A survey of deep learning models in medical therapeutic areas.

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Visual Impairment and Blindness

Blindness and vision impairment affect at least 2.2 billion people worldwide with most individuals having a preventable vision impairment. The majority of people with vision impairment are older than 50 years, however, vision loss can affect people of all ages. Reduced eyesight can have major and long-lasting effects on all aspects of life, including daily personal activities, interacting with the community, school and work opportunities, and the ability to access public services. This book provides an overview of the effects of blindness and visual impairment in the context of the most common causes of blindness in older adults as well as children, including retinal disorders, cataracts, glaucoma, and macular or corneal degeneration

Metabolic Imaging of Early Radiation-Induced Lung Injury Using Hyperpolarized 13C-Pyruvate in Rodent Lungs

Lung cancer is the leading cause of cancer related death. Radiation therapy is a prominent treatment method but leads to adverse consequences. Radiation-Induced Lung Injury (RILI) is the primary adverse consequence that limits further radiation therapy and develops in 5-37% of the treated patients. RILI proceeds in two distinct phases: a) early and reversible Radiation Pneumonitis (RP), and b) late and irreversible radiation fibrosis. Clinically, Dose Volume Histogram (DVH) parameters derived from radiation therapy planning stage are used to determine outcome and severity of RP but have been demonstrated to possess a very low predictive power. Computed Tomography (CT) is the most commonly used modality for the imaging of RP, but often only detects very late RP that leaves little room for intervention to abort the progress to irreversible radiation fibrosis. Early detection of RP using imaging may allow for interventional treatment and management of the disease and the associated symptoms in a better manner. Improvement in Dynamic Nuclear Polarization (DNP) technology has led to advancement of hyperpolarized 13-Carbon-Magnetic Resonance Imaging (13C-MRI). In this thesis, we present the investigation of early detection of RP with 13C-MRI in an animal model with the use of hyperpolarized 13C-pyruvate. A pilot study demonstrated the proof of concept along with a qualitative histological confirmation. 13C-MRI data and histology data were collected 2 weeks post irradiation of whole thorax in rodents. In the subsequent study, regional and longitudinal 13C-MRI and quantitative histology data were analyzed to demonstrate the early organ-wide response of RP. These data were collected at day 5, 10, 15 and 25 post conformal irradiation of the right rodent lung. Finally, we demonstrate a novel approach to map pH using hyperpolarized 13C-bicarbonate with the use of spiral-Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation (IDEAL) pulse sequence. Validation of this approach by comparison to Chemical Shift Imaging (CSI) pH measurement and standard pH measurement with the aid of phantoms along with hyperpolarized 13C-bicarbonate is presented. pH mapping may play a role in the staging and therapeutic intervention of cancer

Nanomedicines for the treatment of tuberculosis

Mycobacterium tuberculosis (Mtb) is the bacterium responsible for the human disease tuberculosis (TB). This study aimed to develop a rapid, low cost assay for screening the anti-mycobacterial properties of new therapies. This assay employed a Green Fluorescent Protein reporter strain of Mycobacteruim avium subspecies paratuberculosis (Map), a pathogenic species causing paratuberculosis in ruminants that can be considered a model for Mtb. Mycobacterial growth over time was monitored by fluorescence, testing new potential therapies including metal and drug nanoparticles (NPs), over a range of concentrations for up to 7 days. The new Map-based assay was sufficiently sensitive to distinguish between the toxicity of different metal/metal oxide NPs, ranked: Ag>Cu(II)O>ZnO. Solid drug NPs (SDNs) of TB antibiotics (rifampicin, isoniazid and pyrazinamide) were compared to conventional antibiotics. SDNs of rifampicin were found to be 100 times more toxic to Map than the conventional antibiotics. Fluorescence microscopy revealed the uptake of SDNs by infected macrophages with possible co-localisation with Map. Pilot data supports the ability of the SDN to kill the intracellular Map. These results support the benefits of nanomedicine and suggest that drug doses could be reduced, if delivered as a nano-formulation

Investigation into mycobacterial persistence and early markers of outcome in the treatment of pulmonary tuberculosis

Background: Development of ultra-short chemotherapy for tuberculosis (TB) is thwarted by drug-tolerant bacillary persistence and a lack of surrogate endpoints to predict outcome from early clinical studies. Characterising bacillary elimination amongst TB patients may provide important new information. Bacilli harbouring intra-cytoplasmic lipid bodies (LBs) may represent a drug-tolerant phenotype, responsible for delayed bacterial clearance. Methods: Malawian adults with pulmonary TB were treated with standard 6 month therapy. Two quantitative sputum culture methods were used to model bacillary elimination during the first 2 months; serial sputum colony counting (SSCC) and time to positivity (TTP) in BACTEC MGIT broth. Fluorescence microscopy was used to assess the proportion of LB positive bacilli on sputum smears. Plasma concentrations of anti-TB drugs were assayed at day 14 or 21. Patients were followed until one year post-treatment. Outcomes were defined as favourable (stable cure) or unfavourable (failure/relapse). The effect of microbiological and pharmacological factors on outcome was assessed. Results: 169 patients (59% with HIV co-infection) were recruited. Of 133 final outcomes, 15 (11%) were unfavourable. Partial likelihood non-linear mixed effects (NLME) modelling of SSCC data from 86 (64%) patients showed biphasic bacillary elimination; slow late-phase eradication of persisters was associated with unfavourable outcome (p=0.001). Linear mixed effects (LME) modelling of TTP data from 124 (93%) patients showed that a slower MGIT Bacillary Elimination Rate (MBER) was associated with unfavourable outcome (p=0.007). 28% (range 0-79%) of acid-fast bacilli in baseline sputum samples were LB positive. During the first month there was a trend towards higher LB counts in patients who went on to have unfavourable vs. favourable outcomes (p=0.085). Low plasma rifampicin and isoniazid concentrations were reported in 87% and 50% patients respectively. A lower isoniazid AUC(0-6hr) exposure was associated with unfavourable outcome (p=0.035). Conclusions: The two main findings were: 1. Modelling of bacillary elimination during the first 2 months of TB therapy predicted long-term outcome. The MBER, in particular, could be calculated for 93% of patients and should be considered as a surrogate marker for early clinical trials. 2. The observation of a higher proportion of LB positive bacilli in later sputum samples from patients with unfavourable outcomes suggests that these may be drug-tolerant persister cells, with negative implications for treatment efficacy

Tuberculosis

Asserts that despite progress in controlling tuberculosis (TB), the decline in incidence has been disappointing, pointing to the need for new strategies and more effective tools. HIV/AIDS is one factor that challenges effective control of TB, especially in Southern African countries. Three key elements are needed to achieve effective TB control and to meet the Sustainable Development Goals: (1) early and accurate diagnosis and drug-sensitivity testing, (2) patient access to and completion of effective treatment, and (3) prevention of progression from latent infection to disease. Prevention requires vaccination and screening of individual at high risk as well as interventions such as air disinfection and the use of masks and respirators in hospitals and other congregate settings. Recommendations stress the need to strengthen health systems in high-burden countries by emphasizing community-based care over hospital care; to improve information systems to ensure patient adherence and manage medication supply chains; and to invest in research to develop the necessary interventions. Fundamentally, current global TB control strategies must undergo revision and receive significant research funding

Novel Approaches to Study the Haematological System During Inflammation

Physiological Science

A novel image analysis approach to characterise the effects of dietary components on intestinal morphology and immune system in Atlantic salmon

The intestinal tract of salmonids provides a dynamic interface that not only mediates nutrient uptake but also functions as the first line of defence against ingested pathogens. Exposure of the immune system to beneficial microorganisms and different dietary immunostimulants via the intestine has been shown to prime the immune system and help in the development of immune competence. Furthermore, the morphology and function of teleostean intestines are known to respond to feed components and to ingested and resident bacterial communities. Histological appraisal is still generally considered to be the gold standard for sensitive assessment of the effects of such dietary modulation. The aim of the present study was to improve understanding of salmonid intestinal function, structure and dynamics and to use the knowledge gained to develop a model for analysis, which would allow intestinal health to be assessed with respect to different intestinal communities and feed components. Virtual histology, the process of assessing digital images of histological slides, is gaining momentum as an approach to supplement traditional histological evaluation methodologies and at the same time, image analysis of digitised histological sections provides a practical means for quantifiable assessment of structural and functional changes in tissues, being both objective and reproducible. This project focused on the development of a rapid, practical analytical methodology based on advanced image analysis, that was able to measure and characterise a range of features of the intestinal histology of Atlantic salmon in a quantitative manner. In the first research chapter, the development of a novel histological assessment system based upon advanced image analysis was described, this being developed with the help of a soybean feed model known to induce enteropathy in Atlantic salmon. This tool targeted the evaluation of the extent of morphological changes occurring in the distal intestine of Atlantic salmon following dietary modulation. The final analytical methodology arrived at, could be conducted with minimal user-interaction, allowing rapid and objective assessment of 12 continuous variables per histological frame analysed. The processing time required for each histological frame was roughly 20-25 min, which greatly improved the efficiency of conducting such a quantitative assessment with respect to the time taken for a subjective semi-quantitative alternative approach. Significant agreement between the fully automated and the manual morphometric image segmentation was achieved, however, the strength of this quantitative approach was enhanced by the employment of interactive procedures, which enabled the operator / observer to rectify preceding automated segmentation steps, and account for the specimen’s variations. Results indicated that image analysis provided a viable alternative to a pathologist’s manual scoring, being more practical and time-efficient. In the second research chapter, feeding Atlantic salmon a high inclusion level of unrefined SBM (25 %) produced an inflammatory response in the distal intestine as previously described by other authors. The model feed trial successfully generated differentiable states, although these were not, for the most part, systemically differentiable through the majority of standard immunological procedures used, being only detectable morphologically. Quantitation of morphometric parameters associated with histological sections using the newly developed image analysis tool successfully allowed identification of major morphological changes. Image analysis was thus shown to provide a powerful tool for describing the histomorphological structure of Atlantic salmon distal intestine. In turn, the semi-automated image analysis methods were able to distinguish normal intestinal mucosa from those affected by enteritis. While individual parameters were less discriminatory, use of multivariate techniques allowed better discrimination of states and is likely to prove the most productive approach in further studies. Work described in the third research chapter sought to validate the semi-automated image analysis system to establish that it was measuring the parameters it was purported to be measuring, and to provide reassurance that it could reliably measure pre-determined features. This study, using the same sections for semi-quantitative and quantitative analyses, demonstrated that the quantitative indices performed well when compared to analogous semi-quantitative descriptive parameters of assessment for enteritis prognosis. The excellent reproducibility and accuracy performance levels indicated that the image analysis system was a useful and reliable morphometric method for the quantification of SB-induced enteritis in salmon. Other characteristics such as rapidity, simplicity and adaptability favour this method for image analysis, and are particularly useful where less experienced interpreters are performing the analysis. The work described in the fourth research chapter characterised changes in the morphology of the intestinal epithelial cells occurring as a result of dietary modulation and aspects of inflammatory infiltration, using a selected panel of enzyme and IHC markers. To accomplish this, image analysis techniques were used to evaluate and systematically optimise a quantitative immunolabelling assessment protocol. Digital computer-assisted quantification of labelling for cell proliferation and regeneration; programmed cell death or apoptosis; EGCs and t-cell like infiltrates; mobilisation of stress-related protein regenerative processes and facilitation of nutrient uptake and ion transport provided encouraging results. Through the description of the intestinal cellular responses at a molecular level, such IHC expression profiling further characterised the inflammatory reaction generated by the enteropathic diet. In addition, a number of potential diagnostic parameters were described for fish intestinal health e.g. the relative levels of antigenicity and the spatial distribution of antigens in tissues. Work described in the final research chapter focused on detailed characterisation of intestinal MCs / EGCs in order to try to elucidate their functional role in the intestinal immune responses. Through an understanding of their distribution, composition and ultrastructure, the intention was to better characterise these cells and their functional properties. The general morphology, histochemical characteristics and tissue distribution of these cells were explored in detail using histochemical, IHC and immunogold staining / labelling, visualised using light, confocal and TEM microscopy. Despite these extensive investigations, their physiological function and the content of their granules still remain somewhat obscure, although a role as immunodulatory cells reacting to various exogeneous signals through a finely regulated process and comparable to that causing the degranulation of mammalian MCs is suggested. The histochemical staining properties demonstrated for salmonid MCs / EGCs seem to resemble those of mammalian mucosal mast cells, with both acidophilic and basophilic components in their granules, and a granule content containing neuromodulator / neurotransmitter-peptides such as serotonin, met-enkephalin and substance-p. Consequently, distinguishable bio-chromogenic markers have been identified that are of utility in generating a discriminatory profile for image analysis of such cells