Medicine (RMH) - Theses

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    Integrating genomics into diagnostic and management strategies for patients with Bone Marrow Failure Syndromes
    Fox, Lucy Claire Buchanan ( 2023-03)
    The bone marrow failure syndromes (BMFS) are a heterogeneous group of diseases with differing underlying pathogenic processes and treatment approaches. Diagnosis remains challenging as these conditions can mimic each other, both in clinical presentation, on morphological examination of the bone marrow and their shared potential to transform to haematological malignancy. The BMFS are associated with poor outcomes and there remain many gains to be made in improving both diagnostic and treatment strategies. Both comprehensive clinical data interrogation and genomic analysis by next generation sequencing (NGS) were employed in an effort to examine the clinical, genomic and molecular determinants of outcome in patients with BMFS. The focus of this thesis was to integrate genomics into diagnostic and management strategies to improve outcomes for patients with BMFS. Initially, the utility of comprehensive genomic sequencing to attain accurate diagnosis in patients presenting with bone marrow failure (BMF) was analysed. This work was a prospective demonstration evaluation study. The observed utility of germline and somatic genetic testing in patients presenting with hypocellular BMF and hereditary predisposition to haematological malignancy (HPHM) led to availability of clinical accredited BMF testing, the uptake and outcomes of which were then analysed in the real world setting. The comprehensive dataset of the Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (the AAR) was interrogated to examine the treatments applied in and outcomes of patients with immune aplastic anaemia (iAA). The AAR was modernised to facilitate enrolment of patients with both traditional inherited BMF (IBMF) and also novel germline conditions, including those recently discovered and described as conferring a HPHM. Consideration of whether a HPHM exists is now considered to represent a crucial component of new leukaemia diagnostic work up. The AAR provides an opportunity to document the Australian experience and natural history of patients with BMFS/HPHM and permit further research including facilitating offering clinical trials and novel therapies to patients with these individually rare conditions. Recognising the poor outcomes of patients with BMFS and HPHM, interview and survey of key stakeholders (patients, patient advocates and clinicians caring for patients with BMFS/HPHM) was performed to formally identify issues faced and barriers experienced by this diverse patient group and their families and care providers. A comprehensive model of care (MoC) for patients with BMFS/HPHM was developed which incorporates the results of stakeholder assessment and also the observations determined during earlier studies detailed above. The MoC is undergoing evaluation with a hybrid implementation-effectiveness study to determine both patient and clinician acceptability and satisfaction with this approach. Overall, the work presented in this thesis demonstrates strategies to improve diagnosis, management and outcomes of Australian patients with BMFS/HPHM and their families.
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    Publication bias and the effect of mandatory trial registration in the anaesthesia literature
    Chong, Simon Woon-Hui ( 2022)
    Publication bias and selective outcome reporting have been demonstrated in many areas of medicine, and can have significant impact on clinical practice through the weighting of published evidence toward selected positive results. Publication bias and selective outcome reporting can influence the findings of meta-analyses and summaries of evidence, and are significant contributors to the substantial problem of increasing waste in research. The aim of this thesis was to investigate publication bias in the anaesthesia literature and the effect of the introduction of mandatory prospective trial registration on this bias. In Chapter 2 we attempted to quantify the amount of publication bias present in the anaesthesia literature in the era prior to introduction of mandatory prospective trial registration. We conducted a review of all randomised controlled trial (RCT) abstracts presented at the American Society of Anesthesiologists (ASA) annual meetings between 2001 to 2004. By assessing whether the primary outcome of the abstract was positive or negative and then eliciting any subsequent journal publication of the abstract, we found significant positive publication bias present; i.e. abstracts with positive results were significantly more likely to proceed to publication than those with negative results (Odds Ratio: 2.01; 95% Confidence Intervals: 1.52 – 2.66; P < 0.001). We then undertook a review of all RCT abstracts presented at the ASA annual meetings between 2010 to 2016. In Chapter 3, we looked to see whether the introduction of mandatory prospective trial registration in 2005 had been followed by a decrease in publication bias in the anaesthesia literature, by comparing the ASA conference abstracts in the first period prior to the introduction of mandatory trial registration (2001-2004) with a period after the introduction of mandatory trial registration (2010-2016). When comparing the odds ratios for abstracts with positive results proceeding to publication over those with negative results, between the two discrete periods of time, we found a marked decrease in the amount of positive publication bias present (P = 0.021) after the introduction of mandatory trial registration. However, after adjustment for study size and abstract quality, a significant amount of publication bias still remained in the anaesthesia literature in the period post introduction of mandatory trial registration (Odds Ratio: 1.34; 95% Confidence Intervals: 1.02 – 1.76; P = 0.037). The results in Chapter 3 contrasted surprisingly to our findings in Chapter 4, where we calculated the proportion of abstracts presented at the ASA annual meetings between 2010 to 2016 that had been prospectively registered, and also quantified the proportion of major discrepancies between prospective trial registration entries and corresponding journal publications. Here, we found that an unacceptably low proportion of RCT abstracts (21%) had undergone prospective trial registration, and almost half (48%) had a major discrepancy, being a primary outcome, sample size, or study intervention change, between their registry data and journal publication. These results signified poor compliance with the implementation of mandatory prospective trial registration, and the presence of significant selective outcome reporting in the anaesthesia literature over the period of time examined. We found no significant reduction of positive outcomes when comparing abstracts without and with prospective registration (Odds Ratio = 0.77; 95% Confidence Intervals: 0.56 – 1.06; P = 0.105). However, rates of journal publication for conference abstracts presented at the ASA annual meeting were found to be substantially higher among prospectively registered trials than in unregistered trials (Odds Ratio = 3.82; 95% Confidence Intervals: 2.73 – 5.35; P < 0.001), indicating that this requirement is clearly influencing publication outcomes and may have contributed to the more even distribution of positive versus negative trial findings among those achieving publication. Improved understanding of the components and contributory factors to publication bias and selective outcome reporting is still required, along with the future implementation and maintenance of more effective strategies against these core problems in medicine and medical research. The uncertainty present in conclusions of meta-analyses and summaries of evidence, stemming from sources of error such as publication bias, needs to be better communicated when guiding clinical practice and future trials.
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    Diagnostic and treatment strategies for the management of acute stroke with special reference to clot retrieval
    Yan, Bernard ( 2017)
    This body of work comprises contributions to human cerebrovascular disease as performed over a period of 12 years (from year 2005 to 2017) as a specialist at major university teaching hospital in Melbourne in collaboration with the most prominent colleagues recognized internationally in this field. The body of work is divided into 2 parts. The first part comprises of 41 peer-reviewed papers submitted in full in hard copy representing the most pivotal and highly cited papers in major specialist journals where I have been either senior and corresponding author, lead author or a major contributor. This body of work is divided into essentially 6 sections based on prognosis, diagnostic factors, pharmacogenetics, aging, relation to epilepsy and other diseases and my own specialty of therapeutics including endovascular clot retrieval. The second part submitted for completion includes the total 114 peer-reviewed papers representing my contribution, less pivotal to the central themes, to the medical literature. It includes for particular interest my collaboration with engineers in the development of endovascular devices for the performance of therapeutic manoeuvres. Each section is preceded by a brief introductory overview to facilitate assessment.
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    Medical rehabilitation in natural disasters
    Amatya, Bhasker ( 2017)
    The number of severe natural disasters (such as earthquakes, storms, draught, floods etc.) has escalated in recent years. Natural disasters often occur unexpectedly, precipitously and with great magnitude of destruction, resulting in significant loss of life and long-term disability from severe injuries including spinal cord injury, traumatic brain injury, limb amputation, fracture, peripheral nerve injury, crush injury and psychological impairment. In the last two decades, advances in disaster response/rescue and field management, have improved the survival rates of disaster victims significantly worldwide. Current data shows a significant increase in the number of injuries sustained relative to mortality, indicating medical rehabilitation is integral to comprehensive disaster management. Empirical evidence on medical rehabilitation following natural disasters is increasing and various studies have reported effectiveness of rehabilitation in survivors. Evidence suggests early provision of rehabilitation programs reduce disability, leading to better clinical outcomes, and improves participation and quality of life of disaster victims. The World Health Organization (WHO) rehabilitation guidelines recommend implementation and access to rehabilitation during all phases of the disaster response. In line with this, there is strong consensus amongst global health authorities that medical rehabilitation should be initiated in the immediate emergency response phase, and should be continued in the community over a longer-term until treatment goals are achieved and survivors are successfully reintegrated into society. Many countries now recognize the importance of disaster planning, preparedness and management initiatives, and their disaster management capacity and collaboration has improved. Unfortunately, major disparities and gaps amongst countries exist, and those with a high disaster risk tend to have a low coping capacity, with inadequate disaster response/management plans. Many countries have limited or lack of access to appropriate services such as rehabilitation, where fragmented healthcare systems are compromised by lack of financial and political support. Rehabilitation-inclusive disaster management strategies/plans are yet to be developed in many countries, particularly in the Asia-Pacific region (where the majority of natural disasters occur). There is a concern in regards to the inadequacy of global organizational capacities and capabilities and matching of resources across the disaster cycle. In past large-scale disasters, it was beyond the capacity of many countries to have optimal disaster management and many were dependent on global humanitarian and medical assistance. This is reflected by the growing number of emergency medical teams (EMTs) responding to disasters worldwide. However, the influx of EMTs during past disasters presented immense challenges regarding response coordination and management. There was lack of standardized protocols/guidelines, coordination and evaluation mechanisms in place. This resulted in inadequate care delivery, particularly rehabilitation, with often devastating consequences for the affected individuals, families and communities. Although there have been improvements in the organization of emergency responses, care and services, this has often not extended to include rehabilitation services. Currently, there is increased scrutiny of the humanitarian response sector driven towards professionalism and accountability, to provide effective and appropriate interventions in different disaster settings. Further, there have been significant developments in international, regional and national collaboration and management capacities in disaster management, including implementation of disaster-risk reduction frameworks, quality and coordination mechanism of EMTs. One of the noteworthy developments is the establishment of the WHO-EMT Initiative and launch of EMT guidelines, including the ‘Minimum technical standards and ecommendations for rehabilitation in sudden onset disasters’. These guidelines not only classify medical response teams per their capability, but also set out the core standards for medical care of disaster victims. The WHO rehabilitation guideline provides standardized protocols for rehabilitation in future emergencies, acknowledging variations in type and patterns of injury, disease and subsequent long-term disability. It provides much needed direction for preparedness for rapid, professional, coordinated medical responses by both national and international response teams. It also provides guidance on building or strengthening the capacity of local and international EMTs within defined coordination mechanisms. A WHO registration system for all EMTs was initiated in July 2015, which enables establishment of a global registry of emergency medical response teams for deployment in future calamities. There are still immense challenges in putting these standards into practice in disaster settings. The successful implementation of these frameworks will require increased resilience of the rehabilitation community with multi-stakeholder partnerships. There is still much progress to be made on tackling the underlying drivers of disaster risk, such as poverty, climate change, rapid urbanization, and factors such as environmental degradation, poor local governance, population growth, economic development patterns, to establish a rehabilitation-inclusive disaster management model for future catastrophes. The aim is to strengthen national capacity, foster an environment of self-empowerment of EMTs and local health services, and work in rehabilitation within defined coordination mechanisms in disaster-affected area. This thesis explores the medical rehabilitation management of disaster survivors, following natural disasters. The aim was to provide evidence and systematic analyses of various rehabilitation interventions trialled in disaster survivors, in terms of their effectiveness, safety and cost-efficiency. Rehabilitation professionals’ role and gaps in evidence for medical rehabilitation in disaster management and Australian perspective were explored, specifically in the Asia-Pacific region. Further, a brief overview of current developments, challenges, and gaps in the rehabilitation-inclusive disaster management plan, including implementation of WHO guidelines, is discussed to improve care for victims of future calamities.
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    Mycobacterium ulcerans on the Bellarine Peninsula: turning observations into science
    O'Brien, Daniel Patrick ( 2015)
    The Bellarine Peninsula in south-eastern Australia has been experiencing an epidemic of M. ulcerans since 1998.[1] It affects local residents, but also visitors from outside the endemic region, with more than 50% of cases managed at the local referral health service, Barwon Health. Since 1998 an electronic database (Epi info 6, Centers for Disease Control and Prevention, Atlanta, Ga, USA), designed and implemented by the author and approved by the Barwon Health Ethics Committee, has been established that prospectively records clinical, epidemiological and treatment information on all cases of M. ulcerans managed by staff of Barwon Health. All data has been collected and entered into the database by the author. During the period 1998 until 2014 the management of M. ulcerans in Barwon Health gradually evolved, largely based on observations obtained by clinicians in Barwon Health during their management of patients with M. ulcerans. The analysis of the data collected has been used to confirm and document these observations on a scientific level and to influence the ongoing evolution of clinical practice. These finding have been further disseminated, helping to influence a change of clinical practice in the management of M. ulcerans both throughout Australia and internationally. The results of this research (turning observations into science) are presented in this thesis and include the following important components: 1. The determination that antibiotics are effective in the treatment of M. ulcerans in Australian patients. This has resulted in nearly universal cures achieved with antibiotic treatment of the disease, the performance of more conservative and less reconstructive surgery, less hospitalizations, lower long-term morbidity and reduced cost of care. (Chapters 1, 2 and 3) 2. The demonstration that all oral antibiotic combinations are effective, better tolerated and less toxic than previously administered injectable antibiotics. This also allowed treatment to be given from home and avoided hospitalization. (Chapters 1, 2 and 3) 3. The first demonstration that fluoroquinolone antibiotics are an effective and safe antibiotic that can be used in combination with other known effective antibiotics in M. ulcerans treatment in humans. This has increased the options for safe and effective oral antibiotic treatment. (Chapters 1, 2 and 3) 4. The first study to describe successful outcomes in the treatment of M. ulcerans in selected patients with antibiotic treatment durations shorter than the current WHO and Australian recommended 8 weeks. This has offered significant benefits in terms of reducing toxicity and improving adherence associated with M. ulcerans antibiotic treatment. (Chapter 4) 5. The first clinical reports of the occurrence of paradoxical reactions resulting from the antibiotic treatment of M. ulcerans. This lead to the realization that previously perceived treatment failures were incorrect and instead were occurring as a result of the effectiveness of antibiotic treatment. This has lead to a dramatic change in management of M. ulcerans leading to a reduction in the need for further surgery, reconstructive surgery and the need to change or prolong M. ulcerans antibiotic treatment regimens. (Chapter 5) 6. A comprehensive description of the incidence, clinical spectrum, diagnostic features and treatment of paradoxical reactions associated with the antibiotic treatment of M. ulcerans. This provided information that will aid clinicians in recognizing, diagnosing and managing paradoxical reactions when treating patients with M. ulcerans. (Chapter 6) 7. The determination of risk factors for the development of paradoxical reactions that may minimize the occurrence and impact of paradoxical reactions during M. ulcerans treatment. It also provides important prognostic information for clinicians managing M. ulcerans. (Chapter 6) 8. The first described use of corticosteroids to treat severe paradoxical reactions occurring during the antibiotic treatment of M. ulcerans. This has lead to a reduced need for further surgery and reconstructive surgery as well as minimizing long-term morbidity from the disease. (Chapter 7) This research has been extended to Africa and to HIV coinfected patients where the first reported safe and effective use of prednisolone to manage a severe paradoxical reaction in an HIV-infected patient was described. (Chapter 14) 9. The determination of risk factors for treatment failure if surgery without antibiotics is used for treatment of M. ulcerans. This allows an improved selection of patients if surgery alone is considered in the treatment of M. ulcerans, but also provides important prognostic information for clinicians managing M. ulcerans. (Chapter 8) 10. A comprehensive description of the clinical features and diagnosis of M. ulcerans in an Australian population. This provided important information to aid health practitioners identify, diagnose and treat M. ulcerans. (Chapter 9) 11. A comprehensive description of the clinical features, diagnosis and risk factors of the severe oedematous form of M. ulcerans. This provided important information that will increase the awareness of odematous M. ulcerans disease, and improve the understanding of its clinical presentation and risk factors. This should allow clinicians to diagnose and treat early oedematous forms of M. ulcerans which will have a major impact on the morbidity and cost of this form of disease. (Chapter 10) 12. The use of available evidence, best practice and expert opinion to develop the first guidelines for the management of M. ulcerans/HIV co-infection. These will be an important aid in managing the complex issues relating to the clinical care of patients in endemic areas where these infections are increasingly found to co-exist. (Chapter 12) 13. The use of field experience, best practice and available evidence to propose a research agenda to improve the effectiveness, accessibility, acceptability and feasibility of care for M. ulcerans in Africa, including in those populations co-infected with tuberculosis or HIV. (Chapters 13 and 15)
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    Understanding the role of infections in the pathogenesis of inflammatory bowel disease, and improving the quality and safety of treatment
    GUPTA, ARUN ( 2014)
    Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis are chronic inflammatory diseases of the gastrointestinal tract. These conditions cause significant morbidity and reduced quality of life in patients who are often young. The pathogenesis of IBD is uncertain, however the current paradigm is that mucosal inflammation is caused by a dysfunctional interaction between the innate immune system and the bacterial microbiota within the gastrointestinal tract. Single nucleotide polymorphisms (SNPs) of genes related to innate immunity such as pattern recognition receptors, mucosal barrier and autophagy are likely to play an important role. Despite the potential role of altered innate immunity, the mainstay of treatment of inflammatory bowel disease is immunosuppressive medications. This includes thiopurine drugs, which affect lymphocyte function, and monoclonal antibody therapy based on inhibition of tumour necrosis factor α. Although often effective, these medications have the potential to increase the risk of infections and malignancy. This thesis examines the role of infections in inflammatory bowel disease, initially assessing the role of the bacterial microbiota through analysis for the putative pathogen Mycobacterium avium subspp. paratuberculosis, and attempts to correlate these findings with a multiplex analysis of SNPs previously associated with IBD. The microbiota is then analysed more broadly using a metagenomic type approach with a custom phylogenetic oligonucleotide microarray based on 16s ribosomal RNA probes. Approaches to improving quality and safety in IBD are then examined. A survey of Australian gastroenterologists in relation to screening for latent infections and vaccination, with respect to immunomodulators and monoclonal antibody therapies was carried out and discussed. A comprehensive audit of the use of infliximab, an anti-TNF α agent at a tertiary metropolitan hospital was undertaken. A novel electronic clinical decision support system was designed with the aim of improving the clinical governance related to these agents, and the impact of this system was examined. A study to assess the use of pharmacogenetics and measurement of thiopurine metabolites to improve the safety of thiopurine use was conducted in addition.
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    Improving the outcome of patients with lymphoproliferative disorders
    Cheah, Chan Yoon ( 2014)
    Lymphoproliferative disorders (LPD) collectively form the commonest category of haematologic malignancy in Australia. Most patients are not cured and improvements in treatments are urgently needed. Within this thesis I have taken two broad approaches to this problem. Optimising standard therapies 1. Using PET-CT in identify patients at risk of early disease relapse The identification of patients at highest risk of failing existing therapies is a rational starting point to improve outcomes. Using clinical datasets from Peter MacCallum Cancer Centre, I studied the ability of PET-CT to identify patients at risk of disease relapse. Theoretically, early detection of relapse when tumour burden may increase the probability of successful salvage therapy and ultimate cure. Therefore I reviewed the outcomes and method of detecting relapse patterns in patients with de novo DLBCL and transformed indolent lymphoma. No clear benefit from a surveillance strategy was demonstrated, meaning that patients can be spared the anxiety and radiation of scanning. I also explored the role of PET-CT in primary mediastinal B-cell lymphoma and found negative end of treatment PET-CT was predictive of excellent progression-free survival, but positive scans require histologic confirmation prior to escalation of therapy. 2. Central nervous system (CNS) relapse in aggressive NHL This complication is typically rapidly fatal and identifying patients at increased risk In the first study I analysed a group of high-risk patients with DLBCL and found that the addition of high dose systemic methotrexate and/or cytarabine was associated with lower rates of CNS relapse compared with intrathecal prophylaxis alone. This finding highlights the benefits obtaining when a customised therapeutic approach is used. In a second study, by collaborating through a large, international multicentre network I collated a large series of patients with mantle cell lymphoma who developed CNS relapse. Within this, I identified blastoid histology, high mantle cell lymphoma international prognostic index, raised serum lactate dehydrogenase and poor performance status as risk factors for CNS involvement. Developing new therapies The second half of this thesis focuses on the development of novel therapeutic strategies. 3. NMP and anti-CD20 monoclonal antibodies in lymphoma N-methyl-2-pyrrolidone (NMP) shares biologic properties with the established anti-cancer immune modulating drug lenalidomide, which is active with rituximab in lymphoma. I have shown that NMP has in vitro enhancement of rituximab-mediated induction of antibody dependent cellular cytotoxicity on lymphoma cell lines. The promising pre-clinical activity of this combination will be assessed in future clinical trials. 4. Rational clinical trial design using immunotherapies Finally, I designed three early phase clinical trial protocols using immunotherapies: 1) oral NMP in myeloma, 2) intra-tumoral αgalactoceramide and CpG and 3) ISCOMAB and rituximab, in indolent B-cell lymphoma. These clinical trial protocols combine correlative scientific with clinical endpoints and are now ready for activation.
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    The HIT epitope
    Vun, Chee Ming ( 2001)
    Heparin-induced thrombocytopenia (HIT) is a disorder found in some patients who developed thrombocytopenia after given heparin and similar glycosaminoglycans, with an incidence of 3%. There is little experimental study on the predisposition to HIT, while the pathogenesis of HIT has been investigated more widely. The currently favoured model is based on the activation of platelets FeγRII by HIT IgG, which only occur when the HIT IgG is in complex with PF4 and glycosaminoglycan. However, no study has looked into platelets activation by the HIT antibody beyond the binding to FeγRII. As the signal transduction pathways of platelets activation become increasingly understood, the activation of platelets by the HIT antibody await further in-depth studies. The involvement of endothelial cells in HIT is also an area that demands further detailed studies. Almost nothing is known about the immunogenesis of HIT, apart from isolated animal study based on idiotype. The possibility of involvement of cellular immunity in HIT is only studied very recently. HIT may be diagnosed by a functional assay based on activation of platelets or immunoasaay based on the detection of anti-PF4-hcparin antibody. A map of the HIT epitope is essential in elucidating the various aspects of HIT. It is now known that the majority, if not all HIT antibodies bind to a complex of hPF4 and heparin. Although the role of heparin or similar glycosaminoglycan is not fully understood, it is plausible that the HIT epitope is presented entirely on the PF4 tetramer. Heparin presumably serves to modify the presentation of the HIT epitope on the PF4 tetramers. One model contends that heparin alters the conformation of each PF4 tetramer, such that a neo-epitope is exposed on binding to heparin. On the other hand, when heparin is absent, the HIT epitope is hidden within the PF4 tetramer. An alternative model is based on the alignment of many PF4 tetramers by chains of heparin polysaccharides. Knowledge of the HIT epitope is crucial in unravelling the interaction between the HIT antibody and its antigen, and the subsequent platelets activation. This study uses site directed mutagenesis to create a comprehensive set of hPF4 mutant proteins. By measuring the binding avidity of these mutant PF4s with a batch of HIT sera, the contribution of the surface residues of PF4 tetramer is estimated. Subsequently, a single HIT population epitope is mapped on hPF4. Using graphical molecular modelling, several possible ways in which the HIT antibody, PF4 and heparin may interact with each other are examined. Viewing PF4 as a six faceted cuboid, the HIT epitope is found to be presented predominantly on one pair of opposite faces. The heparin binding helical pairs are located on a different pair of opposite faces. When a curve is drawn around the PF4 tetramer along the longitudinal axes of the two pairs of α-helices, the HIT epitope bearing faces are the pair that are crossed by this curve. This finding is significant because it is consistent with a model of interaction between PF4 and heparin, in which heparin chains bind to four pairs of lysine residues on each pair of α-helices in a orthogonal orientation between the longitudinal axes of the heparin chain and the helical pair. The finding is also consistent with a modified model in which heparin binds to the pair of opposite faces whose normal axes are directed perpendicular to the longitudinal axes of the paired α-helices. It is of significance to note that the pair of faces containing the HIT epitope are the only pairs which have a paucity of positively charged amino acid residues. If the HIT epitope resides on any of the other two pairs of faces, the HIT antibody will be forced to compete with heparin for binding to regions containing positively charged residues. The localisation of the HIT epitope on the pair of faces poor in positively charged residues is also significant, as PF4 tetramers are free to be aligned into arrays via cross-linking by heparin chains. These arrays of heparin cross-linked PF4 arrays have their HIT epitope bearing facets exposed. HIT IgG are facilitated to bind onto arrays of HIT epitopes aligned in optimal positions for coordinated binding of HIT IgG. The net effect of such coordinated binding is the oligomerisation of HIT IgG. When the oligomerised HIT IgG bind to Feγ receptors, the latter were forced to undergo lateral movement in the cell membrane in order to reach the binding targets. The resultant clustering of Feγ receptors on the cell membrane is expected to serve as trigger for downstream signal transduction which eventually leads to the activation of platelets. It may be some time yet before the finding of this study can be confirmed by 3D structural mapping of the HIT epitope using X-ray crystallography or NMR study. The tetrameric nature of PF4 and the tri-molecular interaction pose enormous barrier to this approach. In the meantime, the functionally determined HIT epitope will serve as a model for further experimental investigation and understanding of HIT.
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    Biliary tract injury
    Thomson, Benjamin Napier John ( 2012)
    Aim - The aim of the thesis was to examine the causes, mechanisms, recognition and treatment of biliary injury. The hypothesis was that the management principles for biliary injury were similar regardless of the cause. Methods - Biliary injuries secondary to operative damage (iatrogenic), following transplantation or as a result of blunt or penetrating (traumatic) trauma were examined. The following databases were analyzed; A prospective database of biliary injuries in Victoria from 1997 - 1999, a database of iatrogenic biliary injuries from the Royal Infirmary of Edinburgh from 1984 - 2003, a prospective database for all liver transplants performed by the Scottish Liver Transplant Unit (SLTU) until September 2001 and the prospectively gathered trauma registry at The Royal Melbourne Hospital from 1999 - 2011. Retrospective case note review was performed for further data collection. Patient data was entered onto a Microsoft Access database and statistical analysis performed with SSPS versions using Cox regression for multivariate analysis, the Mann Whitney U test for independent variables and the Log rank test when appropriate. Not all data sets were of sufficient size to allow statistical analysis. Management of biliary injury included non-operative, percutaneous, endoscopic and surgical options. Results - Iatrogenic injuries were recorded in 33 patients from the Victorian audit and 123 patients from the Royal Infirmary of Edinburgh. Fifty five (14.6%) of 379 consecutive orthotopic liver transplants at the SLTU had biliary complications. Thirty three patients (0.1%) of 26,014 blunt and penetrating trauma patients had injuries to the biliary tree and gallbladder. Of the 123 iatrogenic injuries from the Royal Infirmary of Edinburgh, 55 (44.7%) had an attempted repair prior to referral, 59 (47.9%) were repaired after referral and 9 (7.3%) were managed without surgery. For the 59 patients repaired after referral a successful repair was possible in 22 (88%) of 25 patients repaired within the first two weeks compared with 20 (91%) of 22 repaired after 6 weeks (p=0.615). Nine patients were considered for hepatic resection. Five patients developed hepatic failure and were considered for liver transplantation with only two reaching transplantation. Of the 55 grafts from the SLTU with biliary complications, 28 biliary leaks occurred with 17 anastomotic leaks successfully treated non-operatively. Of the thirty anastomotic strictures, six (38%) of the 16 early anastomotic strictures required surgery for complete resolution, compared with 12 (86%) of the 14 late anastomotic strictures (p=0.0106). Of the blunt and penetrating biliary injuries there were 10 gallbladder and 23 biliary tree injuries. Fourteen patients had injuries to the intra-hepatic biliary tree and nine to the extra-hepatic biliary tree. Delay in the recognition of biliary injury following iatrogenic injury continues to be prevalent, with the delay often associated with sepsis, jaundice and peritonitis. Injury following liver transplantation is complicated by the association of hepatic arterial thrombosis and immunosuppression, whilst traumatic injury is frequently associated with intra-abdominal organ injury. The timing of repair and utilization of temporizing measures such as biliary drainage depends upon the associated injuries and presence of sepsis or jaundice. For all types of biliary injury, surgical reconstruction with Roux-en-Y hepaticojejunostomy remains the gold standard for repair. Successful long lasting repair is possible in the majority when managed by a specialist hepatobiliary team. Conclusion - The management of biliary injuries is multi-factorial and requires tailoring according to patient variables. However, common management pathways exist regardless of the cause.
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    The effect of patient factors and clinician choices on management of colorectal cancer and other malignancies
    Field, Kathryn Maree ( 2011)
    Cancer is one of the leading causes of morbidity and mortality world-wide, and colorectal cancer is one of the most common malignancies in the developed world. Being able to predict the most appropriate strategies for diagnosis, treatment and monitoring for any malignancy, both in the adjuvant and metastatic disease settings, is crucial as more management options come into play. In particular, the choices surrounding chemotherapy dosing can depend on many factors, and increasing interest is developing regarding optimization and individualization of treatment strategies for cancer based on these factors. Modern oncology is currently focused on biomarker-based research and translation to care. Although this thesis does not incorporate any pre-clinical biomarker-based research, patient variables (such as age and comorbidities) can be regarded as a type of clinical ‘biomarker’ – for example, age is a very strong prognostic factor for a number of malignancies, perhaps even more important than particular laboratory-based biomarkers in many circumstances. This research will focus on key aspects of patient care, from surgery to chemotherapy, radiation therapy and disease monitoring, which may be potentially regarded as ‘biomarkers’ - stratifying patients into those who may benefit the most, and least, from various treatment modalities and strategies. This body of work focuses primarily on colorectal cancer. The thesis provides a comprehensive ‘snapshot’ of current management strategies in Australia for colorectal cancer – from diagnosis through to surgical and oncological management – and each paper compares the findings with what is currently regarded as ‘gold-standard’ practice. It is well known that patients on clinical trials are mostly younger and fitter than those seen in routine practice, and treating physicians cannot always apply the findings from randomized controlled studies to the individual cancer patient. It is useful to understand in parallel with the evidence gained from clinical trials, its applicability and modifications employed in routine practice and as such, this research has been largely conducted using a prospectively collected comprehensive cancer database; together with surveys of Australian oncologists and review of available literature. Many issues requiring treatment decisions for colorectal cancer are also applicable to many malignancies, and the thesis also includes some papers which relate to cancer management in general – in particular, the impact of patient age and comorbidity on treatment decisions, and the effect of liver dysfunction on chemotherapy choices for cancer patients.