. Dada la novedad de estos sistemas, existe una falta de conocimiento científico sobre los mecanismos físicos y técnicos que sustentan su funcionamiento. Por lo tanto, el objetivo de esta tesis es aumentar dicho conocimiento, así como estudiar la eficacia de ambas tecnologías para la localización de regiones dominantes en pacientes con FA. En primer lugar, ha visto que los sistemas CES permiten identificar rotores auriculares mediante el reconocimiento de rotores superficiales tras el filtrado en banda estrecha. Además, la posición de los rotores superficiales está relacionada con la localización de dichos rotores, permitiendo la distinción entre rotores de aurícula derecha o izquierda. Por otra parte, se ha visto que los mapas eléctricos superficiales durante FA sufren una gran suavizado espacial por el efecto del volumen conductor del torso, lo que permite que la actividad eléctrica superficial pueda ser estudiada con un número relativamente reducido de electrodos. Concretamente, se ha visto que 12 electrodos uniformemente distribuidos son suficientes para una correcta identificación de frecuencias dominantes, mientras que son necesarios al menos 32 para una correcta identificación de rotores auriculares. Por otra parte, también se ha estudiado el efecto del filtrado en banda estrecha sobre la eficacia de la localización de patrones reentrantes. Así, se ha visto que este procedimiento permite aislar la actividad eléctrica reentrante provocada por el rotor, aumentando la tasa de detección tanto para señal obtenida de manera invasiva como para los mapas superficiales. No obstante, este filtrado temporal sobre la señal de ECGI provoca un gran aumento de la actividad reentrante espúrea que dificulta la detección de patrones reentrantes reales. Sin embargo, los mapas ECGI sin filtrado temporal permiten la detección correcta de la actividad reentrante, por lo el filtrado debería ser aplicado únicamente para señal intracavitaria o superficial. Por último, se ha estudiado la estabilidad de los marcadores utilizados en ECGI para detectar regiones dominantes, como son los mapas de frecuencia o la presencia de rotores. Se ha visto que en presencia de alteraciones en las condiciones del problema inverso, como ruido eléctrico o geométrico, estos marcadores son significativamente más estables que la morfología de la propia señal ECGI. Además, se ha propuesto una nueva metodología para la reducción del error en la localización espacial de la aurícula basado en la curvatura de la curva L. Los resultados presentados en esta tesis revelan que los sistemas de CES y ECGI permiten localizar de manera no invasiva la presencia de rotores de alta frecuencia. Esta detección es univoca y robusta, y se han estudiado los mecanismos físicos y técnicos que sustentan dicho comportamiento. Estos resultados indican que ambos sistemas no invasivos proporcionan información de gran valor clínico en el tratamiento de la FA, por lo que su uso puede ser de gran ayuda para la selección y planificaci
La fibril·lació auricular (FA) és una de les arítmies cardíaques més freqüents. Hui en dia es sabut que el procés fibrilatori està provocat per l'activitat reentrant de certes regions auriculars que propaguen l'activitat fibril·latoria a la resta del teixit auricular, i s'ha demostrat que l'aïllament elèctric d'aquestes regions dominants permet aturar el procés fibrilatori. La localització de les regions dominants suposa un gran repte en el diagnòstic i tractament d'aquesta arítmia. Amb l'objectiu de poder localitzar fonts fibril·latories amb anterioritat al procediment quirúrgic s'han desenvolupat mètodes no invasius com la cartografia elèctrica de superfície (CES) que registra amb gran resolució espacial l'activitat elèctrica en la superfície del tors o l'electrocardiografia per imatge (ECGI) que permet obtenir de manera no invasiva l'activitat elèctrica en la superfície auricular. Donada la relativa novetat d'aquests sistemes, existeix una manca de coneixement científic sobre els mecanismes físics i tècnics que sustenten el seu funcionament. Per tant, l'objectiu d'aquesta tesi és augmentar aquest coneixement, així com estudiar l'eficàcia d'aquestes tecnologies per a la localització de regions dominants en pacients amb FA. En primer lloc, s'ha vist que els sistemes CES permeten identificar rotors auriculars mitjançant el reconeixement de rotors superficials després del filtrat en banda estreta. A més, la posició dels rotors superficials està relacionada amb la localització d'aquests rotors, permetent la distinció entre rotors de aurícula dreta o esquerra. També s'ha vist que els mapes elèctrics superficials durant FA pateixen un gran suavitzat espacial per l'efecte del volum conductor del tors, el que permet que l'activitat elèctrica superficial pugui ser estudiada amb un nombre relativament reduït d'elèctrodes. Concretament, s'ha vist que 12 elèctrodes uniformement distribuïts són suficients per a una correcta identificació de freqüències dominants auriculars, mentre que són necessaris almenys 32 per a una correcta identificació de rotors auriculars. D'altra banda, també s'ha estudiat l'efecte del filtrat en banda estreta sobre l'eficàcia de la localització de patrons reentrants. Així, s'ha vist que aquest procediment permet aïllar l'activitat elèctrica reentrant provocada pel rotor, augmentant la taxa de detecció tant pel senyal obtingut de manera invasiva com per als mapes superficials. No obstant això, aquest filtrat temporal sobre el senyal de ECGI provoca un gran augment de l'activitat reentrant espúria que dificulta la detecció de patrons reentrants reals. A més, els mapes proporcionats per la ECGI sense filtrat temporal permeten la detecció correcta de l'activitat reentrant, per la qual cosa el filtrat hauria de ser aplicat únicament per a senyal intracavitària o superficial. Per últim, s'ha estudiat l'estabilitat dels marcadors utilitzats en ECGI per a detectar regions auriculars dominants, com són els mapes de freqüència o la presència de rotors. S'ha vist que en presència d'alteracions en les condicions del problema invers, com soroll elèctric o geomètric, aquests marcadors són significativament més estables que la morfologia del mateix senyal ECGI. A més, s'ha proposat una nova metodologia per a la reducció de l'error en la localització espacial de l'aurícula basat en la curvatura de la corba L. Els resultats presentats en aquesta tesi revelen que els sistemes de CES i ECGI permeten localitzar de manera no invasiva la presència de rotors d'alta freqüència. Aquesta detecció és unívoca i robusta, i s'han estudiat els mecanismes físics i tècnics que sustenten aquest comportament. Aquests resultats indiquen que els dos sistemes no invasius proporcionen informació de gran valor clínic en el tractament de la FA, pel que el seu ús pot ser de gran ajuda per a la selecció i planificació de procediments d'ablació auricular.
Rodrigo Bort, M. (2016). Non-invasive identification of atrial fibrillation drivers [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/75346
TESIS
Premiado

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.

HiPIMS discharges operated with a titanium and an aluminium-doped zinc target sputtered with the working gas argon were investigated by means of optical 2d-imaging in combination with Abel-inversion. By using optical bandpass filters, the spatial and temporal evolution of the plasma-induced emission of argon atoms and ions and metal atoms and ions were studied. The discharge ignition was found to be accompanied by an intensity maximum observed remote from the target, followed by an asymmetric intensity profile. During the stage of high discharge current, the intensity distribution indicates strong rarefaction of the working gas, efficient ionisation of the sputtered particles above the target and a wider sputter distribution. The off-time is characterised by an initial drop of the intensity by 4 - 6 orders of magnitude and a transition from electron-impact excitation to excitation by electron-electron-ion recombination. Decay constants in the order of 1 ms and the spatial distribution of the emission suggest the loss of electrons and ions due to ambipolar diffusion across the magnetic field. Plasma potential measurements by means of emissive probe revealed strongly negative space potentials of up to -300 V and electric fields in the order of 10000 V/m during discharge ignition, caused by strong charge separation due to the extended sheath. The plasma potential increases to a stable level of more than -25 V during the second half of the discharge pulse, while the electric field is largely reduced to maximal 1500 V/m. It was found that the space potential is consistently 5 V lower when the substrate is kept floating compared to a grounded substrate, which can be explained by the reduced electron loss rate to the substrate due to the potential barrier. This is confirmed by spatially resolved Langmuir probe measurements, showing a density maximum of 1019 m-3 in the confined plasma zone, and an increased density in the vicinity of the floating substrate of 1.3 × �1018 m-3 compared to 0.8 × �1018 m-3 for a grounded substrate. The electron temperature was found to be spatially uniform ranging from 1 eV to 3 eV. A quasi-continuous transport model for sputtered particles confirmed the high degree of ionisation of the sputtered particles of about 90 % and revealed a return probability for titanium ions to the target of 80 % for Ti+ and 96 % for Ti2+. Varying the force caused by a modified two-stream instability [1], showed an increasing sideway defletion of ions also increasing the kinetic energy observed for these particles. The spatial distribution of the relative density confirmed efficient ionisation of sputtered particles in the dense plasma zone adjacent to the target. Average azimuthal velocities of the drifting ion fluid of 3�000 m/s for Ti+ and 7�000 m/s for Ti2+ were obtained.