New techniques for functional testing of microprocessor based systems

Electronic devices may be affected by failures, for example due to physical defects. These defects may be introduced during the manufacturing process, as well as during the normal operating life of the device due to aging. How to detect all these defects is not a trivial task, especially in complex systems such as processor cores. Nevertheless, safety-critical applications do not tolerate failures, this is the reason why testing such devices is needed so to guarantee a correct behavior at any time. Moreover, testing is a key parameter for assessing the quality of a manufactured product. Consolidated testing techniques are based on special Design for Testability (DfT) features added in the original design to facilitate test effectiveness. Design, integration, and usage of the available DfT for testing purposes are fully supported by commercial EDA tools, hence approaches based on DfT are the standard solutions adopted by silicon vendors for testing their devices. Tests exploiting the available DfT such as scan-chains manipulate the internal state of the system, differently to the normal functional mode, passing through unreachable configurations. Alternative solutions that do not violate such functional mode are defined as functional tests. In microprocessor based systems, functional testing techniques include software-based self-test (SBST), i.e., a piece of software (referred to as test program) which is uploaded in the system available memory and executed, with the purpose of exciting a specific part of the system and observing the effects of possible defects affecting it. SBST has been widely-studies by the research community for years, but its adoption by the industry is quite recent. My research activities have been mainly focused on the industrial perspective of SBST. The problem of providing an effective development flow and guidelines for integrating SBST in the available operating systems have been tackled and results have been provided on microprocessor based systems for the automotive domain. Remarkably, new algorithms have been also introduced with respect to state-of-the-art approaches, which can be systematically implemented to enrich SBST suites of test programs for modern microprocessor based systems. The proposed development flow and algorithms are being currently employed in real electronic control units for automotive products. Moreover, a special hardware infrastructure purposely embedded in modern devices for interconnecting the numerous on-board instruments has been interest of my research as well. This solution is known as reconfigurable scan networks (RSNs) and its practical adoption is growing fast as new standards have been created. Test and diagnosis methodologies have been proposed targeting specific RSN features, aimed at checking whether the reconfigurability of such networks has not been corrupted by defects and, in this case, at identifying the defective elements of the network. The contribution of my work in this field has also been included in the first suite of public-domain benchmark networks

Potentially Diagnostic Electron Paramagnetic Resonance Spectra Elucidate the Underlying Mechanism of Mitochondrial Dysfunction in the Deoxyguanosine Kinase Deficient Rat Model of a Genetic Mitochondrial DNA Depletion Syndrome

A novel rat model for a well-characterized human mitochondrial disease, mitochondrial DNA depletion syndrome with associated deoxyguanosine kinase (DGUOK) deficiency, is described. The rat model recapitulates the pathologic and biochemical signatures of the human disease. The application of electron paramagnetic (spin) resonance (EPR) spectroscopy to the identification and characterization of respiratory chain abnormalities in the mitochondria from freshly frozen tissue of the mitochondrial disease model rat is introduced. EPR is shown to be a sensitive technique for detecting mitochondrial functional abnormalities in situ and, here, is particularly useful in characterizing the redox state changes and oxidative stress that can result from depressed expression and/or diminished specific activity of the distinct respiratory chain complexes. As EPR requires no sample preparation or non-physiological reagents, it provides information on the status of the mitochondrion as it was in the functioning state. On its own, this information is of use in identifying respiratory chain dysfunction; in conjunction with other techniques, the information from EPR shows how the respiratory chain is affected at the molecular level by the dysfunction. It is proposed that EPR has a role in mechanistic pathophysiological studies of mitochondrial disease and could be used to study the impact of new treatment modalities or as an additional diagnostic tool

Clinical utility of NGS diagnosis and disease stratification in a multi-ethnic primary ciliary dyskinesia cohort

Background: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests. Methods: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries. Results: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results. Conclusions: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening

On the test of single via related defects in digital VLSI designs

Vias are critical for digital circuit manufacturing, as they represent a common defect location, and a general DfM rule suggests replicating every instance for redundancy. When this is not achievable, a mandatory requirement is that the remaining single vias must be tested. We propose an automated method for generating tests and accurately evaluating test coverage of such defects, ready for use in any digital implementation flow and for integration within EDA tools, and also providing a useful quality metric. A prototype tool implementation and experimental results for an industrial case study are presented

Innovative Techniques for Testing and Diagnosing SoCs

We rely upon the continued functioning of many electronic devices for our everyday welfare, usually embedding integrated circuits that are becoming even cheaper and smaller with improved features. Nowadays, microelectronics can integrate a working computer with CPU, memories, and even GPUs on a single die, namely System-On-Chip (SoC). SoCs are also employed on automotive safety-critical applications, but need to be tested thoroughly to comply with reliability standards, in particular the ISO26262 functional safety for road vehicles. The goal of this PhD. thesis is to improve SoC reliability by proposing innovative techniques for testing and diagnosing its internal modules: CPUs, memories, peripherals, and GPUs. The proposed approaches in the sequence appearing in this thesis are described as follows: 1. Embedded Memory Diagnosis: Memories are dense and complex circuits which are susceptible to design and manufacturing errors. Hence, it is important to understand the fault occurrence in the memory array. In practice, the logical and physical array representation differs due to an optimized design which adds enhancements to the device, namely scrambling. This part proposes an accurate memory diagnosis by showing the efforts of a software tool able to analyze test results, unscramble the memory array, map failing syndromes to cell locations, elaborate cumulative analysis, and elaborate a final fault model hypothesis. Several SRAM memory failing syndromes were analyzed as case studies gathered on an industrial automotive 32-bit SoC developed by STMicroelectronics. The tool displayed defects virtually, and results were confirmed by real photos taken from a microscope. 2. Functional Test Pattern Generation: The key for a successful test is the pattern applied to the device. They can be structural or functional; the former usually benefits from embedded test modules targeting manufacturing errors and is only effective before shipping the component to the client. The latter, on the other hand, can be applied during mission minimally impacting on performance but is penalized due to high generation time. However, functional test patterns may benefit for having different goals in functional mission mode. Part III of this PhD thesis proposes three different functional test pattern generation methods for CPU cores embedded in SoCs, targeting different test purposes, described as follows: a. Functional Stress Patterns: Are suitable for optimizing functional stress during I Operational-life Tests and Burn-in Screening for an optimal device reliability characterization b. Functional Power Hungry Patterns: Are suitable for determining functional peak power for strictly limiting the power of structural patterns during manufacturing tests, thus reducing premature device over-kill while delivering high test coverage c. Software-Based Self-Test Patterns: Combines the potentiality of structural patterns with functional ones, allowing its execution periodically during mission. In addition, an external hardware communicating with a devised SBST was proposed. It helps increasing in 3% the fault coverage by testing critical Hardly Functionally Testable Faults not covered by conventional SBST patterns. An automatic functional test pattern generation exploiting an evolutionary algorithm maximizing metrics related to stress, power, and fault coverage was employed in the above-mentioned approaches to quickly generate the desired patterns. The approaches were evaluated on two industrial cases developed by STMicroelectronics; 8051-based and a 32-bit Power Architecture SoCs. Results show that generation time was reduced upto 75% in comparison to older methodologies while increasing significantly the desired metrics. 3. Fault Injection in GPGPU: Fault injection mechanisms in semiconductor devices are suitable for generating structural patterns, testing and activating mitigation techniques, and validating robust hardware and software applications. GPGPUs are known for fast parallel computation used in high performance computing and advanced driver assistance where reliability is the key point. Moreover, GPGPU manufacturers do not provide design description code due to content secrecy. Therefore, commercial fault injectors using the GPGPU model is unfeasible, making radiation tests the only resource available, but are costly. In the last part of this thesis, we propose a software implemented fault injector able to inject bit-flip in memory elements of a real GPGPU. It exploits a software debugger tool and combines the C-CUDA grammar to wisely determine fault spots and apply bit-flip operations in program variables. The goal is to validate robust parallel algorithms by studying fault propagation or activating redundancy mechanisms they possibly embed. The effectiveness of the tool was evaluated on two robust applications: redundant parallel matrix multiplication and floating point Fast Fourier Transform

Myocardial perfusion in heart disease

Heart disease: Coronary heart disease is a major cause of mortality and morbidity in the UK and globally. It is managed with medical therapy and coronary revascularisation to reduce symptoms and reduce risk of major adverse cardiovascular events. When patients present with chest pain, it is important to risk stratify those that would most benefit from invasive coronary assessment and those that can be managed with medical therapy alone. Myocardial perfusion techniques have been developed in order to do this. Cardiovascular magnetic resonance (CMR) with stress perfusion: CMR allows the non-invasive assessment of coronary artery disease (CAD). Under conditions of vasodilator stress, a gadolinium based contrast agent is injected and during the first pass through the left ventricle, perfusion defects can be observed. There is a strong evidence base for perfusion CMR but the technique is qualitative, relies on experienced operators and potentially misses globally low perfusion such as in cases of “balanced” ischaemia. Quantitative perfusion CMR: In contrast, quantitative perfusion techniques allow the calculation of myocardial blood flow (MBF). It is more objective, less reliant on the expert observer and can give additional insights into microvascular disease and cardiomyopathy. As well as being less subjective, quantitative perfusion has other advantages for example it allows full assessment of ischaemic burden and may contain prognostic information that could be used to risk stratify and improve patient care. However, quantitative perfusion has been outside the realm of routine clinical practice due to difficulties in acquiring suitable data for full quantification and the laborious nature of analysing it. Perfusion mapping: Peter Kellman, Hui Xue and colleagues at the National Institutes for Health, USA developed the “perfusion mapping” technique to address these limitations. Perfusion maps are generated automatically and inline during the CMR scan and each voxel encodes myocardial blood flow. This allows the instant quantification of MBF without complex acquisition techniques and post processing. In this thesis I have taken perfusion mapping and deployed in the real-world at a scale an order of magnitude higher than prior quantitative perfusion studies, developing the evidence base for routine clinical use across a broad range of diseases and scenarios: In coronary artery disease: I have shown that perfusion mapping is accurate to detect coronary artery stenosis as defined by 3D quantitative coronary angiography in a single centre, 50 patient study. Transmural and subendocardial perfusion are particularly sensitive to detect coronary stenoses with performances similar to expert readers. There is a high sensitivity and high negative predictive value making perfusion mapping a good “rule-out” test for coronary disease. Quantitative perfusion and prognosis: I investigated whether stress MBF and myocardial perfusion reserve (MPR) calculated by perfusion mapping would encode prognostic information in a 1049 patient multi-centre study over a mean follow up time of 605 days. Both stress MBF and MPR were independently associated with death and major adverse cardiovascular events (MACE). The hazard ratio for MACE was 2.14 for each 1ml/g/min decrease in stress MBF and 1.74 for each unit decrease in MPR. This work can now be taken forward with prospective studies in order to better risk stratify patients, including those without perfusion defects on clinical read. Reference ranges and non-obstructive coronary disease: I sought to determine the factors that contribute to perfusion in a multi-centre registry study. In patients with no obstructive coronary artery disease, stress MBF was reduced with age, diabetes, left ventricular hypertrophy (LVH) and the use of beta blockers. Rest MBF was influenced by sex (higher in females) and reduced with beta blockers. This study suggests patient factors beyond coronary artery disease (and therefore likely microvascular disease) should also be considered when interpreting quantitative perfusion studies. In cardiomyopathy: I also investigated myocardial perfusion in cardiomyopathy looking at Fabry disease as an example disease. In a prospective, observational, single centre study of 44 patients and 27 controls I found Fabry patients had reduced perfusion (and therefore likely microvascular dysfunction), particularly in the subendocardium and was associated with left ventricular hypertrophy (LVH), glycophospholipid storage and scar. Perfusion was reduced even in patients without LVH suggesting it is an early disease marker. In conclusion, in this thesis, I have developed an evidence base for quantitative perfusion CMR and demonstrated how it can be integrated into routine clinical care. Perfusion mapping is accurate for detecting coronary artery stenosis and encodes prognostic information. Further work in this area could enable patients to be risk stratified based on their myocardial perfusion in order to reduce the morbidity and mortality associated with epicardial and microvascular coronary artery disease. Following on from this work, two further British Heart Foundation Clinical Research Training Fellowships have been awarded to further investigate quantitative perfusion in patients following surgical revascularisation of coronary disease and in patients with hypertrophic cardiomyopathy

Screening, Diagnosis, and Management of Open Angle Glaucoma: An Evidence-Based Guideline for Canadian Optometrists

Glaucoma is the most common form of irreversible blindness in the world, and second only to cataract among all causes of blindness. There is still no universally agreed-upon definition of glaucoma, and as such, it remains a condition for which there are differing views on the classification of individuals within the continuum of suspicion through diagnosis. Regardless, there appears to be consensus that glaucoma refers to a group of diseases that manifest as a characteristic progressive optic neuropathy and retinal ganglion cell loss that eventually leads to a permanent loss of visual field. Glaucoma is a major public health issue because individuals are typically asymptomatic until end stages of the disease when the associated vision loss is significant and irreversible. Studies have shown that the prevalence of undetected glaucoma is as high as 50% even in high income areas including North America and Australia, increasing to 90% in middle and low income areas such as Asia and Africa. This is at least in part a result of inadequate screening tools and strategies to detect this asymptomatic disease: without more individuals accessing routine eye examinations, glaucoma will continue to go undetected. Vision loss from glaucoma imposes significant societal and economic burdens that increase with disease severity: the direct costs of vision loss from glaucoma exceed $300 million annually in Canada, and approach$2 billion across North America

Recent Clinical Research on Glaucoma

In the past few years, knowledge about glaucoma diagnosis and follow up has evolved dramatically through advances in intraocular pressure (IOP) measurement, corneal biomechanics, structural and functional assessment of the ocular surface, anterior chamber, retina, optic nerve and intracranial visual pathways, as well as the advent of artificial intelligence. In addition, the development of new modalities of IOP-lowering and non-IOP-lowering drugs, alternative deliveries, refined laser technologies, and minimally invasive glaucoma surgery (MIGS) techniques with different implants have widened the therapeutic possibilities for treating this disease. Finally, current insights into risk factors and quality of life in relation to glaucomatous impairment are emerging. The purpose of this Special Issue is to present the latest exciting clinical developments that are taking place in the field of glaucoma

Practical guide to genetic screening for inherited eye diseases

Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive RPE65-retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics