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ItemLean body weight adjusted intravenous contrast medium dose for abdominal Computed Tomography in dogs( 2022-01)Contrast-enhanced computed tomography (CT) is a common diagnostic modality to investigate abdominal pathology in dogs. For the animal’s safety, the minimum contrast media (CM) dose to achieve diagnostically appropriate contrast enhancement should be administered. Although acute adverse reaction to non-ionic iodinated CM is rare, moderate (>20% from baseline) alteration of heart rate and systemic blood pressure has been reported in dogs. Use of less iodinated contrast is particularly crucial in patients with pre-existing renal dysfunction, as CM is concentrated in renal tubules, having a direct toxic effect, modulating tubular regulatory mechanisms, and producing renal vasoactive substances. Risk of contrast induced nephropathy is considered low in human patients with no history or symptoms of renal disease. In dogs, iodinated contrast dose is commonly linearly increased based on total body weight (TBW). Lean body weight (LBW) has been considered in particularly obese human patients when prescribing a dose of CM, as body fat is not metabolically active and contributes little to dispersing or diluting the CM in the blood. This thesis consists of two published articles (chapter 2 and 4), of which the final research aim was to determine if less iodinated contrast per kilogram TBW can be administered to overweight/obese dogs while maintaining adequate organ and vessel opacification to make a confident radiologic diagnosis. Chapter 2 is a retrospective study performed to determine the variability of major abdominal vessel and organ contrast enhancement and to establish any relationship with abdominal fat percentage in contrast enhanced CT studies, performed on 62 clinical patients at U-Vet Werribee Animal Hospital between February 2014 and February 2019. Intravenous Iohexol (240 or 350 mgI/ml) with a dose range of 660-880 mgI/kg TBW administered by a power injector (1.8 - 3.0 ml/s) and saline chaser was the standard injection protocol used at this institution. Findings based on a linear regression model showed a positive association of aorta (p = 0.005), liver parenchymal (p = 0.045) and portal vein (p = 0.001) enhancement to abdominal fat percentage during the portal venous phase. Following this retrospective study, variability of abdominal organ/vessel contrast enhancement contributed by CM injection method was evaluated and outlined in chapter 3. This was done in attempt to minimise contribution of varied CM injection techniques on organ/vessel contrast enhancement variances prior to the second part of the research project. Out of the three injection techniques explored, the fixed injection duration protocol was found to have the smallest organ and vessel enhancement interquartile range. The fixed injection duration protocol; Iohexol 350 mgI/ml at 700 mgI/kg TBW administration by a cephalic vein intravenous catheter, and a CT study performed with a fixed injection duration of 20 s, with the arterial and portal venous acquisition triggered 10 s and 35 s after aortic arrival respectively, was used for the subsequent part of the research project. Chapter 4 was a prospective study where we hypothesised that LBW adjusted dosing would not affect the diagnostic quality of the abdominal CT study, will minimise negative physiological effects, and reduce variability of contrast enhancement in major abdominal organs and vessels as compared to dosing according to TBW. Results from 12 dogs showed that LBW dosed abdominal CT studies were of diagnostic quality (based on subjective radiologist’s assessment) and reduced inter-individual enhancement (smaller interquartile range) variability in dogs. Contrary to our second hypothesis, there was no significant difference in the change in heart rate and blood pressure after CM administration when dosed according to TBW or LBW. Based on reports in the human literature and findings from the present study, LBW is a better body size index for determining CM dose compared to TBW and is discussed in the final chapter.
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ItemMultireligious Adherence and the Right to Freedom of Religion in India( 2022-10)This thesis examines the scope for constitutional guarantee for the freedom of ‘multireligious adherence’ in India. Multireligious adherence means the adherence to the norms of more than one religion at the same time. This thesis asks whether multireligious adherents and syncretic religious groups are recognised by the Indian Supreme Court, the highest court in India. To answer this question, the thesis analyses the decisions of the Court from 1950 to 2022 on the interpretation of the right to freedom of religion under Articles 25 and 26 of the Indian Constitution. The thesis finds that multireligious adherents and syncretic religious groups are not judicially recognised due to the Court’s implicit assumption that religious adherence is necessarily exclusive. The thesis argues that the extent to which the Indian Supreme Court recognises multireligious adherents and syncretic religious groups significantly influences the right to freedom of religion of both individuals and religious groups in India. Furthermore, the thesis highlights that Article 25 of the Constitution, which protects a person’s right to freely profess, practise, and propagate religion, is an inclusive provision; it does not differentiate between those who adhere to the norms of a religion exclusively and those who do so non-exclusively. Therefore, Article 25 protects even the right to adhere to multiple religions. The thesis concludes that the Court’s ‘exclusivist understanding’ of religious adherence, which fails to consider the possibility of multireligious adherence, conflicts with this interpretation of Article 25 of the Constitution. This thesis aims to contribute to the fields of ‘law and religion’ and constitutional law: first, it offers an ‘inclusive view’ of religion and religious adherence, where adhering to the norms of one religion does not preclude a person from simultaneously adhering to the norms of another; and second, it shows how the judicial understanding of religious adherence influences the constitutional right to freedom of religion in India.
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ItemNo Preview AvailableYoung people’s experiences of completing a trauma and PTSD screening tool when attending an early psychosis program( 2022-07)It is well established that many people with psychosis have experienced trauma in childhood. Young people with a first episode psychosis (FEP), who receive a service from an early psychosis program, have been identified as having high levels of trauma exposure in their childhood with up to 82% reporting this history. Research findings suggest that childhood trauma is not only a risk factor for psychosis but that this exposure to traumatic experiences is associated with psychosis in a dose-response fashion with increased reports of trauma increasing the risk or severity of psychosis. As there is now a known correlation between trauma experiences and the development of psychosis it is essential that the mental health services provide appropriate interventions following a thorough assessment of the young person’s needs. Best practice guidelines identify that screening for trauma occurs at introduction to mental health services to provide tailored clinical interventions, however the reality is many services do not routinely conduct these assessments. One of the main reasons cited for this is that clinicians are concerned about the potentially distressing and destabilising effect screening would have on the young person. Despite these concerns it is currently unclear how young people experience screening and/or trauma assessments as their voices have not been sought in research around trauma experiences, screening and assessments in early psychosis programs to date. This research therefore focused on exploring how young people experienced a screening process relating to their experiences of trauma and possible post-traumatic stress disorder (PTSD) symptoms. Participants were all engaged in an early psychosis service and had completed trauma and PTSD screening questionnaires in their first three months in the service. The researcher conducted interviews with ten young people and then analysed this data using an interpretative phenomenological analysis (IPA) approach to synthesise data and relay these findings. Four super-ordinate themes are presented in the format of one published journal manuscript and the exploration of these are further reviewed during the discussion section. Whilst most of the participants found the completion of the screening tools to be confronting, with some reporting levels of mild distress during the completion, they were all able to complete them and none of the young people reported ongoing distress following the completion of them. These findings reinforce the recommendations for young people to be screened for trauma experiences when they are engaged in a mental health service and allow the clinicians to have more confidence in being able to support young people during this process.
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ItemCharacterisation of a novel liver progenitor cell marker in biliary atresia( 2022-06)The characterisation of liver progenitor cells (LPC) has proven to be difficult, likely due to plasticity in the regenerative/reparative processes of the liver based on the type and extent of injury. The recent development of an antibody to the GCTM-5 epitope has identified a putative liver progenitor cell population which was not previously described in the paediatric population. GCTM-5 was previously identified to strongly mark cells in the foetal ductal plate, early in the developmental pathway of both hepatocytes and cholangiocytes. This study describes the distribution of this antibody in patients with biliary atresia at time of paediatric liver transplant, and compares it to other known markers for cells with progenitor-like properties. We conducted a chart review of all patients with biliary atresia undergoing a liver transplant between 1995-2015 at the Royal Children’s Hospital, Melbourne. Multiple samples that had been stored from the explanted liver of patients with biliary atresia were stained for ENPRO-1, a second-generation antibody with greater affinity for the same epitope stained by GCTM-5. We found that the ENPRO-1 antibody most strongly marked ductular reaction cells in this human population, which is a histological description known to contain the LPC niche. It also identified undifferentiated EpCAM positive cells, most SOX9-positive cells, all NCAM-positive cells and some Lgr5-positive cells. As such, ENPRO-1 was found to mark a novel subset of liver cells of previously identified cells with progenitor properties. This is critical to validate future studies for a serum biomarker for activation of this LPC niche, as the epitope marked by the ENPRO-1 antibody is known to be secreted into blood. Unexpectedly, we found CD133/PROM1 to strongly mark almost all parenchymal hepatocytes in regenerative nodules, which has not previously been described, and may be unique to patients with end-stage liver failure due to biliary atresia.
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ItemThe effect of in vitro manure nitrogen composition and lignite application on dairy cattle manure ammonia emission( 2022-09)The major objectives of the master study were to estimate the urinary nitrogen (UN) to faecal nitrogen (FN) ratio from sampled dairy cattle, to quantify the effectiveness of lignite application on reducing ammonia (NH3) emission and to establish the relationships between dairy cattle manure NH3 emission, nitrogen (N) isotope fractionation (delta-15N), the N to phosphorus (P) and N to potassium (K) ratios in diverse manure property and environmental conditions. The in vitro manure incubation system was conducted to explore the manure daily changes, daily NH3 emission and the effect of lignite application on reducing NH3 emission. The UN to FN ratios were approximately 1 to 1, calculated via the N balance study. Total 600 g reconstructed manure was put into each incubation system to achieve a manure UN to FN ratio of 1 to 1 for CT and CT+L, and 2 to 1 for 2U1F and 2U1F+L. Further, 250 g lignite powder was added into CT+L and 2U1F+L and mixed with manure. Acid traps were settled to collect emitted NH3 emission. A total of 15 g manure sample and 15 mL of acid sample were collected daily from each incubation system and stored frozen (-20 degrees centigrade). The daily NH3 emission in the non-lignite group decreased with incubation days while it increased with days in the lignite group. The major NH3 emission occurred in the first 7 days in the non-lignite group and in the last 10 days in the lignite group. There was a weak relationship between temperature and daily NH3-N emission (R2 = 0.30, P <= 0.05). The cumulative NH3-N emission of 2 UN to 1 FN ratio (2U1F) treatment was 45.8% higher than control (CT) treatment in non-lignite groups, while it of 2U1F with lignite application (2U1F + L) was 100% higher than CT with lignite application (CT + L). The lignite application reduced the cumulative NH3-N emission by 87.5% compared to CT and CT + L treatments and 82.9% compared to 2U1F and 2U1F + L treatments. The manure delta-15N from the CT and 2U1F treatments increased with incubation days (R2 = 0.85 and 0.91, respectively; P <= 0.001). However, there was no relationship between manure delta-15N from the CT + L, 2U1F + L treatments and incubation day (R2 = 0.07 and 0.08, respectively; P <= 0.001). The manure N to P ratio decreased with incubation days (R2 = 0.81, 0.73, 0.81, and 0.84 in CT, 2U1F, CT + L, and 2U1F + L treatment, respectively; P <= 0.001). There was a weak relationship between manure N to K ratio and incubation days found in CT treatment (R2 = 0.28, P <= 0.001), while manure N to K ratio decreased with incubation days in the other three treatments (R2 = 0.70, 0.79, and 0.90 in 2U1F, CT + L, and 2U1F + L treatment, respectively; P <= 0.001). Overall, the master studies showed that manure delta-15N could not be used as an accurate biomarker to estimate NH3 emission in relatively low NH3 concentrations (R2 = 0.02, P <= 0.001) while the N to P ratio was better to use (R2 = 0.85, P <= 0.001). The manure delta-15N outperformed to be the best biomarker to estimate NH3 emission in relatively high NH3 concentrations (R2 = 0.83, P <= 0.001). The lignite application was an effective method to reduce NH3 emissions. However, further study is required to investigate the maximum absorption ability of lignite for improving the application in livestock industries.
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ItemPrednisolone in canine medicine: How and why it is prescribed systemically and the impact of bodyweight on prescriptions and pharmacokinetics( 2022-11)Background: Prednisolone is a commonly used medication in canine medicine, for a variety of indications. It is prescribed for physiologic maintenance, as an anti-inflammatory and as an immunosuppressant. Unfortunately, it also comes with a variety of adverse effects. There is a lack of research describing what conditions prednisolone is prescribed for and what factors influence dose in dogs. Additionally, there is evidence to suggest that canine bodyweight influences risk of side effects, therefore published dosing recommendations for dogs over 25 kg recommend dosing by body surface area. However, there is no research on whether bodyweight influences dose prescribed by veterinarians and little research as to how bodyweight affects prednisolone pharmacokinetics. Objectives: The aims of this thesis were to review the current literature on prednisolone use and pharmacokinetics in dogs (Chapter 1); to describe prednisolone prescribing practices to for dogs in Australia, indication for prescription and to evaluate what factors influence dose prescribed (Chapter 2); to observe prednisolone pharmacokinetics in client-owned dogs and describe any effect of bodyweight (Chapter 3). Method: Chapter 2 was a cross-sectional study using individual canine clinical records acquired from the VetCompass Australia database. Dogs prescribed prednisolone between 1 July 2016 to 31 July 2018 were identified and a random sample of 2,000 dogs from this population were used for data acquisition. Chapter 3 was a prospective, observational study where dogs receiving prednisolone for medical reasons had a series of plasma samples taken after their normal prednisolone dose. Plasma prednisolone concentrations were measured via liquid- chromatography tandem mass spectrometry and the relationship between dog bodyweight, prednisolone dose and prednisolone area-under-the-curve (AUC) was described. Results: Prednisolone was found to be most prescribed for inflammatory conditions, at an anti-inflammatory dose to Australian dogs. Disease of the integument was the most common indication for prescription. Notably, 8% of dogs (n = 152) were prescribed an immunosuppressant dose, for an inflammatory condition, which was considered inappropriate. Bodyweight was found to have a small, independent, negative effect on dose prescribed. The pharmacokinetic study found that dosing by bodyweight (milligrams per kilogram) resulted in AUC being positively associated with bodyweight. Conclusions: This research describes, for the first time, prednisolone prescriptions for dogs in Australia and confirms that bodyweight influences dose prescribed and impacts prednisolone pharmacokinetics. Veterinary clinicians appear to reduce the prednisolone dose prescribed, in milligrams per kilogram, to larger dogs. Regarding pharmacokinetics, when dosed equivalently in milligrams per kilogram, a larger dog has larger plasma prednisolone AUC compared to a smaller dog. This is potentially a cause for the increased adverse effects experienced by larger dogs. This research will improve veterinary clinician awareness to the potential risk to larger dogs prescribed prednisolone and provide groundwork to further research on prednisolone pharmacokinetics in dogs.
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ItemNOWHERE / NOW HERE( 2022-11)This research investigates the verbal / visual thresholds of the sign, in order to explore the semiotics between memory, meaning, and mark-making. The approach took the form of a series of divergent projects, responding to Michel de Montaigne’s notion of the “essai” — taken, in its original sense, as the imperative to “try” and experiment. In making the works, a wide range of material processes were employed, including frottage, drawing, painting, calligraphy, digital typography, and font-making. Each iteration operates as a poetic mapping of memory, or diagramming of conscious experience. A variety of approaches served to foreground the conceptual resonances across the body of works. While materially diverse, the projects are connected by common lines of enquiry, namely, explorations of the physical manifestation of meaning, via signs. Throughout, language and mark-making are understood as co-extensive gestures. Ferdinand de Saussure’s definition of the sign offers a framework from which to examine the elements whereby meaning is constructed and shared. Text is a unifying element across the projects, seeking as it does to materialise thought. Over the course of these essais, the importance of the hand-made mark emerges, revealing the hand as leitmotif. Tim Ingold’s writings prove valuable in proposing an ontology of “craft,” where thinking happens in conversation with making.
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ItemRubato in Scriabin’s 24 Preludes Op. 11: The Score and Piano Roll Recordings( 2022)The Twenty-Four Preludes Op. 11 of Alexander Scriabin, written over a period of eight years between 1888 and 1896, are a quintessential representation of the composer’s first period of composition. This collection of pieces presents to modern day pianists the challenge of conceiving an interpretation representative of the freer performing culture of Scriabin’s time. In performing the Twenty-Four Preludes Op. 11, performers of the work should give recognition to the score as a communicator of the composer’s rubato style. Within the current literature, studies have thoroughly documented Scriabin’s performing style, focusing particularly on his unique approach to rubato through the analysis of his recordings; however, research has largely ignored the role of the composer’s score markings and indications as directions for rubato. This study aims to explore Scriabin’s use of score directions to convey rubato through a concurrent investigation of his recordings of Preludes Nos. 1, 2, 13 and 14 and the written music. Findings evidence a correlation between Scriabin’s performance of rubato and the different markings and indications in the score, which, aside from his tempo directions, are not necessarily associated with tempo modification. The results of this study provide a framework that performers may use to inform their interpretation of the Twenty-Four Preludes Op. 11, as well as other Scriabin works. This thesis serves as part of a component worth 25% in compliment to larger performance exam worth 75%.
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ItemPigeon paramyxovirus type 1 in pigeons in Victoria( 2022)Pigeon paramyxovirus type 1 (PPMV-1) is a variant strain of avian paramyxovirus type 1 (APMV-1). Although PPMV-1 is mainly detected in birds from the Columbidae family, infection in other avian species has also been reported. PPMV-1 was first isolated from racing pigeons in the Middle East in the 1970s. Several studies have indicated that PPMV-1 has similar genomic features to virulent NDV based on amino acid sequences at the fusion protein cleavage site. Thus, it is important to monitor for genomic mutations at these sites since pigeons can potentially transmit the virus to poultry leading to virulent NDV outbreaks. In 2011, PPMV-1 was first detected in Australia. Details of the virus in Australia are limited and most information available relates to domestic pigeons. Therefore, this thesis reviewed the incursion of PPMV-1 into Australia in detail and estimated its seroprevalence in feral pigeons in Victoria. It also aimed to consider the potential routes of virus transmission from feral pigeons to commercial poultry. PPMV-1 was first identified in 2011 in Victoria before spreading to other Australian states. Data was compiled with contributions from the relevant biosecurity authorities from each Australian State and Territory as well as Wildlife Health Australia. It was then validated using case submission data from the Australian Centre for Disease Preparedness (ACDP). Results showed that PPMV-1 has been found in all Australian states excepted the Northern Territory. Infected birds were mainly detected in Victoria (VIC) and New South Wales (NSW), and largely found in urban areas. The overall epidemic curve started with a point source epidemic pattern reflecting that PPMV-1 was previously exotic to Australian pigeons. In the following years, the pattern became endemic. Most of this PPMV-1 data in Australia was on domestic pigeons. Data on feral pigeons and wild birds was severely limited, and only available through passive collection, if detected. In an attempt to estimate the prevalence of PPMV-1 in feral pigeons in Victoria and to investigate potential routes of virus shedding, feral pigeons in different locations were sampled. Pigeons were either provided by pest controllers or captured using traps and alpha-chloralose bait. Blood samples were taken and tested by the hemagglutination inhibition test, whereas swab samples were investigated using real-time reverse transcriptase polymerase chain reaction (rRT-PCR). Amongst the study population, feral pigeons in Victoria had an apparent seroprevalence of 45% (95% CI: 38, 53) while the adjusted true prevalent estimate was 53.9% (95% CI: 45, 64). Although, PPMV-1 exposure appears to be the highest in Victorian poultry dense locations, especially in the Southeast region, only a small number of the exposed feral pigeons seem to be actively shedding PPMV-1. There is also a risk of PPMV-1 transmission to poultry though contamination of feed at storage facilities accessed by pigeons. The PPMV-1 isolate from this research was phylogenetically close to the PPMV-1 isolate detected in the 2011 Australian outbreak and appears to be highly virulent. To maintain Australia’s Newcastle disease-free country status, the variant strain of PPMV-1 should remain a focus of attention given it represents a risk for ND outbreaks in poultry.
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ItemReaction hijacking tyrosyl-tRNA synthetase as a new anti-infectives strategy( 2022)Malaria is a deadly disease of humans, with Plasmodium falciparum responsible for the most cases. Disappointingly, drug resistance is observed against current front-line therapies; thus, new drugs with novel mechanisms are urgently needed. ML901, a nucleoside sulfamate derivative, has been shown to possess good antimalarial efficacy and to specifically target P. falciparum tyrosyl-tRNA synthetase (PfYRS). PfYRS is a pivotal enzyme that participates in the protein synthesis pathway, in which tyrosine-charged tRNA is formed. ML901 appears to target PfYRS via a novel reaction hijacking mechanism in which PfYRS catalyzes the synthesis of a Tyr-ML901 adduct, which in turn poisons the enzyme. Human YRS is not susceptible to the reaction hijacking mechanism. This project sought to understand the molecular basis for the potency and specificity of ML901 and to determine if reaction hijacking could be exploited more widely. All YRS sequences harbor a conserved motif, referred to as “KMSKS”, in a loop that is reported to change conformation to facilitate ATP binding and the aminoacylation reaction. Sequence alignment across species reveals that most pathogenic parasites, including P. falciparum, possess a KMSKS motif, whereas higher eukaryotes possess an equivalent KMSSS motif. Structural analysis revealed that the motif in human YRS is part of a flexible (unstructured) loop while the equivalent loop is structured in PfYRS. Here we examined the role of the second lysine (K250) in determining loop flexibility and activity of PfYRS as well as the susceptibility of the mutant enzyme to reaction hijacking. Surprisingly, the X-ray crystal structure of recombinant PfYRS harboring the K250S mutation (PfYRSK250S) showed that the KMSSS loop is even more stable than the wildtype KMSKS loop. PfYRSK250S was found to consume substantively less ATP in the initial activation step. However, the weakly active PfYRSK250S is still susceptible to reaction hijacking by ML901. This study shows that the flexibility of the loop is not determined simply by the K250. Moreover, it shows that K250 plays an important role in enzymatic mechanism. Further investigations are required to understand the important factors that contribute to the particular susceptibility of PfYRS to reaction hijacking by ML901. Broad specificity nucleoside sulfamates, such as adenosine sulfamate (AMS), have previously been shown to have inhibitory activity against Gram-positive and Gram-negative bacteria. The equivalent of the KMSKS motif in the Escherichia coli YRS sequence is KFGKT. Here we explored the possibility that bacterial YRS might also be susceptible to inhibition via a reaction hijacking mechanism. A screen of a range of bacterial species revealed that AMS inhibits growth of E. coli and Enterococcus faecium. Targeted mass spectrometry confirmed the production of a range of amino acids adducts upon treatment in E. coli with AMS. Recombinant EcYRS was purified and expressed and shown to be inhibited via the reaction hijacking mechanism by AMS. These data suggest that bacterial amino acyl tRNA synthetases may be exciting new targets for reaction-hijacking nucleoside sulfamates.