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BackgroundRestraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.MethodsUsing Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture.ResultsWe developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.ConclusionsOur method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.

Abstract Background Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. Methods Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. Results We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo. Conclusions Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.

Background Recent studies have established that Medicinal Marijuana (MM) is beneficial in the treatment of spasms, sleep, and pain in adult patients with varying medical diagnoses and symptoms. However, MM has rarely been used for the treatment of Cerebral Palsy (CP) complications in adults. The aim of this systematic literature review was to explore MM interventions globally, with a focus on identifying the best practice with MM for the treatment of complications of CP. Methods A systematic literature search was performed using keywords and synonyms related to MM treatment and CP complications. Inclusions and exclusions were scoped to scholarly peer reviewed academic literature published 2019 to 2021 located in the Deakin Library collection. A screening process confirmed criteria adherence and identified additional papers in referencing. The papers were appraised and evaluated to ensure selections do not have perceived or actual bias. Results From 409 publications, 27 papers were selected for review because they investigated the benefits of MM treatment for patients with sleep, pain, and spasm complications. There was no literature found on the use of MM for adults with CP. Discussion Recent research has demonstrated that with an informed understanding of MM treatment adult patients with varying medical diagnoses and symptoms can use MM to manage sleep disruption and improve relaxation. Therefore, there are potential benefits for the use of MM in treating spasticity, pain, sleep, quality of life, and social and emotional wellbeing in adult patients with CP. No funding was sort or provided for this review and the results are specific to adults with CP, so they are not to be generalized to other populations.

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of [CD8.sup.+] T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation., Introduction The prognosis of glioblastoma patients is poor, with an approximate median overall survival of 21 months (1). Whereas radiation and chemotherapy are standard treatments at the time of diagnosis, [...]

Background Australia does not have a national strategy for Aboriginal and Torres Strait Islander adolescent health and as a result, policy and programming actions are fragmented and may not be responsive to needs. Efforts to date have also rarely engaged Aboriginal and Torres Strait Islander people in co-designing solutions. The Roadmap Project aims to work in partnership with young people to define priority areas of health and well-being need and establish the corresponding developmentally appropriate, evidence-based actions.Methods and analysis All aspects of this project are governed by a group of Aboriginal and Torres Strait Islander young people. Needs, determinants and corresponding responses will be explored with Aboriginal and Torres Strait Islander adolescents (aged 10–24 years) across Australia through an online qualitative survey, interviews and focus group discussions. Parents, service providers and policy makers (stakeholders) will share their perspectives on needs and support required through interviews. Data generated will be co-analysed with the governance group and integrated with population health data, policy frameworks and evidence of effective programmes (established through reviews) to define responsive and effective actions for Aboriginal and Torres Strait Islander adolescent health and well-being.Ethics and dissemination Ethical approval for this study has been obtained from the Aboriginal Health Council of South Australia (Ref: 04-21-956), the Aboriginal Health and Medical Research Council of New South Wales (Ref: 1918/22), the Western Australian Aboriginal Health Ethics Committee (Ref: HREC1147), the Northern Territory Health and Menzies School of Health Research (Ref: 2022–4371), ACT Health Human Research Ethics Committee (Ref: 2022.ETH.00133), the St. Vincent’s Hospital, Victoria (Ref: HREC 129/22), University of Tasmania (Ref: 28020), Far North Queensland Human Research Ethics Committee (Ref: HREC/2023/QCH/89911) and Griffith University (Ref: 2023/135). Prospective adolescent participants will provide their own consent for the online survey (aged 13–24 years) and, interviews or focus group discussions (aged 15–24 years); with parental consent and adolescent assent required for younger adolescents (aged 10–14 years) participating in interviews.Study findings (priority needs and evidence-based responses) will be presented at a series of co-design workshops with adolescents and stakeholders from relevant sectors. We will also communicate findings through reports, multimedia clips and peer-reviewed publications as directed by the governance group.

Today’s agriculture, food, and natural resources (AFNR) sectors face many wicked problems like climate change. Addressing these complex problems will require people to have both social and technical knowledge. However, having knowledge is insufficient. Individuals must be able to think about things as they occur in complex systems. Systems thinking has been proposed as a way of tackling complex problems. The purpose of this study was to determine if there is a continuum of systems thinking paradigms, beyond the hard systems thinking and soft systems thinking dichotomy proposed by Checkland. A novel research method called Q methodology was used, which included two steps: (a) the collection of data that forms the Q-sorts and (b) the by-person factor analysis of the Q-sorts. Overall, the findings from this study support the idea that systems thinking occurs on a continuum which includes (a) Hard systems thinking, (b) HARDsoft systems thinking, (c) SOFThard systems thinking and (d) Soft systems thinking. HARDsoft and SOFThard systems thinking were newly discovered in this research. The four systems thinking paradigms identified in this study better reflect the nuances and complexities that are associated with human thought and can provide a more specialized approach to solving complex issues.

Background: This retrospective analysis of an ongoing prospective cohort study aimed to assess the outcome of revascularisation for treating lifestyle-limiting intermittent claudication caused by peripheral artery disease (PAD) in Aboriginal and Torres Strait Islander Peoples and non-Indigenous North Queenslanders. Methods: Consenting patients with PAD who underwent endovascular or open revascularisation procedures for treating lifestyle-limiting intermittent claudication were included. The primary outcome measure was major adverse limb events (MALEs), defined as major amputation or the requirement for repeat open or endovascular revascularisation. Results: Of the 378 included patients, 18 (4.8%) identified as Aboriginal and/or Torres Strait Islander Peoples. During a mean follow-up (standard deviation) of 6.0 (3.9) years, the incidence of MALE was similar in the Aboriginal and Torres Strait Islander People and non-Indigenous Australians (absolute percentage: 50.0% vs. 40.6%, log rank p = 0.59). In both unadjusted and adjusted analyses, Aboriginal and Torres Strait Islander Peoples and non-Indigenous Australians had similar risks of MALE (unadjusted hazard ratio, HR, 1.20, 95% confidence interval, CI, 0.61, 2.36; adjusted HR 1.02, 95%CI 0.50, 2.06). Conclusions: This study suggests that Aboriginal and Torres Strait Islander People are under-represented in the population of patients undergoing revascularisation to treat intermittent claudication. Due to small numbers it cannot be reliably concluded that Aboriginal and Torres Strait Islander People and non-Indigenous Australians have similar rates of MALE.

IntroductionMinor amputation is commonly needed to treat diabetes-related foot disease (DFD). Remoteness of residence is known to limit access to healthcare and has previously been associated with poor outcomes. The primary aim of this study was to examine the associations between ethnicity and remoteness of residency with the risk of major amputation and death following initial treatment of DFD by minor amputation. A secondary aim was to identify risk factors for major amputation and death following minor amputation to treat DFD.Research design and methodsThis was a retrospective analysis of data from patients who required a minor amputation to treat DFD between 2000 and 2019 at a regional tertiary hospital in Queensland, Australia. Baseline characteristics were collected together with remoteness of residence and ethnicity. Remoteness was classified according to the 2019 Modified Monash Model (MMM) system. Ethnicity was based on self-identification as an Aboriginal and Torres Strait Islander or non-Indigenous person. The outcomes of major amputation, repeat minor amputation and death were examined using Cox-proportional hazard analyses.ResultsA total of 534 participants were included, with 306 (57.3%) residing in metropolitan or regional centres, 228 (42.7%) in rural and remote communities and 144 (27.0%) were Aboriginal or Torres Strait Islander people. During a median (inter quartile range) follow-up of 4.0 (2.1-7.6) years, 103 participants (19.3%) had major amputation, 230 (43.1%) had repeat minor amputation and 250 (46.8%) died. The risks (hazard ratio [95% CI]) of major amputation and death were not significantly higher in participants residing in rural and remote areas (0.97, 0.67-1.47; and 0.98, 0.76-1.26) or in Aboriginal or Torres Strait Islander people (HR 1.44, 95% CI 0.96, 2.16 and HR 0.89, 95% CI 0.67, 1.18). Ischemic heart disease (IHD), peripheral artery disease (PAD), osteomyelitis and foot ulceration (pConclusionMajor amputation and death are common following minor amputation to treat DFD and people with IHD, PAD and osteomyelitis have an increased risk of major amputation. Aboriginal and Torres Strait Islander People and residents of remote areas were not at excess risk of major amputation.

BackgroundMeningiomas are the most common tumor arising within the cranium of adults. Despite surgical resection and radiotherapy, many meningiomas invade the brain, and many recur, often repeatedly. To date, no chemotherapy has proven effective against such tumors. Thus, there is an urgent need for chemotherapeutic options for treating meningiomas, especially those that enhance radiotherapy. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 that has been shown to enhance radiotherapy in preclinical models of other cancers, is well-tolerated in patients, and is used to treat malignancies elsewhere in the body. We, therefore, sought to determine its therapeutic potential in preclinical models of meningioma.MethodsPatient-derived meningioma cells were tested in vitro and in vivo with combinations of palbociclib and radiation. Outputs included cell viability, apoptosis, clonogenicity, engrafted mouse survival, and analysis of engrafted tumor tissues after therapy.ResultsWe found that palbociclib was highly potent against p16-deficient, Rb-intact CH157 and IOMM-Lee meningioma cells in vitro, but was ineffective against p16-intact, Rb-deficient SF8295 meningioma cells. Palbociclib also enhanced the in vitro efficacy of radiotherapy when used against p16-deficient meningioma, as indicated by cell viability and clonogenic assays. In vivo, the combination of palbociclib and radiation extended the survival of mice bearing orthotopic p16 deficient meningioma xenografts, relative to each as a monotherapy.ConclusionsThese data suggest that palbociclib could be repurposed to treat patients with p16-deficient, Rb-intact meningiomas, and that a clinical trial in combination with radiation therapy merits consideration.

Introduction: Globally, primary care organisations responded rapidly to COVID-19 physical distancing requirements through the adoption of telehealth to maintain the delivery of health care to communities. In Australia, temporary Medicare Benefits Schedule (MBS) telehealth items were introduced in March 2020 to enable the provision of telehealth services in the primary care setting. These changes included funding for two modes of telehealth delivery: videoconferencing and telephone consultations. As primary care organisations, Aboriginal Community Controlled Health Organisations (ACCHOs) rapidly adopted telehealth consultations to maintain the delivery of primary care services to Aboriginal and Torres Strait Islander clients. The aim of the present study was to evaluate the implementation (specifically the uptake, acceptability and requirements for delivery) of telehealth primary healthcare services for Aboriginal and/or Torres Strait Islander peoples by a rural ACCHO during COVID-19. Methods: A single-site convergent-parallel mixed-methods study was undertaken in the context of an ongoing research partnership established between a rural ACCHO and a university department of rural health. De-identified health service data from March 2020 to March 2021 was extracted, including MBS telehealth consultations and client demographics (eg age, gender and postcode). Variables were analysed using descriptive statistics to examine the uptake of telehealth by Aboriginal and Torres Strait Islander clients. A geographical analysis of postcode data was also undertaken. Semi-structured interviews were undertaken concurrently with a purposive sample of health service personnel (including health professionals) involved in the implementation or delivery of telehealth, and Aboriginal and/or Torres Strait Islander clients who had accessed telehealth, to explore the acceptability of telehealth and requirements for delivery. Thematic analysis using an inductive approach was undertaken. The analyses of quantitative and qualitative findings were merged to identify key concepts pertaining to the uptake, acceptability and requirements for telehealth delivery. Results: During the first year of implementation, 435 telehealth primary healthcare consultations were delivered to Aboriginal and/or Torres Strait Islander clients. Seven health personnel and six Aboriginal and/or Torres Strait Islander clients participated in interviews. Merged findings from an analysis of quantitative and qualitative data were grouped under three concepts: uptake of telehealth consultations by Aboriginal and Torres Strait Islander clients, maintaining the delivery of ACCHO services during COVID-19, and implications for sustaining telehealth in an ACCHO. Findings identified that telehealth maintained the delivery of ACCHO services to Aboriginal and/or Torres Strait Islander clients across the lifespan during COVID-19, despite a preference for face-to-face consultations. A greater uptake of telephone consultations compared to videoconferencing was identified. Barriers to the utilisation of videoconferencing were largely technology related, highlighting the need for additional support for clients. Conclusion: Telehealth was a useful addition to face-to-face consultations when used in the appropriate context such as the administration of long-term medication prescriptions by a GP. Engaging the ACCHO sector in the policy discourse around telehealth is imperative for identifying requirements for ongoing implementation.

BackgroundRohingya refugees in Bangladesh are vulnerable to infectious diseases such as COVID-19 due to the crowded living conditions with fragile shelters, and limited water, sanitation and hygiene facilities and practices. While risk communication and community engagement (RCCE) is the cornerstone of outbreak control, there is limited evidence available on the effectiveness of the RCCE strategies in this setting.ObjectivesThe goal of this study is to evaluate the effectiveness of RCCE strategies and to explore the challenges and community recommendations in relation to COVID-19 preventive measures in the context of Rohingya refugee camps in Bangladesh.Materials and methodsIt was a qualitative study. Methods used were (a) observation of RCCE intervention by 3 clinical supervisors accompanying 25 Community Health Workers (CHWs) and (b) 5 focus group discussions engaging 60 community representatives. Data were analyzed using a thematic analysis approach, separately for observation and focus group discussions.ResultsThe study identified a number of good practices of RCCE, including selecting CHWs from the local community, engaging female CHWs, using local dialect, and collaborating with community/religious leaders. Certain good practices need scaling up, such as utilization of multiple communication methods and interpersonal communication skills. Some areas need improvement, such as CHWs being overburdened with multiple tasks, less effort to active listening, repeated delivery of same messages, inadequate linkage to culture, context, and resources, and less effort to empower the community. Engaging the community, five critical themes were identified in relation to poor COVID-19 preventive practices: culture, religion, and language; local context and resources; community trust and interaction with aid workers; communication methods; and gender and social inclusion. Religious misinterpretation, cultural barriers, physical barriers, lack of resources, breach of trust between the community and aid workers, inconsistent/complex messages, lack of gender and social inclusion, and stigmatization are among some key factors. Some key actions were recommended to improve COVID-19 RCCE strategy.ConclusionWe urge the RCCE partners to make use of the findings and recommendations to develop a robust RCCE strategy relevant to local culture and context, responsive to people’s concerns and needs, and inclusive of gender, age and social vulnerabilities.

BackgroundSublethal exposure to neonicotinoids, a popular class of agricultural pesticides, can lead to behavioral effects that impact the health of pollinators. Therefore, new compounds, such as flupyradifurone (FPF), have recently been developed as 'safer' alternatives. FPF is an excitotoxic nicotinic acetylcholine receptor agonist, similar to neonicotinoids. Given the novelty of FPF, what data exist are focused mostly on assessing the effect of FPF on pollinator mortality. One important avenue for investigation is the potential effect of FPF on the sensitivity of nectar foragers, such as Apis mellifera, to sucrose concentrations. Neonicotinoids can alter this sucrose responsiveness and disrupt foraging. Compounding this effect, neonicotinoid-containing solutions are preferred by A. mellifera over pure sucrose solutions. We therefore conducted four studies, administering FPF under both acute and chronic conditions, and at field-realistic and higher than field-realistic doses, to assess the influence of FPF exposure on sucrose responsiveness and sucrose solutions with FPF in A. mellifera nectar foragers.ResultsWe found no evidence that FPF exposure under acute or chronic field-realistic conditions significantly altered sucrose responsiveness, and we did not find that bees exposed to FPF consumed more of the solution. However, at the much higher median lethal dose (48 h), among bees that survived, FPF-exposed foragers responded to significantly lower concentrations of sucrose than controls and responded at significantly higher rates to all concentrations of sucrose than controls.ConclusionWe found no evidence that FPF alters the sucrose responsiveness of nectar foragers at field-realistic doses during winter or early spring, but caution and further investigation are warranted, particularly on the effects of FPF in conjunction with other stressors. © 2019 Society of Chemical Industry.

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas.

Socially responsible leadership (SRL) is a "purposeful, collaborative, values-based process that results in positive social change" (Komives, Wagner, & Associates, 2009, p. xii).This approach to leadership focuses on creating leaders that are capable of tackling the predicted wicked problems the world will face in the next few decades. As the number of leadership education programs continue to grow throughout higher education, it is important to assess the impact leadership education and co-curricular programs are having on students. Utilizing the Multi-Institutional Study of Leadership, this study aimed to better understand whether higher education leadership development, community service and study abroad programs are successfully developing students with self-perceived socially responsible leadership.

Incorrect inhaler technique and non-adherence to inhaled preventer therapy often is the cause of poorly controlled asthma. Detecting and correcting non-adherence in asthma therapy has proven difficult. In addition, while patients may be able to demonstrate correct inhaler technique at the clinic recent evidence suggests that critical errors in inhaler technique occur in the home setting. Remote video directly observed therapy (vDOT) has recently been described as a potentially useful tool for addressing non-adherence while also allowing timely correction of inhaler technique errors. In this mini-review we describe the use of vDOT in asthma management.

An amendment to this paper has been published and can be accessed via the original article.