Rational design of serine protease inhibitors

Proteases regulate a spectrum of diverse physiological processes, and dysregulation of proteolytic activity drives a plethora of pathological conditions. Understanding protease function is essential to appreciating many aspects of normal physiology and progression of disease. Consequently, development of potent and specific inhibitors of proteolytic enzymes is vital to provide tools for the dissection of protease function in biological systems and for the treatment of diseases linked to aberrant proteolytic activity. The studies in this thesis describe the rational design of potent inhibitors of three proteases that are implicated in disease development. Additionally, key features of the interaction of proteases and their cognate inhibitors or substrates are analysed and a series of rational inhibitor design principles are expounded and tested. Rational design of protease inhibitors relies on a comprehensive understanding of protease structure and biochemistry. Analysis of known protease cleavage sites in proteins and peptides is a commonly used source of such information. However, model peptide substrate and protein sequences have widely differing levels of backbone constraint and hence can adopt highly divergent structures when binding to a protease’s active site. This may result in identical sequences in peptides and proteins having different conformations and diverse spatial distribution of amino acid functionalities. Regardless of this, protein and peptide cleavage sites are often regarded as being equivalent. One of the key findings in the following studies is a definitive demonstration of the lack of equivalence between these two classes of substrate and invalidation of the common practice of using the sequences of model peptide substrates to predict cleavage of proteins in vivo. Another important feature for protease substrate recognition is subsite cooperativity. This type of cooperativity is commonly referred to as protease or substrate binding subsite cooperativity and is distinct from allosteric cooperativity, where binding of a molecule distant from the protease active site affects the binding affinity of a substrate. Subsite cooperativity may be intramolecular where neighbouring residues in substrates are interacting, affecting the scissile bond’s susceptibility to protease cleavage. Subsite cooperativity can also be intermolecular where a particular residue’s contribution to binding affinity changes depending on the identity of neighbouring amino acids. Although numerous studies have identified subsite cooperativity effects, these findings are frequently ignored in investigations probing subsite selectivity by screening against diverse combinatorial libraries of peptides (positional scanning synthetic combinatorial library; PS-SCL). This strategy for determining cleavage specificity relies on the averaged rates of hydrolysis for an uncharacterised ensemble of peptide sequences, as opposed to the defined rate of hydrolysis of a known specific substrate. Further, since PS-SCL screens probe the preference of the various protease subsites independently, this method is inherently unable to detect subsite cooperativity. However, mean hydrolysis rates from PS-SCL screens are often interpreted as being comparable to those produced by single peptide cleavages. Before this study no large systematic evaluation had been made to determine the level of correlation between protease selectivity as predicted by screening against a library of combinatorial peptides and cleavage of individual peptides. This subject is specifically explored in the studies described here. In order to establish whether PS-SCL screens could accurately determine the substrate preferences of proteases, a systematic comparison of data from PS-SCLs with libraries containing individually synthesised peptides (sparse matrix library; SML) was carried out. These SML libraries were designed to include all possible sequence combinations of the residues that were suggested to be preferred by a protease using the PS-SCL method. SML screening against the three serine proteases kallikrein 4 (KLK4), kallikrein 14 (KLK14) and plasmin revealed highly preferred peptide substrates that could not have been deduced by PS-SCL screening alone. Comparing protease subsite preference profiles from screens of the two types of peptide libraries showed that the most preferred substrates were not detected by PS SCL screening as a consequence of intermolecular cooperativity being negated by the very nature of PS SCL screening. Sequences that are highly favoured as result of intermolecular cooperativity achieve optimal protease subsite occupancy, and thereby interact with very specific determinants of the protease. Identifying these substrate sequences is important since they may be used to produce potent and selective inhibitors of protolytic enzymes. This study found that highly favoured substrate sequences that relied on intermolecular cooperativity allowed for the production of potent inhibitors of KLK4, KLK14 and plasmin. Peptide aldehydes based on preferred plasmin sequences produced high affinity transition state analogue inhibitors for this protease. The most potent of these maintained specificity over plasma kallikrein (known to have a very similar substrate preference to plasmin). Furthermore, the efficiency of this inhibitor in blocking fibrinolysis in vitro was comparable to aprotinin, which previously saw clinical use to reduce perioperative bleeding. One substrate sequence particularly favoured by KLK4 was substituted into the 14 amino acid, circular sunflower trypsin inhibitor (SFTI). This resulted in a highly potent and selective inhibitor (SFTI-FCQR) which attenuated protease activated receptor signalling by KLK4 in vitro. Moreover, SFTI-FCQR and paclitaxel synergistically reduced growth of ovarian cancer cells in vitro, making this inhibitor a lead compound for further therapeutic development. Similar incorporation of a preferred KLK14 amino acid sequence into the SFTI scaffold produced a potent inhibitor for this protease. However, the conformationally constrained SFTI backbone enforced a different intramolecular cooperativity, which masked a KLK14 specific determinant. As a consequence, the level of selectivity achievable was lower than that found for the KLK4 inhibitor. Standard mechanism inhibitors such as SFTI rely on a stable acyl-enzyme intermediate for high affinity binding. This is achieved by a conformationally constrained canonical binding loop that allows for reformation of the scissile peptide bond after cleavage. Amino acid substitutions within the inhibitor to target a particular protease may compromise structural determinants that support the rigidity of the binding loop and thereby prevent the engineered inhibitor reaching its full potential. An in silico analysis was carried out to examine the potential for further improvements to the potency and selectivity of the SFTI-based KLK4 and KLK14 inhibitors. Molecular dynamics simulations suggested that the substitutions within SFTI required to target KLK4 and KLK14 had compromised the intramolecular hydrogen bond network of the inhibitor and caused a concomitant loss of binding loop stability. Furthermore in silico amino acid substitution revealed a consistent correlation between a higher frequency of formation and the number of internal hydrogen bonds of SFTI-variants and lower inhibition constants. These predictions allowed for the production of second generation inhibitors with enhanced binding affinity toward both targets and highlight the importance of considering intramolecular cooperativity effects when engineering proteins or circular peptides to target proteases. The findings from this study show that although PS-SCLs are a useful tool for high throughput screening of approximate protease preference, later refinement by SML screening is needed to reveal optimal subsite occupancy due to cooperativity in substrate recognition. This investigation has also demonstrated the importance of maintaining structural determinants of backbone constraint and conformation when engineering standard mechanism inhibitors for new targets. Combined these results show that backbone conformation and amino acid cooperativity have more prominent roles than previously appreciated in determining substrate/inhibitor specificity and binding affinity. The three key inhibitors designed during this investigation are now being developed as lead compounds for cancer chemotherapy, control of fibrinolysis and cosmeceutical applications. These compounds form the basis of a portfolio of intellectual property which will be further developed in the coming years.

The story of the sixties...a pile-up on the freeway of advanced art

When does 1960s art begin and end? Certainly, aside from a few affinities, the decade’s artistic output does not exactly correspond to its popular conception as the ‘Swinging Sixties’. While it was rare that psychedelic art was truly challenging, the decade saw a number of perceptions change regarding the aims, boundaries and possibilities of experiencing art. Thus, this era has come to represent a watershed or crisis in modernist art. While in the Australian context many of these nascent trends were properly realised in the 1970s – with the full force and impact of post-object art – other challenges were first articulated in the 1950s. So, like any other demarcation of a decade, its limits and boundaries are porous.

The economics of happiness : a lifetime perspective

The three studies in this thesis focus on happiness and age and seek to contribute to our understanding of happiness change over the lifetime. The first study contributes by offering an explanation for what was evolving to a ‘stylised fact’ in the economics literature, the U-shape of happiness in age. No U-shape is evident if one makes a visual inspection of the age happiness relationship in the German socio-economic panel data, and, it seems counter-intuitive that we just have to wait until we get old to be happy. Eliminating the very young, the very old, and the first timers from the analysis did not explain away regression results supporting the U-shape of happiness in age, but fixed effect analysis did. Analysis revealed found that reverse causality arising from time-invariant individual traits explained the U-shape of happiness in age in the German population, and the results were robust across six econometric methods. Robustness was added to the German fixed effect finding by replicating it with the Australian and the British socio-economic panel data sets. During analysis of the German data an unexpected finding emerged, an exceedingly large negative linear effect of age on happiness in fixed-effect regressions. There is a large self-reported happiness decline by those who remain in the German panel. A similar decline over time was not evident in the Australian or the British data. After testing away age, time and cohort effects, a time-in-panel effect was found. Germans who remain in the panel for longer progressively report lower levels of happiness. Because time-in-panel effects have not been included in happiness regression specifications, our estimates may be biased; perhaps some economics of the happiness studies, that used German panel data, need revisiting. The second study builds upon the fixed-effect finding of the first study and extends our view of lifetime happiness to a cohort little visited by economists, children. Initial analysis extends our view of lifetime happiness beyond adulthood and revealed a happiness decline in adolescent (15 to 23 year-old) Australians that is twice the size of the happiness decline we see in older Australians (75 to 86 yearolds), who we expect to be unhappy due to declining income, failing health and the onset of death. To resolve a difference of opinion in the literature as to whether childhood happiness decreases, increases, or remains flat in age; survey instruments and an Internet-based survey were developed and used to collect data from four hundred 9 to 14 year-old Australian children. Applying the data to a Model of Childhood Happiness revealed that the natural environment life-satisfaction domain factor did not have a significant effect on childhood happiness. However, the children’s school environment and interactions with friends life-satisfaction domain factors explained over half a steep decline in childhood happiness that is three times larger than what we see in older Australians. Adding personality to the model revealed what we expect to see with adults, extraverted children are happier, but unexpectedly, so are conscientious children. With the steep decline in the happiness of young Australians revealed and explanations offered, the third study builds on the time-invariant individual trait finding from the first study by applying the Australian panel data to an Aggregate Model of Average Happiness over the lifetime. The model’s independent variable is the stress that arises from the interaction between personality and the life event shocks that affect individuals and peers throughout their lives. Interestingly, a graphic depiction of the stress in age relationship reveals an inverse U-shape; an inverse U-shape that looks like the opposite of the U-shape of happiness in age we saw in the first study. The stress arising from life event shocks is found to explain much of the change in average happiness over a lifetime. With the policy recommendations of economists potentially invoking unexpected changes in our lives, the ensuing stress and resulting (un)happiness warrant consideration before economists make policy recommendations.

Seeing a hard country : Lawrence’s Australian landscape

In 1944 Australian author Eleanor Dark wrote that Australia is a hard country for an outsider to see, citing, in evidence, the writing of the “strange, foreign-looking little man with the beard” -- the self-described by D. H. Lawrence. According to Dark, Lawrence was bewildered by Australia because what his eyes saw was not what they were accustomed to seeing. Kangaroo, she wrote, suggests one long, tormented effort to see. Lawrence appears, for Dark, to be half-blind, struggling, and irritated almost beyond belief with his visit to New South Wales. Eleanor Dark wrote this critique in 1944, long after Lawrence’s 1922 visit, but for her, as for other Australian writers, Kangaroo continued to register as an important book, even if the content rankled. Katharine Susannah Prichard and Christina Stead, both advocates in general of Lawrence, likewise rejected the tenor of Kangaroo, although Lawrence would not have been worried about the response. In 1929 he referred to his irritation with Australia in letters to P.R. “Inky” Stephensen, the Australian nationalist and publisher, and he does not seem to have changed his opinions since writing Kangaroo. Yet the novel continued to be significant for Australian writers, even if as a provocation. My discussion traces the responses of the women authors to Kangaroo, and refers to Lawrence’s letters to Stephensen, as a way of emphasizing this significance, seen especially in relation to ideas about ‘seeing’ and the Australian landscape.

Re-constructing Asianness in Australia : Yumi Umiumare, Owen Leong, and the remobilisation of monstrosity

In the late twentieth and early twenty-first centuries, Australia’s relationship with its Asian neighbours has been the subject of ongoing aesthetic, cultural and political contestations. As Alison Richards has noted, Australia’s colonial legacy, its Asia-Pacific location, and its ‘white’ self-perception have always made Australia’s relations with Asia fraught. In the latter part of the twentieth century, the paradoxes inherent in Australia’s relationships with and within the Asian region became a dominant theme in debates about nation, nationhood and identity, and prompted a shift in the construction of ‘Asianness’ on Australian stages. On the one hand, anxiety about the multicultural policy of the 1970s and 1980s, and then Prime Minister Paul Keating’s push for greater economic, cultural and artistic exchange with Asia via policies such as the Creative Nation Cultural Policy (1994), saw large numbers of Australians latch on to the reactionary, racist politics of Pauline Hanson’s One Nation Party. As Jacqueline Lo has argued, in this period Asian-Australians were frequently represented as an unassimilable Other, a threat to Australia’s ‘white’ identity, and to individual Australians’ jobs and opportunities. On the other hand, during the same period, a desire to counter the racism in Australian culture, and develop a ‘voice’ that would distinguish Australian cultural products from European theatrical traditions, combined with the new opportunities for cross-cultural exchange that came with the Creative Nation Cultural Policy to produce what Helen Gilbert and Jacqueline Lo have characterised as an Asian turn in Australian theatre...

Significant Dot: The 1769 transit of Venus - a tale of astronomy, medicine and empire

This article places the 6 June 2012 transit of Venus in the context of James Cook’s voyage from England to the South Pacific to observe the 1769 transit of Venus. A description is given on how to use a computer program called Stellarium to ‘observe’ the 1769 transit of Venus exactly as Cook saw it from the island of Tahiti in the South Pacific.

Socioeconomic inequalities in weight status among mid-aged adults : the contribution of perceptions of weight status and weight-control behaviours

Background Socioeconomically-disadvantaged adults in developed countries experience a higher prevalence of a number of chronic diseases, such as cardiovascular disease, type 2 diabetes, osteoarthritis and some forms of cancer. Overweight and obesity are major risk factors for these diseases. Lower socioeconomic groups have a greater prevalence of overweight and obesity and this may contribute to their higher morbidity and mortality. International studies suggest that socioeconomic groups may differ in their self-perceptions of weight status and their engagement in weightcontrol behaviours (WCBs). Research has shown that lower socioeconomic adults are more likely to underestimate their weight status, and are less likely to engage in WCBs. This may contribute (in part) to the marked inequalities in weight status observed at the population level. There are few, and somewhat limited, Australian studies that have examined the types of weight-control strategies people adopt, the barriers to their weight control, the determinants of their perceived weight status and WCBs. Furthermore, there are no known Australian studies that have examined socioeconomic differences in these factors to better understand the reasons for socioeconomic inequalities in weight status. Hence, the overall aim of this Thesis is to examine why socioeconomically-disadvantaged group experience a greater prevalence of overweight and obesity than their more-advantaged counterparts. Methods This Thesis used data from two sources. Men and women aged 45 to 60 years were examined from both data source. First, the longitudinal Australian Diabetes, Obesity and Lifestyle (AusDiab) Study were used to advance our knowledge and understanding of socioeconomic differences in weight change, perceived weight status and WCBs. A total of 2753 participants with measured weights at both baseline (1999-2000) and follow-up (2004-2005) were included in the analyses. Percent weight change over the five-year interval was calculated and perceived weight status, WCBs and highest attained education were collected at baseline. Second, the Candidate conducted a postal questionnaire from 1013 Brisbane residents (69.8 % response rate) to investigate the relationship between socioeconomic position, determinants of perceived weight status, WCBs, and barriers and reasons to weight control. A test-retest reliability study was conducted to determine the reliability of the new measures used in the questionnaire. Most new measures had substantial to almost perfect reliability when considering either kappa coefficient or crude agreement. Results The findings from the AusDiab Study (accepted for publication in the Australian and New Zealand Journal of Public Health) showed that low-educated men and women were more likely to be obese at baseline compared to their higheducated respondents (O.R. = 1.97, 95 % C.I. = 1.30-2.98 and O.R. = 1.52, 95 % C.I. = 1.03-2.25, respectively). Over the five year follow-up period (1999-2000 to 2004- 05) there were no socioeconomic differences in weight change among men, however socioeconomically-disadvantaged women had greater weight gains. Participants perceiving themselves as overweight gained less weight than those who saw themselves as underweight or normal weight. There was no relationship between engaging in WCBs and five-year weight change. The postal questionnaire data showed that socioeconomically-disadvantaged groups were less likely to engage in WCBs. If they did engage in weight control, they were less likely to adopt exercise strategies, including moderate and vigorous physical activities but were more likely to decrease their sitting time to control their weight. Socioeconomically-disadvantaged adults reported more barriers to weight control; such as perceiving weight loss as expensive, requiring a lot of cooking skills, not being a high priority and eating differently from other people in the household. These results have been accepted for publication in Public Health Nutrition. The third manuscript (under review in Social Science and Medicine) examined socioeconomic differences in determinants of perceived weight status and reasons for weight control. The results showed that lower socioeconomic adults were more likely to specify the following reasons for weight control: they considered themselves to be too heavy, for occupational requirements, on recommendation from their doctor, family members or friends. Conversely, high-income adults were more likely to report weight control to improve their physical condition or to look more attractive compared with those on lower-incomes. There were few socioeconomic differences in the determinants of perceived weight status. Conclusions Education inequalities in overweight/obesity among men and women may be due to mis-perceptions of weight status; overweight or obese individuals in loweducated groups may not perceive their weight as problematic and therefore may not pay attention to their energy-balance behaviours. Socioeconomic groups differ in WCBs, and their reasons and perceived barriers to weight control. Health promotion programs should encourage weight control among lower socioeconomic groups. More specifically, they should encourage the engagement of physical activity or exercise and dietary strategies among disadvantaged groups. Furthermore, such programs should address potential barriers for weight control that disadvantaged groups may encounter. For example, disadvantaged groups perceive that weight control is expensive, requires cooking skills, not a high priority and eating differently from other people in the household. Lastly, health promotion programs and policies aimed at reducing overweight and obesity should be tailored to the different reasons and motivations to weight control experienced by different socioeconomic groups. Weight-control interventions targeted at higher socioeconomic groups should use improving physical condition and attractiveness as motivational goals; while, utilising social support may be more effective for encouraging weight control among lower socioeconomic groups.

Using digital storytelling as a change agent for women’s participation in the Turkish public sphere

This thesis builds on the scholarship and practical know-how that have emerged from digital storytelling projects around the world with diverse groups of participants in a range of institutions. I have used the results of these projects to explore the opportunities Digital Storytelling workshop practice may hold for women’s participation in the public sphere in Turkey. Through theoretical discussion and practical experimentation, I examine the potential of Digital Storytelling workshop practice as a means to promote agency and self-expression in a feminist activist organisation, focusing in particular on whether Digital Storytelling can be used as a change agent – as a tool for challenging the idea of public sphere in ways that make it more inclusive of women’s participation. The thesis engages with feminist scholarship’s critiques of the public/private dichotomy, as well as the concept of gender, to seek connections with narrative identity in the light of the analysis of the Digital Storytelling workshops and the digital stories that were created in a feminist context. The study on which this thesis is based saw the introduction of Digital Storytelling to Turkey for the first time through workshops in Istanbul and Antakya, conducted in partnership with the feminist activist organisation Amargi Women’s Academy. Applying the principles of feminist post-structuralist discourse analysis as used by Judith Baxter (2003), I examine two sets of data collected in this project. First, I analyse the interactions during the Digital Storytelling workshops, where women from Amargi created their digital stories in a collaborative setting. This is done through participatory observation notes and in-depth interviews with the workshop participants and facilitators. Second, I seek to uncover the strategies that these women used to ‘speak back to power’ in their digital stories, reading these as texts. I conclude that women from the Amargi network used the workshops to create digital content in order to communicate their concerns about issues that can be classified as gender-specific matters. During this process, they also cooperated, established new connections, and at the end of the process even defined new ways of using, circulating and repurposing their digital stories for feminist activism in Turkey. My research thereby contributes equally to feminist discourse analysis, the study of new-media usage and uptake among non-professionals, and the study of media–public sphere interactions in a particular national setting: Turkey. My conclusion indicates that the process of production is as important as the product itself, and from that I am able to draw out some strategies for developing digitally equipped women’s activism in Turkey.

Campbell, Alan Johnston (1895–1982)

Born in 1895, Alan Johnston Campbell was a grazier and political party organiser. In December 1914 he enlisted in the Australian Imperial Force and saw action with the 2nd Light Horse Regiment at Gallipoli and, as a lance corporal, in the Sinai and Palestine. After the war Campbell became active in the Roma branch of the Maranoa Graziers’ Association. In 1935, at Roma, he formed one of the first branches of the Queensland Country Party. In 1943, Campbell was elected president of the QCP. Impressed by the Australian Labor Party’s organisation, Campbell centralised power and rebuked parliamentarians whom he believed were neglecting their constituents. By 1951 the highly disciplined structure had attracted 35,000 members. Campbell died in 1982.

Report on INEX 2011

INEX investigates focused retrieval from structured documents by providing large test collections of structured documents, uniform evaluation measures, and a forum for organizations to compare their results. This paper reports on the INEX 2011 evaluation campaign, which consisted of a five active tracks: Books and Social Search, Data Centric, Question Answering, Relevance Feedback, and Snippet Retrieval. INEX 2011 saw a range of new tasks and tracks, such as Social Book Search, Faceted Search, Snippet Retrieval, and Tweet Contextualization.

Introduction: Is a General Theory of Violence Possible?

"There once was a man who aspired to be the author of the general theory of holes. When asked ‘What kind of hole—holes dug by children in the sand for amusement, holes dug by gardeners to plant lettuce seedlings, tank traps, holes made by road makers?’ he would reply indignantly that he wished for a general theory that would explain all of these. He rejected ab initio the—as he saw it—pathetically common-sense view that of the digging of different kinds of holes there are quite different kinds of explanations to be given; why then he would ask do we have the concept of a hole? Lacking the explanations to which he originally aspired, he then fell to discovering statistically significant correlations; he found for example that there is a correlation between the aggregate hole-digging achievement of a society as measured, or at least one day to be measured, by econometric techniques, and its degree of techno- logical development. The United States surpasses both Paraguay and Upper Volta in hole-digging; there are more holes in Vietnam than there were. These observations, he would always insist, were neutral and value-free. This man’s achievement has passed totally unnoticed except by me. Had he however turned his talents to political science, had he concerned himself not with holes, but with modernization, urbanization or violence, I find it difficult to believe that he might not have achieved high office in the APSA." (MacIntyre 1971, 260)

Frames of Anime: Culture and Image-Building

With the rising popularity of anime amongst animation students, audiences and scholars around the world, it has become increasingly important to critically analyse anime as being more than a ‘limited’ form of animation, and thematically as encompassing more than super robots and pocket monsters. Frames of Anime: Culture and Image-Building charts the development of Japanese animation from its indigenous roots within a native culture, through Japan’s experience of modernity and the impact of the Second World War. This text is the result of a rigorous study that recognises the heterogeneous and polymorphous background of anime. As such, Tze-Yue has adopted an ‘interdisciplinary and transnational’ (p. 7) approach to her enquiry, drawing upon face-to-face interviews, on-site visits and biographical writings of animators. Tze-Yue delineates anime from other forms of animation by linking its visual style to pre-modern Japanese art forms and demonstrating the connection it shares with an indigenous folk system of beliefs. Via the identification of traditional Japanese art forms and their visual connectedness to Japanese animation, Tze-Yue shows that the Japanese were already heavily engaged in what was destined to become anime once technology had enabled its production. Tze-Yue’s efforts to connect traditional Japanese art forms, and their artistic elements, to contemporary anime reveals that the Japanese already had a rich culture of visual storytelling that pre-dates modern animation. She identifies the Japanese form of the magic lantern at the turn of the 19th century, utsushi-e, as the pre-modern ancestor of Japanese animation, describing it as ‘Edo anime’ (p. 43). Along with utsushi-e, the Edo period also saw the woodblock print, ukiyo-e, being produced for the rising middle class (p. 32). Highlighting the ‘resurfacing’ of ‘realist’ approaches to Japanese art in ukiyo-e, Tze-Yue demonstrates the visual connection of ukiyo-e and anime in the …

Impact of opening a new emergency department on healthcare service and patient outcomes : analyses based on linking ambulance, emergency and hospital databases

Background Emergency department (ED) crowding caused by access block is an increasing public health issue and has been associated with impaired healthcare delivery, negative patient outcomes and increased staff workload. Aim To investigate the impact of opening a new ED on patient and healthcare service outcomes. Methods A 24-month time series analysis was employed using deterministically linked data from the ambulance service and three ED and hospital admission databases in Queensland, Australia. Results Total volume of ED presentations increased 18%, while local population growth increased by 3%. Healthcare service and patient outcomes at the two pre-existing hospitals did not improve. These outcomes included ambulance offload time: (Hospital A PRE: 10 min, POST: 10 min, P < 0.001; Hospital B PRE: 10 min, POST: 15 min, P < 0.001); ED length of stay: (Hospital A PRE: 242 min, POST: 246 min, P < 0.001; Hospital B PRE: 182 min, POST: 210 min, P < 0.001); and access block: (Hospital A PRE: 41%, POST: 46%, P < 0.001; Hospital B PRE: 23%, POST: 40%, P < 0.001). Time series modelling indicated that the effect was worst at the hospital furthest away from the new ED. Conclusions An additional ED within the region saw an increase in the total volume of presentations at a rate far greater than local population growth, suggesting it either provided an unmet need or a shifting of activity from one sector to another. Future studies should examine patient decision making regarding reasons for presenting to a new or pre-existing ED. There is an inherent need to take a ‘whole of health service area’ approach to solve crowding issues.

Origins of Australian Football: Victoria's Early History. Volume 1 Amateur Heroes and the Rise of the Clubs, 1858 to 1876

This is volume 1 in a series of four volumes about the origins of Australian football as it evolved in Victoria between 1858 and 1896. This volume addresses its very beginnings as an amateur sport and the rise of the first clubs. Invented by a group of Melbourne cricketers and sports enthusiasts, Australian Rules football was developed through games played on Melbourne's park lands and was originally known as "Melbourne Football Club Rules". This formative period of the game saw the birth of the first 'amateur heroes' of the game. Players such as T.W. Wills, H.C.A. Harrison, Jack Conway, George O'Mullane and Robert Murray Smith emerged as warriors engaged in individual rugby-type scrimmages. The introduction of Challenge Cups was an important spur for this burgeoning sport. Intense competition and growing rivalries between clubs such as Melbourne, South Yarra, Royal Park, and Geelong began to flourish and the game developed as a result. By the 1870s the game "Victorian Rules" had become the most popular outdoor winter sport across the state. In subsequent decades, rapid growth in club football occurred and the game attracted increasing media attention.

Introduction : creative industries and cities

The 2000s were marked by a resurgence of interest in creativity and cities. If the rapid global proliferation of the Internet and digital media technologies in the 1990s had set off enthusiasm for a post-industrial ‘new economy’, where the significance of location would be in decline, the 2000s saw an energetic search by artists, entrepreneurs, investors, policy-makers, journalists and many others to uncover the well-springs of creativity and its relationship to place (Flew 2012a). This chapter begins with a discussion of the discourses or ‘scripts’ that have emerged to try and conceptualise the relationship between creativity and cities, notably theories of creative clusters, creative cities and creative class theories. Such work can be seen as representing a growth in the field of cultural economic geography although – as is noted in the chapter – it possesses some significant gaps. Among the issues that are drawn out in this book, and discussed in this chapter, are: the need to move beyond ‘imagined geographies’ of creative inner cities and come to terms with empirical evidence that suggests significant concentrations of the creative workforce in suburbs and regional cities; the relevance of urban cultural policy as a variable in the rise of cities as creative hubs or, in a different model, media capitals; and the challenges of bringing together cultural research with economic discourses in ways that get beyond caricatured representations of the ‘other’, as found, for instance, in some of the most influential framings of the concept of neo-liberalism.