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DNA polymerase epsilon deficiency causes IMAGe syndrome with variable immunodeficiency
No full textDuring genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins
By the good grace: the moral treatment of the domesticated dog in art and society
No full textThis research uses the focus on the relationship between domesticated dogs and humans in order to generate ethical studio practice and guidelines for the exhibition of art works. Conflicting ideas about the appropriate treatment of domesticated dogs are revealed through investigation into the interactions between humans and dogs. Here, a belief in human supremacy is shown to often negate the basic acknowledgement that dogs have rights as sentient beings. This investigation has elicited a number of guidelines that are applicable to human relationships with dogs whether in the treatment of dogs or in their representation. When humans or artists utilise the innate qualities of dogs, the relationship can be considered exploitative. Such use should not just benefit the human,it should also not harm the dog, as the welfare of dogs should not be over ruled by human needs and desires. Accordingly, this exegesis researches early philosophical views, which allowed ill-treatment of dogs and examines the artistic representation of dogs by specific artists and groups throughout Western art history. Historical ideas around the character of dogs have been challenged through contemporary philosophical concepts, which outline the rights of dogs and demonstrate the need to rethink unethical attitudes towards dogs, which are historically or religiously based
The enduring and evolving influence of Ball and Brown (1968)
No full textIn this virtual special issue (VSI) we acknowledge the contribution of Ball and Brown (1968) [BB68] and select some key papers from the Australian Journal of Management (AJM), published since its inception in 1976, that demonstrate how Ball and Brown influenced, and in many cases inspired, the research agendas of Australian and New Zealand researchers. AJM is particularly proud to acknowledge the connection with Ray Ball and Philip Brown. Not only did these scholars strongly influence the research agenda of AJM authors but Ray and Philip were both instrumental in the establishment and development of the Journal. The Australian Graduate School of Management (AGSM), Sydney, launched AJM in 1976 with the aim to publish scholarly articles in the interdisciplinary field of management. Philip Brown was the first Director of AGSM and Ray Ball was one of the foundation faculty of AGSM and the founding editor of AJM
Chlorhexidine versus saline in reducing the risk of catheter associated urinary tract infection: a cost-effectiveness analysis
No full textBackground: Catheter associated urinary tract infections are one of the most common infections acquired in hospital. A recent randomised control study demonstrated the benefit of using chlorhexidine (0.1%) for meatal cleaning prior to urinary catheter insertion, by reducing both catheter associated asymptomatic bacteriuria and infection. These findings raise the important question of whether a decision to switch from saline to chlorhexidine was likely to be cost-effective. The aim of this paper was to evaluate the cost-effectiveness of adopting routine use of chlorhexidine for meatal cleaning prior to urinary catheter insertion Methods: The outcomes of this cost-effectiveness study are changes to health service costs in 387,909 per 100,000 catherisations, prevent 70 cases of catheter associated urinary tract infections, release 282 bed days and provide a small improvement in health benefits of 1.43 quality adjusted life years. Using a maximum willingness to pay for a marginal quality adjusted life year threshold of AUD$28,000 per 100,000 catherisations, suggests that adopting chlorhexidine would be cost effective and potentially cost-saving. Conclusion: The findings from our work provide evidence to health system administrators and those responsible for drafting catheter associated urinary tract infections prevention guidelines that investing in switching from saline to chlorhexidine is not only clinically effective but also a sensible decision in the context of allocating finite healthcare resources
Family-based prevention programmes for alcohol use in young people
No full textBackground: Alcohol use in young people is a risk factor for a range of short‐ and long‐term harms and is a cause of concern for health services, policy‐makers, youth workers, teachers, and parents. Objectives: To assess the effectiveness of universal, selective, and indicated family‐based prevention programmes in preventing alcohol use or problem drinking in school‐aged children (up to 18 years of age). Specifically, on these outcomes, the review aimed: to assess the effectiveness of universal family‐based prevention programmes for all children up to 18 years (‘universal interventions’); to assess the effectiveness of selective family‐based prevention programmes for children up to 18 years at elevated risk of alcohol use or problem drinking (‘selective interventions’); and to assess the effectiveness of indicated family‐based prevention programmes for children up to 18 years who are currently consuming alcohol, or who have initiated use or regular use (‘indicated interventions’). Search methods: We identified relevant evidence from the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, MEDLINE (Ovid 1966 to June 2018), Embase (1988 to June 2018), Education Resource Information Center (ERIC; EBSCOhost; 1966 to June 2018), PsycINFO (Ovid 1806 to June 2018), and Google Scholar. We also searched clinical trial registers and handsearched references of topic‐related systematic reviews and the included studies. Selection criteria: We included randomised controlled trials (RCTs) and cluster RCTs (C‐RCTs) involving the parents of school‐aged children who were part of the general population with no known risk factors (universal interventions), were at elevated risk of alcohol use or problem drinking (selective interventions), or were already consuming alcohol (indicated interventions). Psychosocial or educational interventions involving parents with or without involvement of children were compared with no intervention, or with alternate (e.g. child only) interventions, allowing experimental isolation of parent components.
Data collection and analysis: We used standard methodological procedures expected by Cochrane. Main results: We included 46 studies (39,822 participants), with 27 classified as universal, 12 as selective, and seven as indicated. We performed meta‐analyses according to outcome, including studies reporting on the prevalence, frequency, or volume of alcohol use. The overall quality of evidence was low or very low, and there was high, unexplained heterogeneity.
Upon comparing any family intervention to no intervention/standard care, we found no intervention effect on the prevalence (standardised mean difference (SMD) 0.00, 95% confidence interval (CI) ‐0.08 to 0.08; studies = 12; participants = 7490; I² = 57%; low‐quality evidence) or frequency (SMD ‐0.31, 95% CI ‐0.83 to 0.21; studies = 8; participants = 1835; I² = 96%; very low‐quality evidence) of alcohol use in comparison with no intervention/standard care. The effect of any parent/family interventions on alcohol consumption volume compared with no intervention/standard care was very small (SMD ‐0.14, 95% CI ‐0.27 to 0.00; studies = 5; participants = 1825; I² = 42%; low‐quality evidence). When comparing parent/family and adolescent interventions versus interventions with young people alone, we found no difference in alcohol use prevalence (SMD ‐0.39, 95% CI ‐0.91 to 0.14; studies = 4; participants = 5640; I² = 99%; very low‐quality evidence) or frequency (SMD ‐0.16, 95% CI ‐0.42 to 0.09; studies = 4; participants = 915; I² = 73%; very low‐quality evidence). For this comparison, no trials reporting on the volume of alcohol use could be pooled in meta‐analysis. In general, the results remained consistent in separate subgroup analyses of universal, selective, and indicated interventions. No adverse effects were reported. Authors' conclusions: The results of this review indicate that there are no clear benefits of family‐based programmes for alcohol use among young people. Patterns differ slightly across outcomes, but overall, the variation, heterogeneity, and number of analyses performed preclude any conclusions about intervention effects. Additional independent studies are required to strengthen the evidence and clarify the marginal effects observed
Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis
No full textIdiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneu monia of unknown cause with a median survival of only three years. Little is known about the mechanisms that precede the excessive collagen deposition seen in IPF, but cellular senescence has been strongly implicated in disease pathology. Senescence is a state of irreversible cell-cycle arrest accompanied by an abnormal secretory profile and is thought to play a critical role in both development and wound repair. Normally, once a senescent cell has contributed to wound repair, it is promptly removed from the environment via infiltrating immune cells. However, if immune clearance fails, the persistence of senescent cells is thought to drive disease pathology through their altered secretory profile. One of the major cell types involved in wound healing is fibroblasts, and senescent fibroblasts have been identified in the lungs of patients with IPF and in fibroblast cultures from IPF lungs. The question of what is driving abnormally high numbers of fibroblasts into senescence remains unanswered. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a role in a myriad of processes, including cell-cycle progression, gene transcription, as well as mitochondrial respiration, all of which are dysregulated during senescence. Activation of STAT3 has previously been shown to correlate with IPF progression and therefore is a potential molecular target to modify early-stage senescence and restore normal fibroblast function. This review summarizes what is presently known about fibroblast senescence in IPF and how STAT3 may contribute to this phenotype
Secure Module Invocation System (SMIS): a study of program execution in a secure operating system environment
No full textWith increasing numbers of successful computer attacks by those who are using the Internet and exploiting weaknesses and security gaps in operating systems, applications and software, software security has become an important issue in computer security. Any successful computer hacking attack can create a disaster for networks and important secret information such as personal data, privileged accounts and email passwords stored in the various computers within the network by exploiting human vulnerabilities. The main aim of this research is to design and present a new program execution environment that will offer secure services for applications that prevent people bypassing the security of the system. It also aims to increase extensibility, flexibility and protection. These aims are not significantly different to those of some other operating systems, though this thesis aims to bring these protections to user space.
This thesis proposes a Secure Module Invocation System (SMIS) for software protection and, once implemented, measures its performance. Our system architecture utilises key components from the SPEEDOS operating system. The SMIS is designed to provide a trusted and secure program execution environment. The architectural model can be used to improve the security of non-secure applications. Protection in SMIS is implemented through various mechanisms such as capabilities and bracket routines, and also supports an information-hiding structure for user resources. These resources are referred to as modules. Capabilities are protected in SMIS by either other capabilities or by passwords. In SMIS, bracket routines are also significant because they provide the foundation for flexible protection and freely programmable access checks. SMIS implements the information-hiding concept, which prohibits direct access to the data of another module unless the client presents the SMIS with a capability that confers the suitable authority. Implementing this concept in SMIS enhances the flexibility of software systems by providing dependencies among software units. Also, SMIS supports a new security mechanism that allows users to qualify their modules. The invocation of the target module is then redirected to the suitable bracket routine(s). Without changing the role of capabilities, bracket routines may accept, or reject, access to the target module based on arbitrary rules. Brackets can be individually and dynamically incorporated with the target module at runtime. The bracketing technique permits users to implement any security policy they consider suitable. A prototype has been implemented to test the proposed environment and evaluate the outcomes of using the different approaches attackers use to damage applications. The results indicate that augmenting a non-secure module with a bracket routine can provide benefits for target modules and an overall benefit for software and applications. Further, adding bracket routines dynamically at runtime can effectively improve the flexibility and extensibility of the software system
Strategies to improve adherence to colorectal cancer screening
No full textColorectal cancer (CRC) is an important health problem globally and nationally. In Australia, every week, over 300 people are diagnosed with CRC, and 80 will die from this disease. When CRC is detected and treated early, there are high survival rates. CRC is amenable to screening as it has a long latency period during which microscopic traces of blood can be detected using a simple test called a faecal occult blood test (FOBT). To support CRC screening, Australians are offered biennial FOBT through the National Bowel Cancer Screening Program (NBCSP). Despite the proven benefits and accessibility of CRC screening in Australia, only 41% of those invited to screen by the NBCSP return completed FOBTs. Data collected from Australian general-practice- and population-based community surveys also suggest CRC screening rates are low. However, the most recent data were collected in 2011. Additionally, not all research assessed whether screening was adherent to Australian CRC screening guidelines. Examining correlates of CRC screening behaviour can illuminate which groups are least likely to adhere to screening guidelines. Those in younger age groups, i.e. 50-59 years, are consistently reported to have higher rates of under-screening compared to those in older age groups. However, other correlates of under-screening for CRC vary depending on the source of data. For example, the NBCSP reports higher rates of under-screening for males, a finding that is contrary to general-practice- and population-based community studies which have reported that females are more likely to be under-screened. Ascertaining correlates of under-screening from healthcare settings can contribute to the current body of evidence and may be used to design targeted interventions to increase CRC screening in those least likely to adhere to guidelines. General practitioner (GP) endorsement of CRC screening is a positive predictor of screening behaviour, and GPs have a recognised role in promoting preventive health activities, including CRC screening. GPs can be integrated into population-based programs, thus potentially having a positive effect on uptake of screening within the program. This thesis by publication consists of an introduction, six papers, a discussion of the key findings, implications and future directions, a review of the strengths and limitations of the research, and conclusions. The data-based papers report data collected from healthcare settings. The studies reported in papers 1 to 3 report new cross-sectional data on CRC screening practices of individuals attending these settings, and include both under- and over-screening, as well as knowledge of CRC risk factors and screening recommendations. Paper 4 reports a review of trends in general-practice-based research into CRC screening prevalence, using descriptive or intervention methodology, over time. The studies reported in papers 5 and 6 describe the protocol and delivery of a general-practice-based randomised controlled trial which aims to increase CRC screening uptake. The results of this thesis suggest that there is an evidence-practice gap for CRC screening adherence in those attending healthcare settings in Australia, with both under- and over-screening reported. Males and those in younger age groups were more likely to report under-screening. Levels of knowledge of CRC risk factors and screening recommendations were low; less than one-third knew the correct age to commence CRC screening, and 40% knew that FOBT was the recommended test. This suggests that strategies may be required to reinforce CRC screening recommendations among patients attending healthcare settings. A review of the peer-reviewed literature reveals that a high proportion of research effort has consistently been directed toward the evaluation of interventions to increase CRC screening in general practice, using robust study designs. Despite this, under-screening in this setting remains an area requiring improvement, suggesting that future research should focus on effectiveness trials, to determine which interventions are likely to be adopted into routine practice. Finally, we found that an intervention involving GP endorsement, and provision of point-of-care FOBT and printed information significantly increased CRC screening uptake among general practice patients. There is potential for the role of GPs in promoting CRC screening to be better integrated into the NBCSP. Effective general-practice-based interventions could be incorporated into routine practice to boost CRC screening participation rates
Pacific decadal variability: uncertainties and implications for water resources
No full textThe influence of low-frequency climate variability, as represented by the Inter-decadal Pacific Oscillation (IPO) and Pacific Decadal Oscillation (PDO), collectively known as Pacific Decadal Variability (PDV), has been explored in a wide collection of studies. Statistical characteristics of rainfall and streamflow, changes of drought, flood and bushfire frequencies have been found to be associated with PDV in some regions. PDV runs refer to periods during which a PDV index lies above (or below) some threshold. These alternating runs have been shown to be associated with predominantly dry (or wet) hydrological conditions in some regions. The goal of this thesis was to understand the statistical characteristics of PDV runs and assess the value of incorporating PDV information in urban water supply system decision making. In pursuit of this goal, this thesis had five objectives
The first objective was to identify the regions in eastern Australia, both east and west of the Great Divide, where PDV significantly influences rainfall and streamflow. It was shown using relative differences that the Australian Water Availability Project (AWAP) gridded rainfall and streamflow product can produce largely unbiased estimates of PDV influence. Furthermore, this thesis showed that rainfall and streamflow over a large portion of eastern Australian are affected by PDV phases with relative differences in mean streamflow exceeding 50% over much of the study region north of Canberra. These regions can potentially benefit from PDV-informed water supply decision making. The remaining four objectives worked towards defining this benefit.
Because of the limited instrumental record, there are many palaeo reconstructions of PDV indices from which PDV runs can be extracted. Using these reconstructions, two fundamental questions of hydrological importance were asked: are PDV wet and dry phases statistically different and have PDV phases been stationary over the last millennium? The results suggest that there is no substantial evidence to support the assumption that run lengths have statistically different distributions during positive and negative PDV phases. Analysis based on three millennium-long reconstructions suggests that it is more likely than not, that the PDV run length has been non-stationarity in the past millennium.
PDV palaeo reconstructions are subject to reconstruction errors, both systematic and random. However, understanding the impact of such errors is limited by the fact that “ground truth” is only possible in the period where palaeoclimate and instrumental data overlap. To develop a deeper insight on the role of such errors, synthetic stochastic experiments were designed to simulate the effect on errors on reconstructed PDV indices and PDV runs. The results showed that reconstruction errors cause the PDV run length standard deviation to be overestimated, in some cases very substantially, with the autocorrelation of the errors having the most significant impact on this overestimation. A new composite index method was introduced to reduce the impact of reconstruction errors. This method was shown to perform better than the composite index method developed by Henley et al. (2013). Using the new composite index method and ten reconstructions of different data lengths, the mean of PDV run length was estimated to be 20.8 years and standard deviation to be 13.7 years. When stochastic models are used to incorporate low and high-frequency climate information in drought risk assessment, a number of parameters must be estimated from limited historical data. These parameters include parameters to simulate PDV run lengths and streamflow conditioned on PDV phase. The impact of uncertainty in these parameters on drought risk assessment was investigated. A case study based on the Warragamba River, the main water source for Sydney, showed that uncertainty in drought risk is considerable and that uncertainty in PDV run length parameters contributes only a small portion to the full uncertainty with most of the uncertainty coming from the streamflow parameters. The final objective assessed the value of PDV information in urban water supply system decision making. This was done using an urban water supply case study based on the Warragamba River and in which demand was growing. Multi-objective optimisation, in which present worth capital cost and expected restriction costs were minimised, was used to identify the optimal schedule of future augmentations for two cases in which streamflow was generated by a lag-one autoregressive streamflow model and a PDV-informed lag-one autoregressive streamflow model. The use of optimisation allows differences in performance to be attributed to the choice of streamflow model. The results showed that ignoring PDV led to a considerable over-investment in capital cost. Moreover, the Pareto front was found to be sensitive to the PDV phase at the start of the simulation
An analysis of the values of websites as a promotional marketing tool: a case study of the institutional catering industry in Hong Kong
No full textThis dissertation aims to evaluate the value of a Website for the institutional catering industry in implementing marketing strategies in Hong Kong. In view of the limited literature exploring why there are firms that are still not establishing Websites, this research investigates whether the adoption of a Website as an Internet marketing tool is under-valued by the firms or is inappropriate to suit a particular industry in a specific geographical location. This research evaluates whether a Website is an effective marketing tool for institutional catering companies in Hong Kong.
This exploratory research adopts a case study approach using qualitative methods. A purposive sampling design is adopted to identify the appropriate respondents. Semi-structured interviews were conducted with 5 firms with and 5 firms without a Website. A comparative analysis and content analysis are used to compare and analyse the findings of these two sub-samples. This research explores the underlying reasons and possible determinants of non-establishment of a Website for some firms. The findings indicated that there is a difference between perceived effectiveness and actual effectiveness of Websites in performing its basic functions as well as in implementing its marketing strategies. The actual usage of company Websites deviates from its intended use in implementing marketing strategies due to an incapability of current Website features to fully match with the desired strategic marketing implementation.
This research also provides a thorough discussion on the firms’ intention of adopting a Website as an Internet marketing tool in future. Moreover, the perceived trend of using a Website as a marketing tool has been examined. Findings indicated that firms with existing Websites would continue employing this marketing tool while those firms without Website would consider adopting one since it is perceived that this Internet marketing tool will increase in importance in the coming decade