Minerva Elements Records
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ItemAdvances in the diagnosis and management of prostate cancer( 2024-01)Prostate cancer (PCa) remains one of the most common cancers in Australia and globally, and ultimately accounts for 3000 deaths / year. Tremendous efforts in research and development has provided technological advances that improve the diagnosis, management and surveillance of PCa. This has and continues to be central to improving treatment management and outcomes for men diagnosed with prostate cancer. To a lesser extent, novel prostate cancer laboratory-based biomarkers are now available and have uses across the spectrum of prostate cancer disease progression. They have, however, been limited in clinical uptake due to their unfavourable cost/benefit ratio. Conversely and to a greater extent, novel prostate cancer radiographic investigations have seen virtually unanimous incorporation into the clinical diagnosis, staging and treatment of prostate cancer. -Initially, this was with prostate MRI. But more recently, PSMA PET has revolutionised the management of prostate cancer. The role of PSMA in the staging of intermediate to high-risk prostate cancer has been well established whereby in centres where available, it now comprises standard of care in European guidelines. Furthermore, it is similarly recommended in the restaging of biochemical recurrent prostate cancer. These two examples demonstrate PSMA’s utility in the more ‘advanced’ stage of disease. Conversely and at the opposing end of the spectrum is PSMA’s role at a diagnostic or ‘pre- to early-stage’ of disease. Research into this has and continues to be led by cancer centres across Australia. There is, however, an intermediate stage of disease where PSMA’s role has yet to be investigated. This ‘intermediate-stage’ of disease exists when a diagnosis of prostate cancer has been established, but treatment recommendation for either active surveillance versus radical treatment may lack certainty. In such an instance the role of PSMA to improve the risk-stratification in these individuals has been hypothesized, but not yet investigated. This manuscript explores the advancements in the clinical management of prostate cancer and ultimately culminates in a clinical research project investigating the role of PSMA in men on active surveillance for prostate cancer.
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ItemSarcopenia as a Comorbid Disease: findings from the RESORT cohort in Australia( 2023-04)Background: Sarcopenia is defined as age-related low muscle mass and muscle strength. The associations between sarcopenia and poor health outcomes have been studied, however sarcopenia should also be studied as a comorbid disease. 1) This thesis aims to find the association between sarcopenia as a comorbid disease and incidence of institutionalisation and mortality. 2) It also aims to find the changes in sarcopenia’s diagnostic parameters (muscle mass, muscle strength, and physical performance) from admission to discharge from geriatric rehabilitation, and the principal diagnoses and geriatric conditions which were determinants of thesis changes. Methods: All patients were recruited from the REStORing health of acutely unwell adulTs (RESORT) cohort. 1) Sarcopenia was defined via three definitions; the European Working Group on Sarcopenia in Older People (EWGSOP), EWGSOP2 (2018), and the Asian Working Group for Sarcopenia 2019 (AWGS 2019). Morbidity was defined via multimorbidity, disease severity, and specific diseases. Incidence of institutionalisation and mortality were recorded from a 3-month follow-up survey and the Australian Births, Deaths and Marriages and medical records, respectively. Logistic regressions were used to find the association between sarcopenia as a comorbid disease and poor health outcomes. 2) Principal diagnoses and geriatric conditions were collected at admission. Patients’ muscle mass (skeletal muscle mass (SMM), SMI index, appendicular lean mass (ALM), ALM index), hand grip strength, and physical performance (Short Physical Performance Battery, gait speed, chair stand test) were measured at admission and discharge. Linear mixed models were used to find the changes in muscle mass, muscle strength, and physical performance from admission to discharge, as well as which principal diagnoses and geriatric conditions were associated with these changes. Results: Sarcopenia when comorbid of high multimorbidity, dementia, diabetes mellitus, and renal impairment had increased odds of institutionalisation 3-months post-discharge and sarcopenia when comorbid of high multimorbidity, high disease severity, chronic obstructive pulmonary disorder, osteoporosis, and renal impairment had increased odds of mortality 3 months post-discharge. Muscle mass, muscle strength, and physical performance all increased from admission to discharge in geriatric rehabilitation. Lowly multimorbid patients had increases in muscle mass and physical performance, whereas highly multimorbid patients had no changes in muscle mass and lesser increases in physical performance. Patients with cognitive impairments had significant increases in muscle strength and physical performance, but those without cognitive impairments had greater increase. Conclusions: Higher odds of incidence of institutionalisation and mortality was associated with sarcopenia as a comorbid disease. Whilst highly multimorbid patients and cognitively impaired patients increased in the sarcopenia parameters, their lowly multimorbid and cognitively intact counterparts improved more. This thesis highlights the needs for sarcopenia diagnostics and interventions in geriatric rehabilitation and that current exercise and nutritional interventions could be adapted to better intervene with lowly multimorbid patients and cognitively impaired patients.
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ItemThe effects of bisphenol A and atrazine on male development in the tammar wallaby (Macropus eugenii)( 2024-03)The mammalian gonad originates as a bipotential gonadal primordium before it differentiates into either a testis or ovary. During the process of differentiation, the gonad can differentiate either into a testis or ovary under the influence of genetic, hormonal and environmental influences. Both androgens and estrogens are critical to this process. Perturbations of these signals at critical stages of development by environmental endocrine disruptors (EEDs) can lead to gonadal sex reversal or gonadal dysgenesis. Xenoestrogens are EEDs that can bind to estrogen receptors, acting via multiple pathways, including the metabolism of reproductive steroids of the androgen synthesis pathway. EEDs are believed to contribute to the increasing incidence of disorders of sex development (DSDs) in vertebrates, including humans. Two of the commonest EEDs are bisphenol A (BPA), used in the production of plastics) and atrazine (the most commonly used herbicide in Australia). This study investigated the effects of bisphenol A and atrazine on testis and phallus differentiation in the tammar wallaby (Macropus eugenii). The tammar is an ideal mammalian model to study sexual development, because all sexual differentiation takes place after birth, when the developing young animals can be handled and treated while still in their mother’s pouches at stages that reflect the in utero stages of eutherian mammals. Developing tammar young were treated daily with BPA (50 microgram/kg/day), from day 0 postpartum (pp) to day 10 pp or from day 20 pp to day 40 pp, and atrazine (5 mg/kg/day), from day 20 pp to day 50 pp, during the male programming window (MPW). The BPA group was analysed immediately after the last treatment on day 10 pp and day 40 pp. Half of the atrazine group were analysed after treatment from day 20 to day 50 pp and the remainder at day 150 pp to assess long term effects. To analyse the role of estrogen on normal male differentiation, an additional group was treated daily with an estrogen receptor degrader, fulvestrant (1 mg/kg) between days 20 to 90 pp and analysed at day 150 pp. BPA treatment significantly downregulated the expression of SOX9 at day 10 pp, reduced the number of Sertoli cells at day 10 pp and downregulated androgen receptor (AR), SOX9, DHH, and androgen pathway genes STAR, CYP17A1, POR, CYP11A1 and PTCH1 at day 40 pp in testes. Atrazine treatment significantly downregulated the expression of SOX9 and NR2F2 and upregulated POR expression at day 50pp in testes. Atrazine treatment also significantly upregulated DHH expression at day 150 pp. Fulvestrant treatment significantly downregulated AR expression in testis. The phallus at day 150 pp was significantly shorter than control phalluses after atrazine and fulvestrant treatments. The results from this research using an alternative model species to examine the effects of EEDs on sexual development highlight the importance of androgen-oestrogen balance for normal sexual male development of the pouch young as it does in developing eutherian mammals (Hess et al, 2021). Disturbance this balance after exposure to EEDs affects the key male sexual differentiation genes and interferes with normal testis and phallus development in the developing tammar.
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ItemCo-optimization of Frequency Regulation Capacity and Performance Offered by Microgrid under Uncertainty( 2023-04)With the increasing penetration of renewable energy sources (RESs), frequency regulation resources such as conventional generators are being replaced by distributed energy resources (DERs), which brings a challenge in providing frequency regulation with guaranteed performance under the uncertain RES generation and also under the potential uncoordinated response of resources with different regulation capabilities. However, the requirement for a minimum 1 MW capacity for participation in the wholesale market for demand-side frequency regulation service may pose a barrier for individual renewable energy sources RESs that lack the necessary generation capacity. To address this limitation, the global energy market is evolving with the involvement of independent demand response (DR) aggregators in the frequency regulation market. The existing studies have extensively examined the utilization of demand-side management of electricity consumption by aggregating various types of end-users, e.g., energy storage systems (ESSs), hydro pumps, and rooftop solar to provide ancillary services. However, the literature lacks consideration for minimizing real-time performance errors embedded in day-ahead and potential intraday optimization to maximize regulation performance payment according to market dynamics. Additionally, the uncertainty generated by RESs can significantly impact frequency regulation performance and pose challenges to coordinating ESSs. To fill those gaps, this study proposes a day-ahead scheduling model for demand-side frequency regulation service offered by microgrids (MGs) with resources belonging to different performance groups. The MG aims at maximizing both performance and capacity payment while minimizing operational costs. The model is based on a scenario-based chance-constrained formulation which determines the hourly baseline and frequency regulation capacity for the next day as well as the real-time control strategies for the resources. Extensive simulations and comparative studies are conducted, and the numerical results show that the proposed mechanism can increase the revenue of the MG by 9%, achieved through providing the frequency regulation service to the utility grid. This improvement is realized while ensuring the security of the power supply under 10000 scenarios of solar power generation and regulation signal conditions. Besides, the case studies also show that the proposed reserve provision mechanism results in a 4% reduction in overall costs compared to the current setup in the Pennsylvania, New Jersey, and Maryland (PJM) market which is based on a proportional reserve allocation method.
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ItemOptimizing Stem Cell Models of the Human Gut-immune Barriers( 2024-01)Summary The adult human gut has an area of about 200 to 400 square meters. This massive surface is covered by a layer of epithelial cells that creates a physical barrier to the environment, whilst absorbing nutrients from food. Appropriate regulation of host immune responses to luminal contents helps maintain both tissue and microbial homeostasis in the gut tract. Impaired inflammatory regulation of the immune-epithelial interface is associated with chronic diseases such as inflammatory bowel disease (IBD). Together with the gut epithelium, intestinal macrophages produce immune regulators that control recruitment and activation of adaptive immune processes, including regulatory T cells in the intestine. We know that macrophages are recruited to the developing gut from the earliest stages of organogenesis, however, the role of these cells in healthy gut development has not been widely studied. Most of our knowledge about gut macrophages comes from studying animal models, especially rodents. This project forms part of a larger program of research aimed at understanding the role of macrophages at epithelial barriers associated with skin, gut, and mucosal surfaces. We will use induced pluripotent stem cells to derive macrophages and test optimal co-culture conditions that mimic the immune-epithelial niche. We hypothesize that introduction of macrophages to a gut epithelial model will improve the development and integrity of the in vitro gut epithelium. The hypothesis will be tested using established models of gut epithelium and introducing iPSC-macrophages to assess epithelial barrier integrity, inflammatory reactivity to injury, and immune tolerance of commensal gut bacteria.
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Itemfor a conversation, now, sometimes, oops- oh no... sorry, i mean, somewhere… for a conversation, somewhere( 2023-11)This practice-led research asks: is it possible to hold a conversation in space forever? It suggests we can find and hold the materialisation of a conversation once it’s left the people that have had it. Over the course of this research, an important strategy became attempting to think not in time, but rather, in space. Thinking in space allowed the ability to wonder not when something was but where it is. In this project conversation has been utilised as inspiration, methodology and material. The exhibition at the Fiona and Sidney Myer Gallery builds a space for a conversation to happen and a space where the remains of those conversations can stay. The project focuses on divine conversation, where the content and outcomes are not important, what is important is that two people share the desire to talk to each other. The space holds two performative representations of conversations. They are: (i) a continuous conversation, where over 50 participants take part to help hold a constant conversation over the duration of the exhibition. (ii) what you are doing, where two actors sporadically perform a scripted dialogue of the narration of their conversation, told through the other. Being inspired by thinking in space - the gallery turns into a piazza consisting of several elements holding these conversations: performance furniture which are structures for the performers and participants to engage with, being designed around places where the vibrations of a conversation might linger, like a horizon or a corner constructed from steel, paint and plywood. Object/Sculpture Characters, which are two operated neon lights, simulating day and night, and a water fountain constructed from steel concrete and water flowing help hold the particles of saliva from the conversations spoken. The dissertation shifts through poetry, comparisons to other artists and theorists, personal accounts and stories. It discusses the process of making this artwork, from its muses to the conversations had during the two years it took to realise the project and the materials used. The writing brings the artwork into conversation with: theorist Carlo Rovelli; writer bell hooks; playwright Caryl Churchill; artists Sophie Calle, Ragnar Kjartansson, Lisa Radford, Damiano Bertoli, and Gian Lorenzo Bernini; choreographers Simone Forti and Pina Bausch; performances by Forced Entertainment, Tino Seghal, Aphids, and Back to Back Theatre company; comedians Andy Kaufmam, Kurt Braunohler, and Kristen Schaal; and poet-artist Madeline Ginns and artist- architect Arakawa.
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ItemEffect of Non-Anticoagulant Heparin on Oral Squamous Cell Carcinoma( 2024-04)Oral squamous cell carcinoma is a global concern with alarming prevalence and poor survival rates. Recent evidence suggests that anticoagulants, such as heparin, may enhance cancer survival, but these medications also present challenges due to the risk of bleeding. Non-anticoagulant heparin, a novel heparin derivative, offers a promising solution to this challenge. We used the MTS proliferation assay (0/24/48/72 hrs), scratch assay (MuviCyte Live-Cell Assay Imaging System, 0-18 hrs), invasion Matrigel (24hrs), and cytotoxic assay (0-24 hrs) to assess the in vitro effects of NAH (10, 20, 40, 80 U/mL) and heparin (10, 20, 40, 80 U/mL) on two human OSCC (H400 and H357) and one normal oral keratinocytes (OKF6) cell lines and their ability to interfere with the chemotherapeutic agents 5-FU (1-5 ug/mL) and cisplatin (1-5 ug/mL). Interestingly, non-anticoagulant heparin (NAH) not only significantly induced cytotoxic effect on H400 and H357 at 80 U/mL but also inhibited the proliferation of cancer cells as early as 48 hours. This inhibition was comparable to that of heparin. Remarkably, neither drug exhibited cytotoxic effects on normal keratinocytes at the tested time points. Furthermore, both heparin and NAH significantly inhibited cell migration in H400 and H357 cells within 12 hours. Additionally, both drugs inhibited the invasion of cancer cell lines up to 24 hours of incubation. Importantly, the combination of these drugs with commonly used chemotherapeutic agents for the treatment of OSCC did not compromise their efficacy against the tested cell lines. Surprisingly, treatment of OKF6 cells with NAH significantly reduced the cytotoxic effects of chemotherapy. In conclusion, non-anticoagulant heparin demonstrates promising potential as an alternative to heparin for improving cancer survival in oral squamous cell carcinoma. NAH significantly reduced proliferation and inhibited migration and invasion in OSCC cells, without compromising the efficacy of commonly used chemotherapeutic agents 5 FU and cisplatin. Our results indicate the need for the immediate translation of this research to preclinical animal models.
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ItemWho is singing? An examination of models for proactive persona construction in popular music( 2023-10)This practice-led thesis is an investigation of approaches to constructing musical and visual persona within popular music. My creative work is used as a case study in which 4 personas are developed with reference to exemplars of practice in historical and current popular music. In exploring effective persona development this thesis draws on performance studies, persona studies, musicology, sociology and communication studies as a theoretical basis. The often-debated concept of authenticity, which interacts directly with perceptions of who a performer actually is when they perform, will be examined and its influence on the practitioner and popular music discourse in general will be addressed. The thesis investigates the following questions: 1) what effect does proactively exploring musical persona in the songwriting process have on creative outcomes? 2) what effect does proactively exploring visual persona have on how a singer-songwriter presents themselves in music videos and online content? 3) how do musical and visual persona interrelate? The answers to these questions will provide direction towards a model for a more deliberate approach to persona construction for singer-songwriters and other musical artists. In doing so this thesis positions persona in popular music within artistic practice rather than being discussed primarily in terms of marketing and branding.
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ItemThe use of robot-assisted surgery in reconstructive and functional urology( 2023-11)As surgical technology advances, bringing forth new devices and techniques, it becomes imperative for the medical profession to engage in rigorous due diligence to minimise potential harm to patients. Many countries have established robust processes for scrutinising medications, devices, and prostheses before their implementation in patient care. Both the general public and the medical community rely on these regulatory authorities to ensure safe access to medical devices and to safeguard patients from harm. Nevertheless, in recent years we have witnessed legal actions being taken against various medical device companies for their failure to adequately test products, resorting to shortcuts in the application process, which has subsequently led to permanent and debilitating harm. These failures emphasise the critical need for effective oversight by medical and public health authorities while also underscoring the individual responsibility of medical professionals and surgeons in upholding patient safety. A recent example of this failing is the incorrect use and insertion of pelvic mesh, which has been associated with complications from implantation. Whilst there were problems associated with implantation that ultimately became apparent, the complications associated with explantation are potentially much more severe. This low-volume, at-risk surgery, requires a different and more advanced skill set. The value of the credentialing process is intricately linked to the demonstration of thorough education and training, adherence to accreditation standards, compliance with reimbursement requirements, and alignment with state and federal laws. While the specifics of the credentialing processes may vary across healthcare institutions, it is imperative to consistently verify the authenticity of submitted documents to guard against fraudulent representations. A well-structured credentialing process serves as a robust defence against the admission of healthcare professionals with inadequate qualifications or training, thereby upholding the standard of patient care. Beyond the initial credentialing, ongoing audits of healthcare workers are essential. In the contemporary landscape of healthcare, characterised by an emphasis on quality, maintaining a detailed approach is crucial. This ongoing scrutiny ensures that the healthcare workforce remains in line with the highest standards, leaving minimal room for errors in the pursuit of delivering optimal patient care. The primary goal of this thesis is to develop credentialing guidelines on the use of robotic assistance surgery for reconstruction and functional urology. Underpinning this new field of surgical treatment, a critical review delves into the transferability of surgical skills, issues pertaining to training competency generally, credentialing of robotics-assisted surgery for related surgery and evaluation of other specialities robotic programmes. A Modified Delphi study was conducted to establish clinical consensus for the first guidelines on this topic. The second part of this project featured the introduction of a new robotic surgical procedure that implemented some of the ideas raised in Chapters 1 and 2. A critical review is included of the outcomes of this procedure as a multi-centre case series assessing the rate of successful removal of mesh, the functional outcomes at 12 months follow-up, recurrence of stress urinary incontinence and pelvic organ prolapse, and sexual function outcomes.
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ItemReal-world Management and Outcomes for Anaplastic Lymphoma Kinase (ALK)- rearranged Advanced Non-small Cell Lung Cancer and Impact of COVID-19 on Cancer Service Delivery( 2023-09)This thesis is divided into two parts. Part 1 - Real-world Management and Outcomes for Anaplastic Lymphoma Kinase (ALK)-rearranged Advanced Non-small Cell Lung Cancer (ALK+ aNSCLC) ALK-rearrangements are found in 4% of Non-small cell lung cancers (NSCLC). Although this condition remains incurable, survival appears to be improving over time, with a multitude of selective oral tyrosine kinase inhibitors (ALK-inhibitors) now available and with many patients receiving multiple lines of therapy. Whilst next-generation ALK-inhibitors are standard of care in the first line, how to best sequence available therapies beyond this remains unclear. This thesis examines outcomes for real-world patients with ALK+ aNSCLC, using cohorts from AURORA (Australia) and Flatiron health (United States). Key findings: median overall survival (mOS) of 84 months in the AURORA cohort (n=171) and 37 months in the Flatiron cohort (n=737). Positive prognostic factors: never-smoking history, treatment in an academic setting and initial early stage at diagnosis. Gender was not prognostic. Treatment patterns varied and changed over time. Initial treatment with 2nd generation ALK-inhibitor was associated with improved survival over chemotherapy; initial treatment with 1st generation ALK-inhibitor followed by 2nd generation ALK-inhibitor was associated with improved survival compared to initial chemotherapy followed by 1st generation ALK-inhibitor. These retrospective observational studies represent the largest for people with ALK+ aNSCLC in Australia (AURORA) and globally (Flatiron). Future research may focus on intensifying treatment for people with a smoking history. Further work is required to determine why treatment in a community setting correlated with poorer survival in the US. Identifying optimal treatment sequences will require larger contemporary patient databases; collaboration is required among research organisations and with pharmaceutical companies conducting post-marketing studies. Part 2 - Impact of COVID-19 on Cancer Service Delivery Amid the early stages of the COVID-19 pandemic, significant shifts in patient presentation and oncology health service provision for people with lung and other cancer-types were observed globally. This research aimed to obtain timely real-world data on how clinicians perceived alterations in cancer service delivery due to COVID-19. Surveys were distributed to oncology clinicians through international professional societies in 2020. Clinicians highlighted substantial changes in oncology services. In the early period (May-June 2020), 89% of clinicians reported altering their practice due to COVID-19; including being less likely to initiate and more likely to cease systemic therapy in palliative and curative settings. Telehealth use was rapidly expanded; many clinicians reported concerns that this may negatively impact patient outcomes. Clinicians reported seeing fewer new patients in clinic. In the later period (October-November 2020), clinicians reported more advanced disease presentations and a swing back towards pre-COVID practice. Clinicians’ reported concerns regarding potential negative impact on cancer-related outcomes are further substantiated by global reports of fewer cancer diagnoses across 2020 and modelling studies predicting increase cancer-related mortality and health-care costs due to such changes. For cancer-related outcomes to be optimised through future pandemic events, heath-systems and policy makers need to have implementable action plans to rapidly upscale mitigation strategies, such as public education campaigns, telehealth and hospital in the home.