Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide : Phase I clinical trial of three dosing schedules in patients with solid malignancies

Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-limiting toxicities in 55 patients with malignant solid tumours refractory to standard chemotherapies. Lenalidomide capsules were consumed once daily for 12 weeks according to one of the following three schedules: (I) 25 mg daily for the first 7 d, the daily dose increased by 25 mg each week up to a maximum daily dose of 150 mg; (II) 25 mg daily for 21 d followed by a 7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg daily continuously. Twenty-six patients completed the study period. Two patients experienced a grade 3 hypersensitivity rash. Four patients in cohort I and 4 patients in cohort II suffered grade 3 or 4 neutropaenia. In 2 patients with predisposing medical factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was detected in 6 patients. One complete and two partial radiological responses were measured by computed tomography scanning; 8 patients had stable disease after 12 weeks of treatment. Fifteen patients remained on treatment as named patients; 1 with metastatic melanoma remains in clinical remission 3.5 years from trial entry. This study indicates the tolerability and potential clinical efficacy of lenalidomide in patients with advanced solid tumours who have previously received multi-modality treatment. Depending on the extent of myelosuppressive pre-treatment, dose schedules (II) or (III) are advocated for large-scale trials of long-term administration. © 2006 Elsevier Ltd. All rights reserved.

Phase II trial of Oxaliplatin and 5-Fluorouracil/Leucovorin combination in epithelial ovarian carcinoma relapsing within 2 years of platinum-based therapy

Objective To evaluate the efficacy and toxicity of Oxaliplatin and 5-Fluorouracil (5-FU)/Leucovorin (LV) combination in ovarian cancer relapsing within 2 years of prior platinum-based chemotherapy in a phase II trial. Methods Eligible patients had at least one prior platinum-based chemotherapy regimen, elevated CA-125 ≥ 60 IU/l, radiological evidence of disease progression and adequate hepatic, renal and bone marrow function. Patients with raised CA-125 levels alone as marker of disease relapse were not eligible. Oxaliplatin (85 mg/m 2) was given on day 1, and 5-Fluorouracil (370 mg/m 2) and Leucovorin (30 mg) was given on days 1 and 8 of a 14-day cycle. Results Twenty-seven patients were enrolled. The median age was 57 years (range 42-74 years). The median platinum-free interval (PFI) was 5 months (range 0-17 months) with only 30% of patients being platinum sensitive (PFI > 6 months). Six patients (22%) had two prior regimens of chemotherapy. A total of 191 cycles were administered (median 7; range 2-12). All patients were evaluable for toxicity. The following grade 3/4 toxicities were noted: anemia 4%; neutropenia 15%; thrombocytopenia 11%; neurotoxicity 8%; lethargy 4%; diarrhea 4%; hypokalemia 11%; hypomagnesemia 11%. Among 27 enrolled patients, 20 patients were evaluable for response by WHO criteria and 25 patients were evaluable by Rustin's CA-125 criteria. The overall response rate (RR) by WHO criteria was 30% (95% CI: 15- 52) [three complete responses (CRs) and three partial responses (PRs)]. The CA-125 response rate was 56% (95% CI: 37-73). Significantly, a 25% (95% CI: 9-53) radiological and a 50% (95% CI: 28-72) CA-125 response rate were noted in platinum resistant patients (PFI < 6 months). The median response duration was 4 months (range 3-12) and the median overall survival was 10 months. Conclusion Oxaliplatin and 5-Fluorouracil/ Leucovorin combination has a good safety profile and is active in platinum-pretreated advanced epithelial ovarian cancer. © 2004 Elsevier Inc. All rights reserved.

Intraurban rail access : policy implications of five revealed perspectives from a Q-sorting exercise in three Australian cities

This project advances the current understanding of intraurban rail passengers and their travel experiences to help rail industry leaders tailor policy approaches to fit specific, relevant segments of their target population. Using a Q-sorting technique and cluster analysis, preliminary research identified five perspectives occurring in a small sample of rail passengers who varied in their frequency and location of rail travel as well as certain sociodemographic characteristics. Revealed perspectives (named to capture the gist of their content) included "Rail travel is about the destination, not the journey"; "Despite challenges, public transport is still the best option"; "Rail travel is fine"; "Rail travel? So far, so good"; and "Bad taste for rail travel." This paper discusses each of the perspectives in detail and considers them in relation to tailored policy implications. An overarching finding from this study is that improving railway travel access requires attention to physical, psychological, financial, and social facets of accessibility. For example, designing waiting areas to be more socially functional and comfortable has the potential to increase ridership by addressing social forms of access, decreasing perceived wait times, and making time at the station feel like time well spent. Even at this preliminary stage, the Q-sorting technique promises to provide a valuable, holistic, albeit fine-grained, analysis of passenger attitudes and experiences that will assist industry efforts in increasing ridership.

State-of-the-art : track degradation at bridge transitions

Transition zones between bridge decks and rail tracks suffer early failure due to poor interaction between rail vehicles and sudden changes of stiffness. This has been an ongoing problem to rail industry and yet still no systematic studies appear to have been taken to maintain a gradually smoothening transmission of forces between the bridge and its approach. Differential settlement between the bridge deck and rail track in the transition zone is the fundamental issue, which negatively impacts the rail industry by causing passenger discomfort, early damage to infrastructure and vehicle components, speed reduction, and frequent maintenance cycles. Identification of mechanism of the track degradation and factors affecting is imperative to design any mitigation method for reducing track degradation rate at the bridge transition zone. Unfortunately this issue is still not well understood, after conducting a numbers of reviews to evaluate the key causes, and introducing a wide range of mitigation techniques. In this study, a comprehensive analysis of the available literature has been carried out to develop either a novel design framework or a mitigation technique for the bridge transition zone. This paper addresses three critical questions in relation to the track degradation at transition zone: (1) what are the causes of bridge transition track degradation?; (2) what are the available mitigation techniques in reducing the track degradation rate?; (3) what are the factors affecting on poor performance of the existing mitigation techniques?. It is found that the absence of soil-water response, dynamic loading response, and behaviour of geotechnical characteristics under long-term conditions in existing track transition design frameworks critically influence on the failures of existing mitigation techniques. This paper also evaluates some of the existing design frameworks to identify how each design framework addresses the track degradation at the bridge transition zone.

Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden

Over 80% of women diagnosed with advanced-stage ovarian cancer die as a result of disease recurrence due to failure of chemotherapy treatment. In this study, using two distinct ovarian cancer cell lines (epithelial OVCA 433 and mesenchymal HEY) we demonstrate enrichment in a population of cells with high expression of CSC markers at the protein and mRNA levels in response to cisplatin, paclitaxel and the combination of both. We also demonstrate a significant enhancement in the sphere forming abilities of ovarian cancer cells in response to chemotherapy drugs. The results of these in vitro findings are supported by in vivo mouse xenograft models in which intraperitoneal transplantation of cisplatin or paclitaxel-treated residual HEY cells generated significantly higher tumor burden compared to control untreated cells. Both the treated and untreated cells infiltrated the organs of the abdominal cavity. In addition, immunohistochemical studies on mouse tumors injected with cisplatin or paclitaxel treated residual cells displayed higher staining for the proliferative antigen Ki67, oncogeneic CA125, epithelial E-cadherin as well as cancer stem cell markers such as Oct4 and CD117, compared to mice injected with control untreated cells. These results suggest that a short-term single treatment of chemotherapy leaves residual cells that are enriched in CSC-like traits, resulting in an increased metastatic potential. The novel findings in this study are important in understanding the early molecular mechanisms by which chemoresistance and subsequent relapse may be triggered after the first line of chemotherapy treatment.

Narratives of possession : reading for saga authorship

The aim of this thesis is to show how character analysis can be used to approach conceptions of saga authorship in medieval Iceland. The idea of possession is a metaphor that is adopted early in the thesis, and is used to describe Icelandic sagas as works in which traditional material is subtly interpreted by medieval authors. For example, we can say that if authors claim greater possession of the sagas, they interpret, and not merely record, the sagas' historical information. On the other hand, tradition holds onto its possession of the narrative whenever it is not possible for an author to develop his own creative and historical interests. The metaphor of possession also underpins the character analysis in the thesis, which is based on the idea that saga authors used characters as a vehicle by which to possess saga narratives and so develop their own historical interests. The idea of possession signals the kinds of problems of authorship study which are addressed here, in particular, the question of the authors' sense of saga writing as an act either of preservation or of creation. While, in that sense, the thesis represents an additional voice in a long-standing debate about the saga writers' relation to their source materials, I argue against a clear-cut distinction between creative and non-creative authors, and focus instead on the wide variation in authorial control over saga materials. This variation suggests that saga authorship is a multi-functional activity, or one which co-exists with tradition. Further, by emphasising characterisation as a method, I am adding to the weight of scholarship that seeks to understand the sagas in terms of their literary effects. The Introduction and chapter one lay out the theoretical scope of this thesis. My aim in these first two sections is to inform the reader of the type of critical questions that arise when authorship is approached in relation to characterisation, and to suggest an interpretive framework with which to approach these questions. In the Introduction this aim manifests as a brief discussion of the application of the term "authorship" to the medieval Icelandic corpus, a definition of the scope of this study, and an introduction to the connections, made throughout this thesis, between saga authors, the sagas' narrative style, and the style of characterisation in the sagas. Chapter one is a far more detailed discussion of our ability to make these connections. In particular, the chapter develops the definition of the analytical term "secondary authorship" that I introduce in order to delineate the type of characterisation that is of most interest in this thesis. "Secondary authorship" is a literary term that aims to sharpen our approach to saga authors' relationship to their characters by focusing on characters who make representations about the events of the saga. The term refers to any instance in which characters behave in a manner that resembles the creativity, interpretation, and understanding associated with authorship more generally. Character analysis cannot, however, be divorced from socio-historical approaches to the saga corpus. Most importantly, the sagas themselves are socio-historical representations that claim some degree of truth value. This claim that the sagas make by implication about their historicity is the starting point of a discussion of authorship in medieval Iceland. Therefore, at the beginning of chapter one I discuss some of the approaches to the social context of saga writing. This discussion serves as an introduction to both the culture of saga writing in medieval Iceland and to the nature of the sagas' historical perspective, and reflects my sense that literary interpretations of the sagas cannot be isolated from the historical discourses that frame them. The chapter also discusses possession, which, as I note above, is used alongside the concept of secondary authorship to describe the saga authors' relationship with the stories and characters of the past. At the close of chapter one, I offer a preliminary list the various functions of saga authorship, and give some examples of secondary authorship. From this point I am able to tie my argument about secondary authorship to specific examples from the sagas. Chapter two examines the effect of family obligations and domestic points of view in the depiction of characters' choices and conception of themselves. The examples that are given in that chapter - from Gisla saga Súrssonar and Íslendinga saga - are the first of a number of textual analyses that demonstrate the application of the concepts of secondary authorship and possession of saga narratives. The relationship between narratives about national and domestic matters shows how authorial creativity in the area of kinship obligation provides the basis for the saga's development of historical themes. Thus, the two major case studies given in chapter two tie authorial engagement with characters to the most influential social institution in early and medieval Iceland, the family. The remaining chapters represent similar attempts to relate authorial possession of saga characters to central socio-historical themes in the sagas, such as the settlement process in early Iceland and its influence on the development of regional political life (chapter three). Likewise, the strong authorial interest in an Icelander's journey to Norway in Heimskringla is presented as evidence of the author's use of a saga character to express an Icelandic interpretation of Norwegian history and to promote a sense that Iceland shared the ownership of regal history with Norway (chapter four). In that authorial engagement with the Icelander abroad, we witness saga characterisation being used as a basis for historical interpretation and the means by which foreign traditions and influence, not least the narratives of royal lives and of the Christianisation, are claimed as part of medieval Icelanders' self-conception. While saga authors observe the conventions of saga narration, characters are often subtly positioned as the authors' interpretive mirrors, especially clear than when they act as secondary authors. Nowhere is this more apparent than in Brennu- Njáls saga, which contains many characters who voice the author's claim to interpret the past. Even Hrútr Herjólfsson, through his remarkable perception of events and his conspicuous comments about them, acts as a secondary author by enabling the author to emphasise the importance of the disposition of characters. In Laxdœla saga and Þorgils saga ok Hafliða, authorial interest in characters' perception is matched by the thematising of learning, from the inception of knowledge as prophecy or advice to complete understanding by saga characters (chapter six). In Þorgils saga skarða, a character's inner development from an excessively ambitious and politically ruthless youth to a Christian leader killed by his kinsman allows the author to shape a political life into a lesson about leadership and the community's ability to moderate and contain the behaviour of extraordinary individuals. The portrayal draws on methods of characterisation that we can identify in Grettis saga Ásmundarson, Fóstbrœðra saga, and Orkneyinga saga. A comparison of the characterisation of figures with intense political or military ambitions suggests that saga authors were interested in the community's ability to balance their strength and ability with a degree of social moderation. The discussion of these sagas shows that character study can be used to analyse how the saga authors added their own voice to the voices passed down to medieval Icelanders in traditional narratives. Authorial engagement with characters allowed inherited traditions about early Norway and Iceland and records of thirteenth century events to be transformed into sophisticated historical works with highly creative elements. Through secondary authorship, saga authors took joint-possession of narratives and contested the power of tradition in setting the interpretive framework of a saga.

Short-term changes in axial length during simulations of typical far, intermediate and near tasks

Purpose: To investigate the changes in axial length with the combined effect of accommodation and angle of gaze (convergence and downward gaze) over 5 minutes in groups of myopes and emmetropes. Methods: A total of 31 subjects (nine emmetropes, 10 low myopes, and 12 moderate to high myopes) aged from 18 to 31 years were recruited. To measure ocular biometrics in inferonasal gaze with accommodation, an optical biometer (Lenstar LS900) was inclined on a tilt and height adjustable stage, with the subject’s chinrest mounted on a rotary stage to induce various levels of convergence by rotation of the subject’s head in primary or downward gaze. Initially, the subjects performed a distance viewing task in primary gaze for 10 minutes to provide a ‘wash-out’ period for prior visual tasks, and then the subject’s axial length and ocular biometrics were measured in nine different combinations of gaze/accommodation over 5 minutes. These nine sessions for all gaze measurements (i.e. three levels of accommodation 9 three levels of convergence) were completed across 3 days of testing (one accommodation condition on each day).The nine combinations of gaze/accommodation were based on those required to view the centre, right and left edges of a distant TV at 6 m in primary gaze, an intermediate task (i.e. computer at 50 cm in 10° downward gaze) and a near task (i.e. reading A4 page at 20 cm in 20° downward gaze). Subjects were wearing a custom built three-axes head tracker throughout the experiment that monitored subjects’ relative head movements (roll, pitch and yaw) during measurements. Results: A significant increase in axial length occurred with the combined effect of accommodation, convergence and downward gaze (repeated measures ANOVA, p < 0.001), with the greatest axial elongation during the near task in downward gaze with convergence (i.e. downward 20°/inward 33°, with 5 D accommodation) (mean change 33 ± 13 lm, after 5 minutes task) followed by the intermediate task (i.e. downward 10°/inward 25°, with 2 D accommodation) (mean change 14 ± 11 lm, after 5 minutes task).Changes in axial length for the distance task (i.e. primary gaze/9° convergence, with 0.16 D accommodation) were not statistically significant (mean change 4 ± 8 lm, after 5 minutes task, p > 0.05). Moderate to high myopes had a greater change in the axial length (mean change 40 ± 11 lm after 5 minutes of near task) than that of emmetropes (mean change 29 ± 15 lm after 5 minutes of near task) and low myopes (mean change 29 ± 16 lm after 5 minutes of near task) associated with time (p = 0.02) and accommodation by time (p = 0.03). Conclusions: The combination of accommodation, convergence and downward angle has a significant short term effect on axial length over time. The near task in downward gaze with convergence caused a greater change in axial length than the intermediate and distant visual tasks. The greater axial elongation measured in the infero-nasal direction with accommodation is most likely associated with a combination of biomechanical factors such as, extraocular muscle forces and ciliary muscle contraction.

Long-term persistence of tissue-engineered adipose flaps in a murine model to 1 year : an update

BACKGROUND Tissue engineering of patient-specific adipose tissue has the potential to revolutionize reconstructive surgery. Numerous models have been described for the production of adipose tissue with success in the short term, but little has been reported on the stability of this tissue-engineered fat beyond 4 months. METHODS A murine model of de novo adipogenesis producing a potentially transplantable adipose tissue flap within 4 to 6 weeks was developed in the authors' laboratory. In this study, the authors assess the ability of three-chamber (44-μl volume) configurations shown to be adipogenic in previous short-term studies (autograft, n = 8; open, n = 6; fat flap, n = 11) to maintain their tissue volume for up to 12 months in vivo, to determine the most adipogenic configuration in the long term. RESULTS Those chambers having the most contact with existing vascularized adipose tissue (open and fat flap groups) showed increased mean adipose tissue percentage (77 ± 5.6 percent and 81 ± 6.9 percent, respectively; p < 0.0007) and volume (12 ± 6.8 μl and 30 ± 14 μl, respectively; p < 0.025) when compared with short-term controls and greater adipose tissue volume than the autograft (sealed) chamber group (4.9 ± 5.8 μl; p = 0.0001) at 1 year. Inclusion of a vascularized fat flap within the chamber produced the best results, with new fat completely filling the chamber by 1 year. CONCLUSIONS These findings demonstrate that fat produced by tissue engineering is capable of maintaining its volume when the appropriate microenvironment is provided. This has important implications for the application of tissue-engineering techniques in humans.

MT1-MMP-dependent and -independent regulation of gelatinase A activation in long-term, ascorbate-treated fibroblast cultures: Regulation by fibrillar collagen

Human skin fibroblasts were cultured long-term in the presence of ascorbic acid to allow formation of a three-dimensional collagen matrix, and the effects of this on activation of secreted matrix metalloproteinase-2 (MMP-2) were examined. Accumulation of collagen over time correlated with increased levels of both mature MMP-2 and cell-associated membrane type 1-MMP (MT1-MMP), and subsequently increased mRNA levels for MT1-MMP, providing temporal resolution of the "nontranscriptional" and "transcriptional" effects of collagen on MT-1MMP functionality. MMP-2 activation by these cultures was blocked by inhibitors of prolyl-4-hydroxylase, or when fibroblasts derived from the collagen α1(I) gene-deficient Mov-13 mouse were used. MMP-2 activation by the Mov-13 fibroblasts was rescued by transfection of a full-length α1(I) collagen cDNA, and to our surprise, also by transfection with an α1(I) collagen cDNA carrying a mutation at the C-proteinase cleavage, which almost abrogated fibrillogenesis. Although studies with ascorbate-cultured MT1-MMP-/- fibroblasts showed that MT1-MMP played a significant role in the collagen-induced MMP-2 activation, a residual MT1-MMP-independent activation of MMP-2 was seen which resembled the level of MMP-2 activation persisting when wild-type fibroblasts were cultured in the presence of both ascorbic acid and MMP inhibitors. We were also unable to block this residual activation with inhibitors specific for serinyl, aspartyl, or cysteinyl enzymes.

Diode-clamped three-level inverter-based battery/supercapacitor direct integration scheme for renewable energy systems

This paper describes a diode-clamped three-level inverter-based battery/supercapacitor direct integration scheme for renewable energy systems. The study is carried out for three different cases. In the first case, one of the two dc-link capacitors of the inverter is replaced by a battery bank and the other by a supercapacitor bank. In the second case, dc-link capacitors are replaced by two battery banks. In the third case, ordinary dc-link capacitors are replaced by two supercapacitor banks. The first system is supposed to mitigate both long-term and short-term power fluctuations while the last two systems are intended for smoothening long-term and short-term power fluctuations, respectively. These topologies eliminate the need for interfacing dc-dc converters and thus considerably improve the overall system efficiency. The major issue in aforementioned systems is the unavoidable imbalance in dc-link voltages. An analysis on the effects of unbalance and a space vector modulation method, which can produce undistorted current even in the presence of such unbalances, are presented in this paper. Furthermore, small vector selection-based power sharing and state of charge balancing techniques are proposed. Experimental results, obtained from a laboratory prototype, are presented to verify the efficacy of the proposed modulation and control techniques.

Measuring child work and residence adjustments to parents' long-term care needs

This article estimates the effects of various parent and child characteristics on the choice of care arrangement of the parent, taking into account the potential endogeneity of some of the child characteristics. Three equations are estimated: a care choice equation, a child location equation, and a child work equation. Results suggest a hierarchy of family decision making; child locations affect the care decision, which affects child work decisions. The results also question previous research attempting to explain causes of secular trends in long-term care.

A three-level flying-capacitor rectifier based supercapacitor direct integration scheme for distributed generation systems

Supercapacitors are increasingly used as short term energy storage elements in distributed generation systems. The traditional approach in integrating them to the main system is the use of interfacing dc-dc converters which introduce additional costs and power losses. This paper therefore, presents a novel direct integration scheme for supercapacitors and thereby eliminates associated costs and power losses of interfacing converters. The idea is simply to replace ordinary capacitors of three-level flying-capacitor rectifiers with supercapacitors and operate them under variable voltage conditions. An analysis on the reduction of power losses by the proposed system is presented. Furthermore, supercapacitor sizing and implementation issues such as effects of the variable voltage operation and resistive behavior of supercapacitors at high frequencies are also discussed. Simulation results are presented to verify the efficacy of the proposed system in suppressing short term power fluctuations in wind generation system.

An analysis on the possibility of using capacitors of a three-level capacitor clamped inverter as power smoothing elements for wind power systems

This paper presents a new direct integration scheme for supercapacitors that are used to mitigate short term power fluctuations in wind power systems. The idea is to replace ordinary capacitors of a 3-level flying capacitor inverter by supercapacitors and operate them under variable voltage conditions. This approach eliminates the need of interfacing dc-dc converters for supercapacitor integration and thus considerably improves the overall efficiency. However, the major problem of this unique system is the change of supercapacitor voltages. An analysis on the effects of these voltage variations are presented. A space vector modulation method, built from the scratch, is proposed to generate undistorted current even in the presence of dynamic changes in supercapacitor voltages. A supercapacitor voltage equalisation algorithm is also proposed. Furthermore, resistive behavior of supercapacitors at high frequencies and the need for a low pass filter are highlighted. Simulation results are presented to verify the efficacy of the proposed system in suppressing short term wind power fluctuations.

Young people and citizenship-delayed, diminished and empty?

This paper is presented in workshop format in order to meet the style and themes of the conference, and seeks to explore as fully as possible with participants issues, concerns and proposals around the discourse of young people and citizenship. This paper takes the position that the relationship between young people and citizenship is complex and in places contradictory, and while Ruth Lister (1998), argues for an 'inclusionary potential', a central concern is that the citizenship that young people get is as Hartley Dean (1997), suggests, at best 'ambiguous', and at its worst, 'diminished'. Under not so new Labour, the term has according to Gail Lewis (1998) re-emerged as a 'category of political articulation', imbued with the pronouncements of Charles Murray (1995) on the underclass, and Amitai Etzioni (1996), on the virtues of Communitarianism and the central assertion that in relation to young people and certain communities, 'rights have exceeded responsibilities'. This body of opinion has proved to be seductive to a government dedicated to joined up solutions in the battle against social exclusion and to the reconfiguration of the welfare state to place the onus for welfare and social provision on to individuals and communities. Those who work with young people and young people themselves may wish to be proactive in asserting the kind of citizenship they require, rights-based, expansive and supportive, rather than accept an imposed version devoid of rights but full to the brim of authoritarian measures, vindictive proposals and narrow horizons. This paper will engender debate and reflection and offer a context of the erosion of young people's rights over the last 20 years, Hartley Dean (1996), and will consider the work of T.H. Marshall (1950) in dividing citizenship into three elements: the civil element, the political element, and the social element. The paper will explore in workshop tradition, strategies and proposals for action relevant to practitioners and academics, such as the reduction in the voting age to 16.

Modelling the water, energy and economic nexus

The mining industry faces three long term strategic risks in relation to its water and energy use: 1) securing enough water and energy to meet increased production; 2) reducing water use, energy consumption and emissions due to social, environmental and economic pressures; and 3) understanding the links between water and energy, so that an improvement in one area does not create an adverse effect in another. This project helps the industry analyse these risks by creating a hierarchical systems model (HSM) that represents the water and energy interactions on a sub-site, site and regional scales; which is coupled with a flexible risk framework. The HSM consists of: components that represent sources of water and energy; activities that use water and energy and off-site destinations of water and produced emissions. It can also represent more complex components on a site, with inbuilt examples including tailings dams and water treatment plants. The HSM also allows multiple sites and other infrastructure to be connected together to explore regional water and energy interactions. By representing water and energy as a single interconnected system the HSM can explore tradeoffs and synergies. For example, on a synthetic case study, which represents a typical site, simulations suggested that while a synergy in terms of water use and energy use could be made when chemical additives were used to enhance dust suppression, there were trade-offs when either thickened tailings or dry processing were used. On a regional scale, the HSM was used to simulate various scenarios, including: mines only withdrawing water when needed; achieving economics-of-scale through use of a single centralised treatment plant rather than smaller decentralised treatment plants; and capturing of fugitive emissions for energy generation. The HSM also includes an integrated risk framework for interpreting model output, so that onsite and off-site impacts of various water and energy management strategies can be compared in a managerial context. The case studies in this report explored company, social and environmental risks for scenarios of regional water scarcity, unregulated saline discharge, and the use of plantation forestry to offset carbon emissions. The HSM was able to represent the non-linear causal relationship at the regional scale, such as the forestry scheme offsetting a small percentage of carbon emissions but causing severe regional water shortages. The HSM software developed in this project will be released as an open source tool to allow industry personnel to easily and inexpensively quantify and explore the links between water use, energy use, and carbon emissions. The tool can be easily adapted to represent specific sites or regions. Case studies conducted in this project highlighted the potential complexity of these links between water, energy, and carbon emissions, as well as the significance of the cumulative effects of these links over time. A deeper understanding of these links is vital for the mining industry in order to progress to more sustainable operations, and the HSM provides an accessible, robust framework for investigating these links.