Veterinary and Agricultural Sciences Collected Works - Theses
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ItemInvestigation of equine hoof biomechanics using experiment, finite element and machine learning methods( 2022)This thesis investigates the biomechanics of the horse hoof, emphasising on its shape, deformation during movement, and influencing variables. Previous in vivo studies evaluated hoof shape parameters, such as proximal hoof circumference, to examine hoof conformation. In the majority of cases, a traditional measuring method, such as a measuring tape, was used, and, in a few instances, advanced measuring technology was utilised. To replace conventional measurement tools with modern technologies, it is necessary to assess their accuracy, reliability, and practicality. Therefore, the current study conducted a technical comparison between the measuring tape, 3D scanning and photogrammetry for measuring proximal hoof circumference. Considering the 3D scanner to be the most accurate method, the measuring tape was more accurate than photogrammetry. In addition, the inter- and intra-rater reliabilities of tape measurements were reported to be excellent. In the next step, a finite element analysis of the horse hoof deformation was performed. An artificial neural network was trained to obtain the whole deformation response of the hoof for varied tissue hydration levels, and trotting and standing locomotion modes. Results showed that increasing environmental hydration significantly increased strains on the hoof wall. The study also demonstrated how adopting advanced material models, such as hyperelastic compared to linear elastic, improved the accuracy of finite element analysis. Dynamic finite element analysis of the hoof was then conducted over a full trot stride and in vivo measurements were obtained to examine the impact of a toe-in conformation on the hoof's biomechanical response. The study hypothesised that different deformation patterns and hoof kinematics in toe-in hooves are caused by a different path of the centre of pressure under the hoof. Consequently, the model was allocated two distinct centres of pressure paths associated with normal and toe-in conformations. The finite element model generated similar strain patterns to those seen in vivo on the hoof walls and successfully demonstrated the distinct kinematics of toe-in and normal hooves. Lastly, the study examined the effect of toe-in conformation on laminitis. A total of 100 trotting loading cycles were applied to the model. The laminar junction injury was simulated by decreasing the tissue's elastic modulus in the presence of excessive maximum principal stresses. In both the normal and toe-in models, the injury began in the quarters. In the normal hoof, however, laminar junction tissue degeneration was distributed symmetrically at the quarters, whereas the toe-in model had a lateral concentration of degeneration. The models replicated clinical observations, indicating the third phalanx dorsal rotation, a symmetric distal displacement of the third phalanx dorsal in the normal model, and an asymmetric distal displacement of the third phalanx dorsal in the toe-in model.
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ItemUse of telesimulation to teach veterinary cardiopulmonary resuscitation advanced life support management: a comparison with traditional online training modalities( 2022)Cardiopulmonary resuscitation (CPR) is the only means of treatment for cardiopulmonary arrest. The goal of CPR is not only to achieve return of circulation in the patient, but ultimately for survival to hospital discharge. Guidelines outlining best practice for CPR have existed for several decades in humans and similar guidelines for companion animals, known as the Reassessment Campaign on Veterinary Resuscitation (RECOVER) guidelines were published in 2012. There is strong evidence that adherence to CPR guidelines leads to improved patient outcomes in humans, and a similar trend is seen in companion animals with the RECOVER guidelines. Over the last 10-20 years, the importance of education in CPR has been recognised. Without adequate training in the delivery of high-quality CPR, patient survival is compromised. Simulation training for CPR is widely accepted in human medicine, but is not well studied in veterinary medicine. This thesis aims to review the development of CPR, the evidence surrounding the impact of CPR guidelines and the merits of simulation training. It includes a prospective, randomised crossover study comparing simulation to more conventional online learning methods to teach veterinary CPR advanced life support (ALS). Changes to the project due to impacts of the Covid-19 pandemic meant a type of simulation known as telesimulation was utilised. Six cases covering CPR topics were developed for both the case-based learning and telesimulation training modules. Forty-five students undertook the training using both modalities. Pre-, mid- and post-training telesimulation assessments were used to assess trainee compliance to veterinary ALS guidelines. Students also completed self-efficacy scores and provided feedback on the training course. A mixed effects logistic regression model was used to analyse student ALS compliance. Results showed telesimulation training was as effective as online lectures and cases for student compliance (OR 1.1, 95% CI 0.8-1.5). There was no difference in student self-efficacy scores between the two training modalities. Student feedback favoured telesimulation training (55%) or a combination of the two training methods (43%), as opposed to online lectures and case-based teachings alone (2%). The study highlights the benefits of telesimulation including the ability to provide remote simulation training to learners, opportunities for shared resource management between institutions, and an overall engaging learning experience for trainees. Limitations include technical difficulties, increased complexities of educational resources compared to online lectures and case-based learnings, and lack of validation given the relative novelty of telesimulation. The findings can be used to guide future veterinary CPR training and contributes to the growing body of literature on telesimulation.
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ItemDevelopment of 3D printed training simulation models for veterinary clinical procedures( 2021)This study aimed to develop 3D printed anatomical models (3DPAM) to be utilised as simulation training tools for three veterinary procedures: equine cranial artery occlusion for the treatment of guttural pouch mycosis, canine bronchoscopy, and canine cerebrospinal fluid (CSF) collection. Creating and validating 3DPAMs enables minimally invasive procedural training methods, thus improving patient safety when novice clinicians transfer simulator-learned skills to live clinical settings. 3DPAMs also provide a safe, low stress learning environment for students compared to learning with live patients or expensive and limited cadavers. The three target veterinary procedures were selected due to being technically demanding, high-risk when performed by novice clinicians, and currently lacking suitable commercially available veterinary-specific simulators. 3D printing produces high fidelity, anatomically accurate models with rapid prototyping at low cost. This study created six 3DPAMs for the three veterinary procedures of interest: an equine skull and vasculature model, two canine airway models, and canine skull and lumbar spine models. The standard of these models has been improved from previous prototypes created by the Small Animal Surgery Service (U-Vet Hospital, Melbourne Veterinary School, University of Melbourne), with the addition of cerebrospinal fluid collection simulators to the suite of models that are currently being developed. We hypothesised that evaluators would deem the occlusion and CSF collection 3DPAMs as sufficient simulators for their respective procedures, while optimisations and improvements would be required due to being rudimentary prototypes. We hypothesised that the most advanced 3DPAM, the canine bronchoscopy model, would achieve face and content validation. The occlusion and cerebrospinal fluid collection 3DPAMs were evaluated for capacity to simulate occlusion procedures or cerebrospinal fluid collection by a small number of veterinarians from the U-Vet Hospital familiar with these procedures. Evaluators deemed that the models simulated their respective procedures, whilst noting that significant improvements and optimisations are required prior to validation testing. A face and content validation study was conducted for the canine airway model with four veterinarians familiar with bronchoscopy procedures. Results suggest that the model has face and content validity and requires further optimisations to enhance the canine airway model as a simulator of canine bronchoscopy.
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ItemInvestigating bone health in dairy cows during pregnancy and lactation( 2022)Selection of dairy cattle for high milk yields creates a significant metabolic demand for all nutrients including calcium, which is met by changes in bone homeostasis. The effects of selective breeding to increase milk yield on bone loss and skeletal health in dairy cows have not been fully studied and recent reports of fractures in dairy cattle suggest that there may be significant welfare implications related to poor bone health in these animals. The current study undertook to investigate the bone health of cows during pregnancy and lactation. It was hypothesised that biochemical markers of bone turnover, the structure of cortical bone and systemic levels of cytokines are related to stages of production in dairy cattle. Investigation of biochemical markers of bone turnover showed that the plasma CTX-I levels were highest during early lactation and its levels declined with decrease in milk yield while plasma osteocalcin levels were highest during mid lactation and constant at other stages of lactation. To further investigate the changes in bone turnover at tissue level, rib biopsies were collected for micro-CT and dynamic histomorphometry analysis. The micro-CT and dynamic histomorphometry data demonstrated loss in bone mass during early lactation while increase in bone mass and decrease in porosity with decreased milk yield during late lactation. However, the newly formed bone was found to be less mineralised during periods of rapid bone formation. Investigation of the systemic levels of osteoclastogenic and anti-osteoclastogenic cytokines demonstrated high levels of IL-6 at late pregnancy and IFN-gamma and IL-4 at late lactation. This study provides evidence that dairy cows adapt to high demands of calcium during lactation and pregnancy by changes in bone turnover. The high levels of bone resorption during early lactation corresponded with high circulating levels of the osteoclastogenic cytokine IL-6 and increased porosity of the cortical bone of cattle. Decreased milk yield in late lactation was accompanied by increased the bone formation and higher circulating levels of the anti-osteoclastic cytokines IFN-gamma and IL-4 and reduced porosity of the cortical bone. Together these results suggest that systemic cytokines may in part regulate bone resorption and formation associated with stages of production and that in late lactation bone formation increases to recover the calcium reserves lost during peak lactation. Further work is required to determine if bone loss is fully recovered by the increased bone formation observed during late lactation or if over multiple production cycles, the cortical bone mass decreases significantly or cortical bone becomes increasingly less mineralised.
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ItemBoosting amphibian resilience to the pandemic fungal disease chytridiomycosis using vaccines and artificial environmental refugia( 2022)Amphibian biodiversity is under threat from an infectious disease called chytridiomycosis (caused by Batrachochytrium dendrobatidis-Bd). Due to a lack of solutions for mitigating the disease in the wild, many species are maintained in captivity to prevent extinction. This, however, is not sustainable and the ecological function of the species is not restored in the wild. My PhD research approaches this challenge by providing disease mitigation approaches that can be applied in nature. In laboratory studies, I found that low virulence strains of Bd can be used as a transmissible inoculum that can spread between frogs and provide protection against more virulent strains. Transmissible, resistance-boosting strains of Bd (similar to a transmissible vaccine) would be uniquely suited for controlling chytridiomycosis in nature, because only a fraction of populations would need to be directly inoculated. I also found that I could similarly boost amphibian resistance to Bd by infecting frogs with Bd and then treating them with heat or antifungals (exposure-clearance). In a surprising experiment, I found that treating frogs with the antifungal itraconazole alone can increase amphibian resistance to chytridiomycosis. This approach and the exposure-clearance approach would be useful for captive breeding for release programs because frogs could be resistance-boosted prior to release. In a separate set of experiments, I exploited differences in host and pathogen physiology to develop thermal refugia that can protect frogs from Bd. The Bd pathogen is a psychrophile, preferring cool, moist environments. Under warm temperatures (> 28 C) the pathogen will stop growing and may die. Using an optimized artificial refuge, I found that thermophilic frogs that were able to access high temperatures in these refugia had drastically lower infections. These structures could serve as self-propagating resistance engines, allowing infected frogs to cure their infections and become resistant to future infections through acquired immunity.
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ItemParticipation levels and factors associated with racing career duration in Australian Thoroughbreds( 2022)The thoroughbred industry contributed over AUD 6.3 billion dollars to the Australian economy in 2017, with the racing industry contributing nearly AUD 3.9 billion of that figure [1]. Despite the racing industry’s significant contribution to the Australian economy, the wider community’s concern for the welfare of racehorses threatens the industry’s acceptance by the general public [2]. Increasingly there is recognition by the horse racing and breeding industry of the role of community groups and non-government organisations (NGOs) as industry stakeholders to influence the standards to which these industries are held. These standards, or ‘social licence’, can exceed regulations, requiring the industries to go beyond their statutory obligation to earn or maintain the public’s approval to operate [3]. The areas of greatest concern in the context of horse racing’s social licence include the number of thoroughbred foals that do not enter race training, the racing of two-year-old horses, the fate of horses after leaving the racing industry and the incidence of injuries and fatalities sustained by horses when training and racing [4-28]. The paucity of data available on the outcomes for horses exiting the thoroughbred industry prior to or after their racing career has also impacted the industry’s social license. The research findings of this thesis clearly demonstrate that the majority of Australian thoroughbred foals train and race, only a small proportion (14%) of thoroughbreds started in a race at two-years of age, and the majority (59%) of racehorses left their racing careers for reasons other than injury (i.e. voluntary) reasons and were undertaking productive second careers post-racing. The perceptions of how Australian thoroughbred are managed throughout their life are often based on previous research which used biased subsets of the population and/or misquoting of these early research findings [29, 30]. Figures from these previous studies have erroneously been applied to the published numbers of foals born in Australia to claim there is substantial overbreeding and a focus on two-year-old racing that is detrimental to those horses. Only by examining the population level data in a transparent way can both the industry and the general public engage in an informed discussion about the social license of the racing industry.
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ItemDevelopment of Natural Language Processing Tools to Understand Veterinary Antimicrobial Usage Patterns( 2022)Antimicrobial resistance is a global threat to which veterinarians contribute through their use of antimicrobials in animals. Antimicrobial stewardship programs have been shown to be an effective means to reduce antimicrobial resistance in hospital environments. Knowledge of antimicrobial usage patterns and the ability to automate the monitoring of these usage patterns are critical for the success of veterinary antimicrobial stewardship programmes. VetCompass Australia collects medical records from 181 clinics in Australia (as of January 2022). These records contain detailed information regarding the medications dispensed and the clinical notes made by the practitioner at the time of the consultation. Unfortunately, these notes are in the form of unstructured medical free text and therefore are not readily queried. Natural Language Processing is an area of computer science and Artificial Intelligence that can be used to provide structure to free-text clinical data so that it can be analysed at scale. This research project aims to develop and apply Natural Language Processing methods to apply structure to the data in VetCompass to enable the automated extraction of antimicrobial usage to inform veterinary antimicrobial stewardship programs. A transformer based deep learning model contextualized on VetCompass clinical notes, “VetBERT”, was developed. Use of VetBERT, along with development of methods to minimise the number of annotations required to train for various tasks, such as classifying the indication of an antimicrobial or labelling the treatments performed during a consultation enabled extraction of elements necessary to determine appropriateness of antimicrobial prescriptions. This included identification of the antimicrobial ingredient given at each consultation, as well as the route of administration, the indication, dose and duration for each antimicrobial prescribed. These methods were applied to over 4.4 million records from VetCompass from the years 2013 to 2017 inclusive. Veterinarians used mostly medium or low importance rated antimicrobials in their general practice. The exceptions were systemic use of cefovecin in cats and topical use of polymyxin. A clear description of the clinical indication for antimicrobial administration was present in approximately 85% of the clinical records, however fewer than 40% of the records had all the elements necessary to determine if the antimicrobial administration was appropriate (indication, antimicrobial agent, dose, duration of treatment). A novel application of this method was the use of NLP to extract temporal phenotypes of patient journeys for cats with abscesses. This method described the various interventions and treatments for each cat from the time of first presentation to the clinic until treatment for the abscess concluded, to better understand the effects of treatments performed at consultations and their impact on the antimicrobial usage behaviours of veterinarians. This research explores the development and application of these Natural Language Processing methods to overcome many of the difficulties of harvesting antimicrobial usage information out of free text data from clinical records to support antimicrobial stewardship programs in Australia.
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ItemIn-water antimicrobial dosing of pigs( 2021)Antimicrobials are an essential tool for safeguarding the health, welfare and productivity of pigs. On many farms, groups of growing pigs are mass-medicated with antimicrobials for short periods through their building’s piped water distribution system (WDS) at pre-planned intervals for metaphylaxis, and, when necessary, to treat clinical disease caused by bacterial pathogens. In-water antimicrobial dosing offers several advantages over continuous antimicrobial administration in feed: the ability to respond rapidly if disease is detected, to target administration of antimicrobials to specific groups of pigs, and to adjust readily the dose administered and the dosing commencement time and duration. The process of in-water antimicrobial dosing a group of pigs in a weaner or grower/finisher building requires sequential steps that determine the antimicrobial concentration over time at the infection site in each pig. The process is complex and dynamic and influences the clinical efficacy of treatment and suppression of emergence of antimicrobial resistance. The between-animal variability in systemic exposure to an antimicrobial is substantial, resulting in under-dosing or over-dosing of many pigs. There are three sources of between-animal variability in exposure: 1) variability in the dose supplied, i.e., the concentration of antimicrobial in water available to pigs at drinking appliances (drinkers) in each pen over time; 2) variability in the dose consumed, i.e., the pattern of consumption of medicated water by pigs in each pen over time; and 3) variability in pharmacokinetics, i.e., oral bioavailability, volume of distribution and clearance between pigs and within pigs over time. The pig industry has been practising in-water antimicrobial dosing since the 1980s. However, the factors operating in each farm building that influence the range of systemic exposures of pigs in a group to an antimicrobial when administered in-water have remained poorly understood. Furthermore, evidence-based strategies have not been developed to increase the probability that most pigs in a group medicated in-water attain the systemic exposure to the antimicrobial required for high clinical efficacy and suppression of antimicrobial resistance. The studies described in this thesis aimed to address these deficiencies using a multi-disciplinary approach, generating data in commercial pig production environments. The studies focused on the first two sources of between-animal variability in systemic exposure to antimicrobials described above. The dosing practices of the farm manager, the characteristics of the building’s WDS and the daily water demand and water use pattern within each day of each group of pigs affect the flow of water and antimicrobial through the WDS during and after an in-water dosing event, and therefore affect the antimicrobial dose supplied at drinkers, consumed by pigs over time and passing to the site of infection. The studies described here found that all of these factors varied widely across pig farms. The WDSs within many conventional buildings and some eco-shelters were ‘over-sized’, comprising large -diameter main pipelines of substantial length with high holding volumes. This resulted in low velocity water flows through sections of a WDS’s main pipeline that increased variability in the dose supplied and dose consumed. Many buildings had insufficient drinkers per pen and WDS sanitisation was not practised on many farms. The water use patterns of cohorts of pigs within each day varied; some were unimodal, while others were bimodal. It was therefore concluded that the water use pattern of a cohort of pigs could not be used reliably to predict the patterns of other cohorts of pigs, even if reared in the same building. When a particular group of pigs in a building was dosed, the antimicrobial concentration in water delivered to pigs at drinkers in each pen over time was profoundly influenced by the characteristics of the WDS (looped or branched configuration, length and diameter of its main pipe sections, and head pressure), the daily water demand and use pattern of the pigs within each day, and the dosing event’s commencement time and duration. Differences in the antimicrobial concentration at drinkers over time during a dosing event due to the natural, demand-driven hydraulic behaviour of a looped WDS could be eliminated by using a circulator pump to establish and maintain a high, steady, uni-directional water flow; however, there were several factors that should be considered before opting for this approach. Alignment of a dosing regimen with the water use pattern of a group of pigs within each day had a substantial impact on the antimicrobial dose consumed by pigs drawing water from drinkers at different points along the length of the WDS over the first few hours that the antimicrobial was available to them, and therefore on pigs’ systemic exposure to the antimicrobial over time. Water wastage can be a confounding factor when in-water dosing. A study described here showed that it is feasible to quantify the water consumption and wastage behaviour of groups of pigs in farm buildings using a water metering system. This system could support more accurate dosing calculations and regimen design, while helping to reduce the quantities of antimicrobials used and disseminated into the environment. The studies described in this thesis contributed to development of a process to evaluate alternative in-water antimicrobial dosing regimens, based on different WDS characteristics, water use patterns and dosing practices, for a specific group of pigs in a building, and determine the optimal regimen. Several strategies were developed that should increase the proportion of a group of pigs that attain the systemic exposure to an antimicrobial required for high clinical efficacy and suppression of antimicrobial resistance. The studies culminated in development of a concept for an ‘intelligent’, adaptive dosing system that would be a significant advance on in-water dosing as currently practised on pig farms. Much of the new knowledge acquired in the studies described here is applicable to other additives administered to pigs through their building’s WDS for which the degree of efficacy is dependent on the dose administered. These additives include vaccines, parasiticides, organic acids, electrolytes, minerals, vitamins, amino acids, sweeteners, direct-fed microbials, essential oils and potential new therapeutic products, such as bacteriophages.
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ItemSensitivity of canine haematological cancers to BH3 mimetics( 2022)Background: Haematological cancers such non-Hodgkin lymphoma (NHL) and acute and chronic leukaemias are common in both humans and dogs. Whilst these cancers can be treated with cytotoxic chemotherapy (and immunotherapy in people), development of treatment resistance is common. A frequently identified mechanism associated with resistance to chemotherapy-induced cell death is overexpression of the antiapoptotic B cell lymphoma 2 (BCL2) protein. Highly specific small molecule inhibitors of antiapoptotic BCL2 proteins, known as B cell lymphoma Homology 3 (BH3) mimetics, result in rapid induction of apoptosis in vitro and in vivo in human haematological cancer cells. This has led to the approval of the BCL2-specific inhibitor, venetoclax (VEN), for the treatment of chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML) in Australia, North America and Europe. Expression of BCL2 has been reported in canine nodal lymphoma, however sensitivity of primary canine cells to BH3 mimetics has not been evaluated. Objectives: This study aimed to assess the in vitro sensitivity of non-neoplastic lymphocytes and primary haematological cancer cells from dogs to VEN or the dual BCL2/BCLxL inhibitor, navitoclax (NAV). The second aim was to evaluate the association between BCL2 protein expression and sensitivity to VEN. Methods: Nine dogs without cancer and 30 dogs with haematological cancers were recruited. Lymphocytes were isolated from peripheral blood, lymph node and/or bone marrow and incubated with VEN or NAV for 24 hours. Viable cells were enumerated using flow cytometry and the half maximal effective concentration (EC50) was calculated; BCL2 protein from whole cell lysates was assessed via immunoblotting. Results: Non-neoplastic lymph node-derived B and T canine lymphocytes were more sensitive to VEN than circulating lymphocytes (P = 0.02). Eighteen dogs with haematological cancers were included in the final analysis, including six cases of non-indolent multicentric B cell lymphoma, four cases of acute leukaemia, three cases of non-indolent multicentric T cell lymphoma, two cases each of indolent T-zone lymphoma and T-cell CLL, and one case of multiple myeloma. Neoplastic T lymphocytes (7/7) showed marked sensitivity to BH3 mimetics, with an EC50 <100nM, whilst 6/7 samples of non-indolent B cell cancers were resistant to VEN, with an EC50 >1000nM. All samples of acute leukaemia showed sensitivity to NAV, however sensitivity to VEN varied. Canine BCL2 protein was detected in all samples sensitive to VEN and was variably detected in resistant samples. All samples that lacked BCL2 were resistant to VEN. Conclusion and Clinical Importance: Neoplastic canine T lymphocytes are sensitive to VEN at concentrations achievable in vivo, thus VEN may be a novel therapeutic agent for treatment of canine T cell cancers. Detection of BCL2 protein is insufficient to predict in vitro sensitivity to VEN.
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ItemStudies of Exercise induced pulmonary haemorrhage in Thoroughbred and Standardbred Racehorses( 2022)Exercise induced pulmonary haemorrhage (EIPH) or ‘bleeding’ is an important disease of exercising horses. Though it is a disease commonly identified by equine veterinary practitioners, there is a lack of information regarding the impact of an episode of EIPH to career after examination or whether occurrence of EIPH is predictive of a horse’s lifetime athletic potential. There also exists a lack of consensus as whether the commonly used treatment, frusemide (a loop diuretic) is an effective medication to reduce or prevent EIPH. This research project addresses these two questions, with the aim of producing high quality information which can be used to underpin evidence based clinical recommendations for EIPH in horses.