Dementia is a major public health issue with rising prevalence rates, but many individuals remain undiagnosed. Accurate and timely diagnosis is key for the optimal targeting of interventions. A ...noninvasive, easily measurable peripheral biomarker would have greatest utility in population-wide diagnostic screening. Epigenetics, including DNA methylation, is implicated in dementia; however, it is unclear whether epigenetic changes can be detected in peripheral tissue. This study aimed to systematically review the evidence for an association between dementia and peripheral DNA methylation. Forty-eight studies that measured DNA methylation in peripheral blood were identified, and 67% reported significant associations with dementia. However, most studies were underpowered and limited by their case-control design. We emphasize the need for future longitudinal studies on large well-characterized populations, measuring epigenetic patterns in asymptomatic individuals. A biomarker detectable in the preclinical stages of the disease would have the greatest utility in future intervention and treatment trials.
•Forty-eight manuscripts investigating peripheral DNA methylation in dementia were included.•Most have been small cross-sectional studies, and findings have been mixed.•Longitudinal studies of individuals before dementia diagnosis are needed.•Preclinical biomarkers have the greatest clinical utility enabling early diagnosis.•Continual advances in epigenetic technologies will ensure new discoveries.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives and importance of study: Genetic discrimination is a health policy issue of international concern to clinicians, patients, researchers, and policy makers, and threatens the success of ...genomic medicine. In Australia, genetic discrimination in life insurance is legal and leads to public health harms, including deterring at-risk individuals from clinically indicated testing. In 2018, a Parliamentary Joint Committee recommended an urgent ban on the use of predictive genetic test results in life insurance underwriting in Australia, to be implemented in a form similar to the UK Code on genetic testing and life insurance. In 2019, the insurance industry, through the Financial Services Council (FSC), introduced a self-regulated moratorium that applies until 2024, but only to life insurance policies up to certain financial limits. The FSC moratorium will be reviewed in late 2022, but has no government oversight.
Policy implementation evaluation Methods: We used policy evaluation methods to 1) summarise the key recommendations of the 2018 Parliamentary Committee that are directed towards practical aspects of policy development and content; and 2) assess the level of disparity between the implemented moratorium and the recommendations of the Committee.
There is a substantial disparity between the Australian moratorium and the Parliamentary Committee recommendations across key areas, including addressing self-regulation, co-development of policy, protection of tests taken during its term, and similarity with the UK Code. The FSC moratorium offers less protection to consumers than the UK Code on a number of measures, including the level of financial coverage, the involvement of government, certainty provided to individuals who have genetic testing, and the treatment of research results.
The FSC moratorium is a step forward for Australia, but falls short of the Parliamentary recommendations. Further regulation by the Australian Government may be required to achieve the aims of the Parliamentary recommendations and ensure the intended level of consumer protection.
Rare diseases (RDs) affect approximately 8% of all people or > 400 million people globally. The Australian Government's National Strategic Action Plan for Rare Diseases has identified the need for a ...national, coordinated, and systematic approach to the collection and use of RD data, including registries. Rare disease registries (RDRs) are established for epidemiological, quality improvement and research purposes, and they are critical infrastructure for clinical trials. The aim of this scoping review was to review literature on the current state of RDRs in Australia; to describe how they are funded; what data they collect; and their impact on patient outcomes.
We conducted a literature search on MEDLINE, EMBASE, CINAHL and PsychINFO databases, in addition to Google Scholar and grey literature. Dissertations, government reports, randomised control trials, conference proceedings, conference posters and meeting abstracts were also included. Articles were excluded if they did not discuss RDs or if they were written in a language other than English. Studies were assessed on demographic and clinical patient characteristics, procedure or treatment type and health-related quality of life captured by RDRs or databases that have been established to date.
Seventy-four RDRs were identified; 19 were global registries in which Australians participated, 24 were Australian-only registries, 10 were Australia and New Zealand based, and five were Australian jurisdiction-based registries. Sixteen "umbrella" registries collected data on several different conditions, which included some RDs, and thirteen RDRs stored rare cancer-specific information. Most RDRs and databases captured similar types of information related to patient characteristics, comorbidities and other clinical features, procedure or treatment type and health-related quality of life measures. We found considerable heterogeneity among existing RDRs in Australia, especially with regards to data collection, scope and quality of registries, suggesting a national coordinated approach to RDRs is required.
This scoping review highlights the current state of Australian RDRs, identifying several important gaps and opportunities for improvement through national coordination and increased investment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the ...identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3β,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway.
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► Macrophage PRR sensing of virus or IFN activation induce 25HC synthesis and secretion ► Stat1 rapidly binds and activates the promoter of cholesterol-25-hydroxylase (Ch25h) ► 25HC exerts multilevel antiviral function for a range of different viruses ► 25HC is an intrinsic paracrine and autocrine effector of the IFN antiviral response
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dementia can result from a number of distinct diseases with differing etiology and pathophysiology. Even within the same disease, there is considerable phenotypic heterogeneity with varying symptoms ...and disease trajectories. Dementia diagnosis is thus very complex, time-consuming, and expensive and can only be made definitively post-mortem with histopathological confirmation. These inherent difficulties combined with the overlap of some symptoms and even neuropathological features, present a challenging problem for research in the field. This has likely hampered progress in epidemiological studies of risk factors and preventative interventions, as well as genetic and biomarker research. Resource limitations in large epidemiologically studies mean that limited diagnostic criteria are often used, which can result in phenotypically heterogeneous disease states being grouped together, potentially resulting in misclassification bias. When biomarkers are identified for etiologically heterogeneous diseases, they will have low specificity for any utility in clinical practice, even if their sensitivity is high. We highlight several challenges in in the field which must be addressed for the success of future genetic and biomarker studies, and may be key to the development of the most effective treatments. As a step toward achieving this goal, defining the dementia as a biological construct based on the presence of specific pathological features, rather than clinical symptoms, will enable more precise predictive models. It has the potential to lead to the discovery of novel genetic variants, as well as the identification of individuals at heightened risk of the disease, even prior to the appearance of clinical symptoms.
We report previously undocumented evidence of genetic discrimination by Australian insurance companies, obtained through direct consumer reports. We surveyed 174 consumers with cancer-predisposing ...variants, recruited by cancer organisations Lynch Syndrome Australia and Pink Hope. Questions related to experiences accessing risk-rated insurance after genetic testing. Results indicate that both legal (permitted under current regulation) and illegal discrimination is occurring. Although some respondents had not applied for risk-rated insurance, or had insurance in place before genetic testing (n = 100), those seeking new policies (n = 74) commonly experienced difficulties obtaining insurance (86%, 64/74). Of those experiencing difficulties, 50% (32/64) had no prior history or symptoms of cancer, and had undertaken risk reduction through surveillance and/or preventative surgery. Seventy-seven percent (49/64) reported difficulties related to life insurance. Follow-up telephone interviews with four respondents further described cases of apparent illegal breaches. All reports of discrimination identified were, to our knowledge, previously unreported in the literature. The number of cases suggests a systemic problem with the Australian life insurance industry. We support calls for government oversight of the inherently conflicted model of industry self-regulation in Australia, and an immediate ban on the use of genetic test results in insurance underwriting.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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