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D.Phil. (Biokinetics) / Please refer to full text to view abstract

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The need for a more secure cyber future is apparent in the information age that we live in. Information is fast becoming, and already is, one of the biggest assets in all domains of life. Access to information and specifically personal information must be regulated and secured in a trusted way. The use of passwords and tokens (example: bank card) that’s currently the most popular and well known mechanism for electronic identification can only identify the password or token but NOT the physical user using the password or token for identification. Biometrics addresses the above issue by being part of the physical user. For example: your fingerprint, retina or iris. Current biometric technologies provide an enabling medium to help with more accurate identification and verification. Thereby protecting and securing electronic information…BUT: One of the biggest problem areas surrounding biometrics is the fact that most biometric tokens (fingerprints, hand geometry and the human eye) can be used in some cases to identify the owner of the biometric token even after death as if the owner was still alive. The problem becomes apparent in the case of a person that passed away and the possibility of using the biometric tokens of the deceased to obtain access to his/her bank account. Therefore the importance of effective liveness testing is highlighted. Current liveness testing technologies can not be trusted in a way that would be necessary to provide the trust needed in the example of access to a personal bank account at an ATM (automatic teller machine). This dissertation reports on the initial stages of a research project that addresses the above problem by proposing the use of biometric tokens that doesn’t exist if the owner is not alive, thus the dissertation coins the new term – Inherent Liveness Biometrics. The way the human heart beats as a biometric token to identify or verify a person, might solve the issue of liveness testing, because “The way the human heart beats” might prove to be a natural biometric token that is only valid for a living person, thus an inherent liveness biometric. / Prof. S.H. Von Solms

Heart failure (HF) is one of the commonest complications of Diabetes Mellitus (DM) with the prevalence of DM reported at around 30% in many pivotal heart failure studies. However the pathophysiological mechanisms that contribute to HF development in diabetes are poorly understood. To investigate this we used a novel human relevant mouse model of DM (GENA348) in which there is a point mutation in the glucokinase (Gck) gene, the glucose sensor which regulates insulin secretion. A mutation in the same gene is known to underlie Maturity Onset Diabetes of the Young Type 2 (MODY 2) in humans. The mutant mice developed significant hyperglycaemia with normal insulin levels due to the altered glucose sensing. We examined the molecular mechanisms that contribute to the HF phenotype in DM. Mean random blood glucose was found to be increased in the GENA348 mutant(HO) mice compared to wild type (WT) litter mates (WT 6.9±0.3mmol/L vs HO20.6±0.8mmol/L, P<0.001). Serial echocardiography was performed, at 3, 6 and 12 months. No significant changes in echocardiographic parameters were observed at 3 months, although by 6 months development of significant cardiachypertrophy in HO mice was observed characterised by a 20% increase in the diastolic posterior wall thickness (dPW). At 12 months of age left ventricular dilatation was also evident. Systolic function was preserved although significant diastolic dysfunction was evident at 6 and 12 months. Histological staining illustrated significant cellular hypertrophy with real time PCR data demonstrating a relative 150% increase in the hypertrophic marker BNP. Hypertrophic pathways were examined through western blot analysis revealing an age dependent increase in Akt phosphorylation (6 months-140%, 12 months-460%). Serum levels of advanced glycation end products (AGEs) and expression of their receptors RAGE were also elevated. In vitro cellular experiments also revealed AGEs directly activate Akt through phosphorylation and increase levels of the receptor RAGE. AGE induced phosphorylation of Akt is inhibited in the presence of wortmannin, suggesting a PI3K dependent signalling mechanism. Wortmannin blocked the development of cardiac hypertrophy in the diabetic mice. In conclusion we demonstrate that the human relevant GENA348 mouse model of diabetes develops a progressive cardiac phenotype including cardiachypertrophy, LV dilatation and diastolic dysfunction similar to the clinical manifestations of diabetic cardiomyopathy. We propose a novel RAGE/PI3K/Akt pathway that for the first time provides insight into the molecular mechanisms that underlie the development of HF. Moreover, we show raised glucose alone is able to cause cardiotoxicity independently of insulin.

Chronic diabetic patients have a higher incidence of and mortality from cardiac disease. A wide spectrum of cardiac problems plague the chronic diabetic including coronary artery disease, congestive heart failure and diabetic cardiomyopathy. Cardiac disease in the diabetic is not simply due to accelerated atherosclerosis alone, but is also due to a combination of microangiopathy, autonomic neuropathy, and various other factors which produce biochemical, functional and structural alterations in the heart. Recently, cardiac function was studied in animals with experimentally-induced diabetes and cardiac-dysfunction was reported in acute as well as chronic phases of experimental diabetes. Since cardiac disease is a consequence of long-standing diabetes in diabetic patients, investigation of myocardial function at various time points after induction of experimental diabetes would yield information regarding the development and progression of cardiac dysfunction in diabetes. We. therefore investigated cardiac function and pharmacology in isolated perfused working hearts obtained from 7, 30, 100, 180, 240 and 360-day alloxan and streptozotocin (STZ) diabetic and age-matched control hearts. Diabetes was induced in the rat by injecting either alloxan (65 or 40 mg/kg) or STZ (50 or 60 mg/kg) into the tail vein. Diabetic and age-matched control rats were sacrificed at various time points after the induction of diabetes and hearts were isolated and perfused on a working heart apparatus. Cardiac function was studied at various left atrial filling pressures and was expressed in terms of left ventricular developed pressure (LVDP), rate of rise of left ventricular pressure (positive dP/dt) and rate of decline of left ventricular pressure (negative dP/dt). Dose-response curves to carbachol and isoproterenol were also performed. Blood samples were collected at the time of sacrifice, serum was separated and analyzed for insulin and glucose content. Both alloxan and STZ produced diabetes in the rat as shown by fasting hypoinsulinemia and hyperglycemia. Cardiac function was not altered in 7-day alloxan and STZ diabetic rats. Depressed function at various left atrial filling pressures was seen in hearts isolated from 30-day alloxan diabetic rats but not in 30-day STZ diabetic rats. Hearts isolated from 100-day alloxan and STZ diabetic rats, 180- and 360-day STZ diabetic rats and 240-day alloxan diabetic rats, all exhibited cardiac functional abnormalities. Cardiac functional abnormalities observed in d.iabetic rats were, depressed >LVOP and -positive«.and negative dP/dt at high left atrial filling pressures. Diabetic rat hearts exhibited no change in either sensitivity or responsiveness to the negative inotropic effect of carbachol at 7 and 30 days after induction of the disease. A sub-sensitivity to carbachol was observed in diabetic rat hearts at 100 days after induction of diabetes as compared to age-matched control rat hearts. However, 180- and 240-day diabetic rat hearts exhibited supersensitivity to the negative inotropic effect of carbachol. Isoproterenol produced an identical positive inotropic effect in control as well as diabetic rat hearts at all of the time points studied. However, the maximum changes produced by isoproterenol in negative dP/dt of diabetic rat hearts were depressed at various time points as compared to those in age-matched control rat hearts. We also studied the effect of isoproterenol on the cyclic AMP content and phosphorylase a activity in hearts obtained from 3 and 100 to 120 day control and diabetic rats. Basal cyclic AMP content and phosphorylase a activity were not altered in acute and chronic diabetic and age-matched control rat hearts. Isoproterenol produced similar time- and dose-dependent changes in cyclic AMP content and positive and negative dP/dt in isolated perfused working hearts obtained from 3 and 100 to 120 day control and diabetic rats. However, isoproterenol caused a significantly greater activation of phosphorylase enzyme in hearts isolated from 3 and 100 to 120 day diabetic rats as compared to age-matched controls. Diabetic rat hearts had a significantly higher total phosphorylase activity at 100 to 120 days as compared to age-matched controls. Prostaglandin E₁, a drug which increases cyclic AMP content without altering phosphorylase a activity in perfused rat hearts, increased phosphorylase a activity in acute as well as chronic diabetic rat hearts but not in control rat hearts. Cholinergic muscarinic receptors in the ventricles obtained from 180-day control and STZ diabetic rats were studied by performing radioligand binding studies. [³H]NMS was used as a radioligand to stereospecifically label all of the muscarinic receptor binding sites present in the ventricular membrane preparation. There was no change in either the receptor density or in the binding constants for antagonists and agonists at the muscarinic receptor site in 180-day diabetic rat hearts as compared to control. Ventricular noradrenaline content was estimated using an HPLC method, in 180-day alloxan and STZ diabetic and age-matched control rat hearts. There was no significant change in the noradrenaline content of diabetic rat hearts. Results obtained in the above studies demonstrate that various functional, pharmacological and biochemical alterations occur in the heart in experimental diabetes. Depressed cardiac performance was observed in isolated perfused diabetic rat hearts at various time points after the induction of diabetes and may represent the preclinical ventricular dysfunction phase of a developing diabetic cardiomyopathy. Changes noticed in the sensitivity of the.diabetic myocardium towards the negative inotropic effect of carbachol may represent various stages of a parasympathetic autonomic neuropathy of the heart in diabetes. The unaltered positive inotropic effect of Hsoproterenol and unchanged noradrenaline content in diabetic rat hearts indicate the absence of a sympathetic autonomic neuropathy. The depressed cardiac relaxant effect (maximum changes produced in negative dP/dt) of isoproterenol in diabetic rat hearts suggest defects in cardiac muscle relaxation, Ca²⁺ handling by the sarcoplasmic reticulum and perhaps ATP production and utilization. The enhanced sensitivity of the phosphorylase enzyme to agonists in diabetic rat hearts may be an outcome of alterations in Ca²⁺ homeostasis and other acute metabolic derangements in the heart caused by diabetes. All these changes could contribute to the pathogenesis of a diabetic cardiomyopathy. / Pharmaceutical Sciences, Faculty of / Graduate

Several studies have been carried out recently with the aim of achieving cardiac modelling of the whole heart for a full heartbeat. However, within the context of the Galerkin method, those simulations require high computational demand, ranging from 16 - 200 CPUs, and long calculation time, lasting from 1 h - 50 h. To solve this problem, this research proposes to make use of a Reduced Order Method (ROM) called the Proper Orthogonal Decomposition with Interpolation method (PODI) to achieve real-time modelling with an adequate level of solution accuracy. The idea behind this method is to first construct a database of pre-computed full-scale solutions using the Element-free Galerkin method (EFG) and then project a selected subset of these solutions to a low dimensional space. Using the Moving Least Square method (MLS), an interpolation is carried out for the problem-at-hand, before the resulting coefficients are projected back to the original high dimensional solution space. The aim of this project is to tackle real-time modelling of a patient-specific heart for a full heartbeat in different stages, namely: modelling (i) the diastolic filling with variations of material properties, (ii) the isovolumetric contraction (IVC), ejection and isovolumetric relation (IVR) with arbitrary time evolutions, and (iii) variations in heart anatomy. For the diastolic filling, computations are carried out on a bi-ventricle model (BV) to investigate the performance and accuracy for varying the material parameters. The PODI calculations of the LV are completed within 14 s on a normal desktop machine with a relative L₂-error norm of 6x10⁻³. These calculations are about 2050 times faster than EFG, with each displacement step generated at a calculation frequency of 1074 Hz. An error sensitivity analysis is consequently carried out to find the most sensitive parameter and optimum dataset to be selected for the PODI calculation. In the second phase of the research, a so-called "time standardisation scheme" is adopted to model a full heartbeat cycle. This is due to the simulation of the IVC, ejection, and IVR phases being carried out using a displacement-driven calculation method which does not use uniform simulation steps across datasets. Generated results are accurate, with the PODI calculations being 2200 faster than EFG. The PODI method is, in the third phase of this work, extended to deal with arbitrary heart meshes by developing a method called "Degrees of freedom standardisation" (DOFS). DOFS consists of using a template mesh over which all dataset result fields are projected. Once the result fields are standardised, they are consequently used for the PODI calculation, before the PODI solution is projected back to the mesh of the problem-at-hand. The first template mesh to be considered is a cube mesh. However, it is found to produce results with high errors and non-physical behaviour. The second template mesh used is a heart template. In this case, a preprocessing step is required where a non-rigid transformation based on the coherent point drift method is used to transform all dataset hearts onto the heart template. The heart template approach generated a PODI solution of higher accuracy at a relatively low computational time. Following these encouraging results, a final investigation is carried out where the PODI method is coupled with a computationally expensive gradient-based optimisation method called the Levenberg- Marquardt (PODI-LVM) method. It is then compared against the full-scale simulation one where the EFG is used with the Levenberg-Marquardt method (EFG-LVM). In this case, the PODI-LVM simulations are 1025 times faster than the EFG-LVM, while its error is less than 1%. It is also observed that since the PODI database is built using EFG simulations, the PODI-LVM behaves similarly to the EFG-LVM one.

BACKGROUND: Researchers recently created a new scoring system for characterizing organ dysfunction in critically ill pediatric patients, named the pSFOA (pediatric sequential organ failure assessment). Support for applying this scoring system in pediatric patients who suffer from cyanotic and acyanotic congenital heart diseases has not been evaluated. OBJECTIVES: To compare the pSOFA scores between pediatric patients with acyanotic and cyanotic congenital heart disease (CHD). Exampine the pSOFA results of CHD patients with pediatric patients who underwent hematopoietic stem cell transplantations. METHODS: A retrospective case-study of pediatric patients with congenital heart disease admitted to the CICU at Boston Children’s Hospital in 2018. Patients were included if between 1 and 5 years of age, neonates of less than a month old were excluded. A total of 101 patients were reviewed, 50 with cyanotic CHD and 51 with acyanotic CHD. Patient vital signs were assessed using the pSOFA scoring system, with scores assigned based on indices of respiratory, coagulation, hepatic, cardiovascular, neurologic, and renal system function. Scores were analyzed using two-tailed nonparametric Mann-Whitney tests with an alpha of 0.05. The pSOFA scores of CHD patients were then compared to patients who were admitted to the ICU at Boston Children’s Hospital after they received a hematopoietic stem cell transplantation (HSCT). Dunn’s multiple comparisons tests were performed for the two CHD groups and the HSCT patients. An alpha value of 0.05 was also used for these tests. RESULTS: Parameters determined to be statistically significant between the cyanotic and acyanotic CHD patients were, Total High Direct score, Total Average Direct score, Total Low Indirect Score, Total High Indirect score, Neurologic High score, Average Neurologic score, Renal High score, Average Renal score, and Hepatic Low Indirect score. The parameters that were statistically different between the CHD groups and the HSCT group were Age, Maximum Coagulation, Maximum Renal, Maximum Hepatic, and Maximum Total pSOFA scores. Parameters that were significantly different only between cyanotic CHD and HSCT were Maximum Cardiovascular and Maximum Respiratory. Scores that were significantly different between acyanotic CHD and HSCT were Maximum Neurologic. CONCLUSIONS: There were significant differences in pSOFA scores between children with cyanotic CHD and acyanotic CHD, specifically regarding total direct, total indirect, neurologic, and renal scores. Additional research is required to explain these scores differences and validation of these scores in predicting morbidity and mortality outcomes in these patient populations. / 2022-06-02T00:00:00Z