Australian Research Council Research Articles

Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants

Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

All-cause, cardiovascular, and respiratory mortality and wildfire-related ozone: a multicountry two-stage time series analysis

Wildfire activity is an important source of tropospheric ozone (O3) pollution. However, no study to date has systematically examined the associations of wildfire-related O3 exposure with mortality globally. We did a multicountry two-stage time series analysis. From the Multi-City Multi-Country (MCC) Collaborative Research Network, data on daily all-cause, cardiovascular, and respiratory deaths were obtained from 749 locations in 43 countries or areas, representing overlapping periods from Jan 1, 2000, to Dec 31, 2016. We estimated the daily concentration of wildfire-related O3 in study locations using a chemical transport model, and then calibrated and downscaled O3 estimates to a resolution of 0·25° × 0·25° (approximately 28 km2 at the equator). Using a random-effects meta-analysis, we examined the associations of short-term wildfire-related O3 exposure (lag period of 0-2 days) with daily mortality, first at the location level and then pooled at the country, regional, and global levels. Annual excess mortality fraction in each location attributable to wildfire-related O3 was calculated with pooled effect estimates and used to obtain excess mortality fractions at country, regional, and global levels. Between 2000 and 2016, the highest maximum daily wildfire-related O3 concentrations (≥30 μg/m3) were observed in locations in South America, central America, and southeastern Asia, and the country of South Africa. Across all locations, an increase of 1 μg/m3 in the mean daily concentration of wildfire-related O3 during lag 0-2 days was associated with increases of 0·55% (95% CI 0·29 to 0·80) in daily all-cause mortality, 0·44% (-0·10 to 0·99) in daily cardiovascular mortality, and 0·82% (0·18 to 1·47) in daily respiratory mortality. The associations of daily mortality rates with wildfire-related O3 exposure showed substantial geographical heterogeneity at the country and regional levels. Across all locations, estimated annual excess mortality fractions of 0·58% (95% CI 0·31 to 0·85; 31 606 deaths [95% CI 17 038 to 46 027]) for all-cause mortality, 0·41% (-0·10 to 0·91; 5249 [-1244 to 11 620]) for cardiovascular mortality, and 0·86% (0·18 to 1·51; 4657 [999 to 8206]) for respiratory mortality were attributable to short-term exposure to wildfire-related O3. In this study, we observed an increase in all-cause and respiratory mortality associated with short-term wildfire-related O3 exposure. Effective risk and smoke management strategies should be implemented to protect the public from the impacts of wildfires. Australian Research Council and the Australian National Health and Medical Research Council.

Interview with Journal of Cell Science Editor Rob Parton

ABSTRACT Rob Parton is a Group Leader and Australian Research Council Laureate Fellow in the Institute for Molecular Bioscience and Deputy Director of the Centre for Microscopy and Microanalysis at the University of Queensland in Brisbane, Australia. He completed his doctorate at the University of Leicester in the UK. After using electron microscopy (EM) during his PhD to study trafficking of tetanus toxin in neurons, he was inspired to continue using advanced microscopy approaches to further our understanding of the fundamental cellular process of membrane trafficking. After several years fostering international collaborations as a postdoctoral fellow and junior Group Leader at the European Molecular Biology Laboratory in Heidelberg, Germany, his lab moved to the University of Queensland in 1996. In 2023, he was elected an Associate Member of the European Molecular Biology Organization (EMBO). Rob joined Journal of Cell Science as an Editor in March 2024 and brings to the journal his expertise in multiscale analysis of membrane function, membrane microdomains, lipid droplets and advanced microscopy techniques in cell biology. We spoke to Rob over Zoom to hear more about his career journey, the evolution of the membrane trafficking field and his advice for running a highly collaborative lab.

Current and future burden of Ross River virus infection attributable to increasing temperature in Australia: a population-based study

Ross River virus (RRV), Australia's most notifiable vector-borne disease transmitted through mosquito bites, has seen increased transmission due to rising temperatures. Quantifying the burden of RRV infection attributable to increasing temperatures (both current and future) is pivotal to inform prevention strategies in the context of climate change. As RRV-related deaths are rare in Australia, we utilised years lived with disability (YLDs) associated with RRV infection data from the Australian Institute of Health and Welfare (AIHW) Burden of Disease database between 2003 and 2018. We obtained relative risks per 1°C temperature increase in RRV infection from a previous meta-analysis. Exposure distributions for each Köppen-Geiger climate zone were calculated separately and compared with the theoretical-minimum-risk exposure distribution to calculate RRV burden attributable to increasing temperatures during the baseline period (2003-2018), and projected future burdens for the 2030s and 2050s under two greenhouse gas emission scenarios (Representative Concentration Pathways, RCP 4.5 and RCP 8.5), two adaptation scenarios, and different population growth series. During the baseline period (2003-2018), increasing mean temperatures contributed to 35.8 (±0.5) YLDs (19.1%) of the observed RRV burden in Australia. The mean temperature attributable RRV burden varied across climate zones and jurisdictions. Under both RCP scenarios, the projected RRV burden is estimated to increase in the future despite adaptation scenarios. By the 2050s, without adaptation, the RRV burden could reach 45.8 YLDs under RCP4.5 and 51.1 YLDs under RCP8.5. Implementing a 10% adaptation strategy could reduce RRV burden to 41.8 and 46.4 YLDs, respectively. These findings provide scientific evidence for informing policy decisions and guiding resource allocation for mitigating the future RRV burden. The current findings underscore the need to develop location-specific adaptation strategies for climate-sensitive disease control and prevention. Australian Research Council Discovery Program.

The carbon footprint of health care delivery in Western Australia's public health system

Health systems have a dual imperative to take action on climate change. First, they must develop climate resilient health services in response to the direct and indirect impacts of climate change on health. Second, they must reduce their own carbon footprint since health systems are a significant contributor to global greenhouse gas emissions. An environmentally-extended multi-region input-output analysis was carried out, incorporating National Accounts data for Australia and annual expenditure data from WA Health for financial year 2019-20. Expenditure data were categorised to one of 344 economic sectors and by location of the provider of goods or services purchased. WA Health contributes 8% of WA's total carbon footprint, driven by expenditure on chemicals (23.8% of total), transport (20.2% of total), and electricity supply (19.7% of total). These 3 sectors represent 63.7% of WA Health's carbon footprint, but only 10.8% of its total expenditure. Reducing emissions related to health service provision in WA will require a holistic approach that leverages carbon footprinting insights and integrates them into organisational decision-making across all health programs. The high carbon-intensity of the transport and chemicals sectors supports previous research calling for a reduction in unnecessary pathology testing and the transition to delivery of non-urgent health care via sustainable models of telehealth. The impact of WA's size and location presents challenges, with a predominantly non-renewable energy supply and reliance on transport and supply chains from other states adding significantly to emissions. The study received funding from the Australian Research Council, The University of Sydney, and the WA Department of Health. The full list of funding information can be found in Acknowledgements.

A Patient-Level Meta-Analysis of Intensive Glucose Control in Critically Ill Adults

BackgroundWhether intensive glucose control reduces mortality in critically ill patients remains uncertain. Patient-level meta-analyses can provide more precise estimates of treatment effects than are currently available.MethodsWe pooled individual patient data from randomized trials investigating intensive glucose control in critically ill adults. The primary outcome was in-hospital mortality. Secondary outcomes included survival to 90 days and time to live cessation of treatment with vasopressors or inotropes, mechanical ventilation, and newly commenced renal replacement. Severe hypoglycemia was a safety outcome.ResultsOf 38 eligible trials (n=29,537 participants), 20 (n=14,171 participants) provided individual patient data including in-hospital mortality status for 7059 and 7049 participants allocated to intensive and conventional glucose control, respectively. Of these 1930 (27.3%) and 1891 (26.8%) individuals assigned to intensive and conventional control, respectively, died (risk ratio, 1.02; 95% confidence interval [CI], 0.96 to 1.07; P=0.52; moderate certainty). There was no apparent heterogeneity of treatment effect on in-hospital mortality in any examined subgroups. Intensive glucose control increased the risk of severe hypoglycemia (risk ratio, 3.38; 95% CI, 2.99 to 3.83; P<0.0001).ConclusionsIntensive glucose control was not associated with reduced mortality risk but increased the risk of severe hypoglycemia. We did not identify a subgroup of patients in whom intensive glucose control was beneficial. (Funded by the Australian National Health and Medical Research Council and others; PROSPERO number CRD42021278869.)

Characterising HIV-1 transmission in Victoria, Australia: a molecular epidemiological study

In Australia the incidence of HIV has declined steadily, yet sustained reduction of HIV transmission in this setting requires improved public health responses. As enhanced public health responses and prioritisation of resources may be guided by molecular epidemiological data, here we aimed to assess the applicability of these approaches in Victoria, Australia. A comprehensive collection of HIV-1 pol sequences from individuals diagnosed with HIV in Victoria, Australia, between January 1st 2000 and December 31st 2020 were deidentified and used as the basis of our assessment. These sequences were subtyped and surveillance drug resistance mutations (SDRMs) identified, before definition of transmission groups was performed using HIV-TRACE (0.4.4). Phylodynamic methods were applied using BEAST (2.6.6), assessing effective reproductive numbers for large groups, and additional demographic data were integrated to provide a high resolution view of HIV transmission in Victoria on a decadal time scale. Based on standard settings for HIV-TRACE, 70% (2438/3507) of analysed HIV-1 pol sequences were readily assigned to a transmission group. Individuals in transmission groups were more commonly males (aOR 1.50), those born in Australia (aOR 2.13), those with probable place of acquisition as Victoria (aOR 6.73), and/or those reporting injectable drug use (aOR 2.13). SDRMs were identified in 375 patients (10.7%), with sustained transmission of these limited to a subset of smaller groups. Informative patterns of epidemic growth, stabilisation, and decline were observed; many transmission groups showed effective reproductive numbers (R e ) values reaching greater than 4.0, representing considerable epidemic growth, while others maintained low R e values. This study provides a high resolution view of HIV transmission in Victoria, Australia, and highlights the potential of molecular epidemiology to guide and enhance public health responses in this setting. This informs ongoing discussions with community groups on the acceptability and place of molecular epidemiological approaches in Australia. National Health and Medical Research Council, Australian Research Council.

New angles and long walks: building regional networks through union education

PurposeThis article examines the role the Australian Trade Union Training Authority (TUTA) played in international education through the provision of trade union courses and exchanges. We consider how an investigation of trade union networks contributes to a richer understanding of international education linkages.Design/methodology/approachThis paper is based on research conducted for an Australian Research Council (ARC)-funded project: Trade union training: reshaping the Australian industrial landscape (ARC LP180100500). This research involved a critical analysis of 60 semi-structured oral history interviews and textual archives, including the official records held by the National Archives of Australia and papers held by the Noel Butlin Archives, the Australian Council of Trade Unions and in private collections.FindingsTUTA was established primarily as a national union training organisation, but from its inception, it also acted as a hub for the development of regional and international labour networks. The nature of TUTA’s work placed it at the intersection of international trade union and educational domains. Although there were some points of contact with formal international programs (e.g. Japan–Australia and Kellogg Foundations, the Colombo Plan and US Department of Labour exchanges schemes), the specific contribution of TUTA is overlooked in the educational exchange literature. The role of TUTA is revealed through institutional connections and individual experiences.Research limitations/implicationsFurther research is required to gain a deeper understanding of the impact of TUTA from the perspective of former participants in international TUTA course and current and former trade unionists in the Asia–Pacific.Originality/valueThis article builds new knowledge by examining the connections forged in the Asia–Pacific region at the intersection of trade union and educational networks, an area often overlooked in the literature on educational exchange.

Reimagining unbound road pavement technology: Integrating testing, design, construction and performance in the post-digital era

The Industry 4.0 revolution signifies a pivotal transition in pavement technology, emphasising the integration of digital and physical systems to revamp traditional, empirical-based pavement design, construction, and maintenance practices. This shift promises enhanced efficiency, sustainability, and a move towards integrated practices, highlighted by adopting “Digital Twin” technology. Unlike traditional Building Information Modeling (BIM), Digital Twin technology offers a real-time, dynamic representation of physical infrastructure, enabling improved asset management through distributed sensing and predictive performance analytics. Leveraging findings from the Australian Research Council (ARC)’s Industry Transformation Research Hub for Smart Next Generation Transport Pavements (SPARC Hub), this paper focuses on the integration of pavement testing, design, construction, condition assessment and asset management into the lifecycle of unbound road pavements. The paper outlines how such technological integration streamlines decision-making processes and significantly boosts the functionality and longevity of pavement infrastructures. Despite facing challenges like cost, data security, and the need for specialised skills, the potential for digital technologies to improve pavement durability, efficiency, and sustainability is significant. Future research directions are identified to overcome implementation barriers, explore untapped technological potentials, and assess the sustainability benefits of digital approaches in pavement engineering, aiming to forge more resilient, efficient, and sustainable road networks for future generations.

Restarting pre-exposure prophylaxis (PrEP) for HIV: a systematic review and meta-analysis

High coverage of pre-exposure prophylaxis (PrEP) will reduce HIV transmission and help end the HIV/AIDS pandemic. However, PrEP users face challenges, including long-term adherence. The study aimed to document the proportions of individuals who restart HIV PrEP after they stop and the reasons for restarting PrEP. This study is a systematic review and meta-analysis. We systematically searched CINAHL, Embase, Emcare, Global Health, Medline, Scopus, and PsychINFO for peer-reviewed with no date restrictions. A grey literature search was conducted through Google search, a search of abstract books of AIDS conferences and the websites of WHO and UNAIDS. The data search was conducted in April 2023 and updated in February 2024. Two authors extracted data on the proportion of people who stopped and then restarted PrEP, reasons for restarting, and strategies to support people restarting PrEP. Two authors appraised the data using the Joanna Briggs Institute Appraisal Tools. We used a random-effects meta-analysis to pool estimates of restarting. We conducted meta-regression to determine potential sources of heterogeneity. This study is registered with PROSPERO, CRD42023416777. However, we deviated from our original plan as we did not identify enough studies for strategies to support restarting PrEP (primary objective). Subsequently, we revised our plan to strengthen our secondary objective to quantify the proportion of people who stopped and restarted PrEP, and explore possible reasons for its heterogeneity. Of 988 studies, 30 unique studieswere included: 27 reported the proportion restarting PrEP, and of these, 7 also reported reasons for restarting PrEP, and 3 studies reported only on the reasons for restarting PrEP. No study evaluated interventions for restarting PrEP. For the meta-analysis, we included 27 studies. Most studies were from high-income countries (17/27, 63%) or the USA (15/27, 56%). Overall, 23.8% (95% CI: 15.9-32.7, I2=99.8%, N=85,683) of people who stopped PrEP restarted PrEP. There was a lower proportion of restarting in studies from middle-income countries compared to high-income countries (adjusted odds ratio (aOR) 0.6, 95% CI: 0.50-0.73, p<0.001). There was higher restarting in studies from Africa compared to the USA (aOR 1.55, 95% CI: 1.30-1.86), heterosexual populations compared to men who have sex with men or transgender women (aOR 1.50, 95% CI: 1.25-1.81, p<0.001) and in studies defining restarting as those who had stopped PrEP for >1 month compared to those who stopped <1 month (aOR 1.20, 95% CI: 1.06-1.36, p<0.001). Reasons for restarting PrEP included perceived higher risk for HIV acquisition and removal of barriers to access PrEP. In terms of quality assessment, overall, both randomised controlled trials had a low risk of bias, while the observational studies used in the meta-analysis had some potential risk of bias related to not explicitly addressing potential confounders (15/25, 60%) or not describing strategies to address incomplete follow-up (24/25, 96%). About a quarter of people who stopped PrEP would restart, with substantial variation across countries and populations. It is important to understand the motivations and contextual factors influencing restarting PrEP and the support systems to enable restarting PrEP for those at ongoing risk. Australian National Health and Medical Research Council.

Targeting Cardiomyocytes with Adeno Associated Viruses to Protect Hearts from Trastuzumab-induced Cardiotoxicity

Amplification of HER2 occurs in 20% of breast cancers. HER2 (known as ErbB2 in mouse) belongs to the Epidermal Growth Factor Receptor (EGFR) family that is responsible for cell growth and survival. While HER2 does not bind ligands, it forms heterodimers with HER1 (also known as EGFR) in the presence of its ligand EGF, and HER4 following stimulation with Neuregulin. In HER2-positive breast cancer where HER2 expression is high, HER2 homodimerizes leading to excessive activation of downstream signalling and cell proliferation. Current HER2-positive breast cancer treatment involves chemotherapy with drugs called anthracyclines, such as Doxorubicin, and an antibody targeting HER2 called Trastuzumab. This combination is effective in killing HER2-positive breast tumours, however, Trastuzumab alone or in combination with anthracyclines leads to severe cardiotoxicity and heart failure in 2.6-11% of cases, making it a dose-limiting side effect. We hypothesise that cardiac toxicity can be mitigated by targeting cardiomyocytes exclusively to express a mutated (but functional) version of HER2 that is not recognised by trastuzumab. We designed 3 HER2 variants wherein the trastuzumab binding domain was mutated to disrupt binding. These HER2 mutants were transfected into HEK293T cells, and we confirmed that all 3 successfully localised to the cell membrane, and did not bind trastuzumab. We have used bioluminescence resonance energy transfer to examine the capacity of all 3 mutants to activate recruitment of Grb2 to the HER2 as part of HER1/HER2 and HER4/HER2 heterodimers; Western blotting also confirming mutants were capable of stimulating ERK and Akt phosphorylation. Future studies will evaluate the effcacy of using AAVs to instruct cardiomyocytes to express these HER2 mutants in a murine model of breast cancer. We predict that this new therapy would not only mitigate cardiac toxicity, but would also permit higher doses of trastuzumab to be used to treat breast cancer. This work is supported by Australia's National Health and Medical Research Council and the Australian Research Council. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Democracy in Divided Societies: Electoral Engineering for Conflict Management “Chapter 3 Centripetal Incentives and Political Engineering in Australia”

Benjamin Reilly is a professor of political science and international relations at the University of Western Australia. Benjamin previously served as dean of the Sir Walter Murdoch School and was director of the Centre for democratic institutions at the Australian National University (ANU). Benjamin is also an expert in the Australian government, the United Nations, and other international organizations. As a professor of political science, Benjamin was invited to various scientific forums to speak at well-known campuses, such as Harvard, Oxford, and Johns Hopkins. Publicizing scientific papers and books earned Benjamin numerous international grants from the Carnegie Corporation of New York, the United StatesInstitute of Peace, the East-West Center, the National Endowment for Democracy, and the Australian Research Council. Benjamin’s ideas and thoughts were widely published in various international and national newspapers, including the New York Times, Financial Times, Wall Street Journal, Washington Post, and Time Magazine.

Effectiveness of a universal, school-based, online programme for the prevention of anxiety, depression, and substance misuse among adolescents in Australia: 72-month outcomes from a cluster-randomised controlled trial

The CSC study found that the universal delivery of a school-based, online programme for the prevention of mental health and substance use disorders among adolescents resulted in improvements in mental health and substance use outcomes at 30-month follow-up. We aimed to compare the long-term effects of four interventions-Climate Schools Combined (CSC) mental health and substance use, Climate Schools Substance Use (CSSU) alone, Climate Schools Mental Health (CSMH) alone, and standard health education-on mental health and substance use outcomes among adolescents at 72-month follow-up into early adulthood. This long-term study followed up adolescents from a multicentre, cluster-randomised trial conducted across three states in Australia (New South Wales, Queensland, and Western Australia) enrolled between Sept 1, 2013, and Feb 28, 2014, for up to 72 months after baseline assessment. Adolescents (aged 18-20 years) from the original CSC study who accepted contact at 30-month follow-up and provided informed consent at 60-month follow-up were eligible. The interventions were delivered in school classrooms through an online delivery format and used a mixture of peer cartoon storyboards and classroom activities that were focused on alcohol, cannabis, anxiety, and depression. Participants took part in two web-based assessments at 60-month and 72-month follow-up. Primary outcomes were alcohol use, cannabis use, anxiety, and depression, measured by self-reported surveys and analysed by intention to treat (ie, in all students who were eligible at baseline). This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12613000723785), including the extended follow-up study. Of 6386 students enrolled from 71 schools, 1556 (24·4%) were randomly assigned to education as usual, 1739 (27·2%) to CSSU, 1594 (25·0%) to CSMH, and 1497 (23·4%) to CSC. 311 (22·2%) of 1401 participants in the control group, 394 (26·4%) of 1495 in the CSSU group, 477 (37·%) of 1289 in the CSMH group, and 400 (32·5%) of 1232 in the CSC group completed follow-up at 72 months. Adolescents in the CSC group reported slower year-by-year increases in weekly alcohol use (odds ratio 0·78 [95% CI 0·66-0·92]; p=0·0028) and heavy episodic drinking (0·69 [0·58-0·81]; p<0·0001) than did the control group. However, significant baseline differences between groups for drinking outcomes, and no difference in the predicted probability of weekly or heavy episodic drinking between groups were observed at 72 months. Sensitivity analyses increased uncertainty around estimates. No significant long-term differences were observed in relation to alcohol use disorder, cannabis use, cannabis use disorder, anxiety, or depression. No adverse events were reported during the trial. We found some evidence that a universal online programme for the prevention of anxiety, depression, and substance use delivered in early adolescence is effective in reducing the use and harmful use of alcohol into early adulthood. However, confidence in these findings is reduced due to baseline differences, and we did not see a difference in the predicted probability of drinking between groups at 72-month follow-up. These findings suggest that a universal prevention programme in adolescence is not sufficient to have lasting effects on mental health and substance use disorders in the long term. In addition to baseline differences, substantial attrition warrants caution in interpretation and the latter factor highlights the need for future long-term follow-up studies to invest in strategies to increase engagement. Australian National Health and Medical Research Council.

Factors associated with HIV pre-exposure prophylaxis use among Asian men who have sex with men in Sydney and Melbourne, Australia: a cross-sectional study

Asian-born MSM are a priority population as Australia aims to end HIV transmission, but they reported additional barriers to access PrEP and other HIV prevention methods. This study investigates factors associated with PrEP use among Asian MSM in Sydney and Melbourne, Australia, to inform strategies to improve PrEP uptake in this population. This was a sub-analysis of a community-based cross-sectional survey conducted from March to June 2021. We recruited participants online in Sydney and Melbourne, Australia. Univariable and multivariable logistic regression analyses were performed to identify the factors associated with PrEP use in the last six months and lifetime. Latent class analyses were used to identify subgroups of Asian MSM sharing similar characteristics related to their risk practices for HIV. Overall, 870 Asian MSM were included: 288 Oceanian-born Asian MSM and 582 Asian-born MSM. Three latent classes were identified: 1) Asian-born MSM who recently arrived in Australia with limited English, were less likely to use PrEP and at higher risk of HIV infection (e.g., had condomless anal sex with a casual sex partner in the last six months) (4.6%); 2) Asian MSM who were at lower risk of HIV infection and less likely to use PrEP (69.3%) and; 3) Asian MSM who were at substantial risk of HIV infection and more likely to use PrEP (26.1%). Compared to Oceanian-born Asian MSM, those who were born in Southeast Asia (adjusted odds ratio (aOR)=0.5, 95% confidence interval (CI) 0.3-0.7) and South Asia (aOR=0.4, 95% CI 0.2-0.8) were less likely to ever use PrEP. Compared to Oceanian-born Asian MSM, those who were born in Southeast Asia (aOR=0.4, 95% CI 0.3-0.7), Northeast Asia (aOR=0.5, 95% CI 0.3-0.8) and South Asia (aOR=0.4, 95% CI 0.2-0.7) were less likely to use PrEP in the last six months. To end HIV transmission in Australia, it will be necessary to develop strategies to improve PrEP access for the significant minority of Asian-born MSM who are at substantial risk of HIV infection. EPFC and JJO are supported by an Australian National Health and Medical Research Council (NHMRC) Emerging Leadership Investigator Grant (EPFC: GNT1172873 and JJO: GNT1193955). CKF is supported by an Australian National Health and Medical Research Council (NHMRC) Leadership Investigator Grant (GNT1172900).

Viral clearance as a surrogate of clinical efficacy for COVID-19 therapies in outpatients: a systematic review and meta-analysis

Surrogates of antiviral efficacy are needed for COVID-19. We aimed to investigate the relationship between the virological effect of treatment and clinical efficacy as measured by progression to severe disease in outpatients treated for mild-to-moderate COVID-19. In this systematic review and meta-analysis, we searched PubMed, Scopus, and medRxiv from database inception to Aug 16, 2023, for randomised placebo-controlled trials that tested virus-directed treatments (ie, any monoclonal antibodies, convalescent plasma, or antivirals) in non-hospitalised individuals with COVID-19. We only included studies that reported both clinical outcomes (ie, rate of disease progression to hospitalisation or death) and virological outcomes (ie, viral load within the first 7 days of treatment). We extracted summary data from eligible reports, with discrepancies resolved through discussion. We used an established meta-regression model with random effects to assess the association between clinical efficacy and virological treatment effect, and calculated I2 to quantify residual study heterogeneity. We identified 1718 unique studies, of which 22 (with a total of 16 684 participants) met the inclusion criteria, and were in primarily unvaccinated individuals. Risk of bias was assessed as low in 19 of 22 studies for clinical outcomes, whereas for virological outcomes, a high risk of bias was assessed in 11 studies, some risk in ten studies, and a low risk in one study. The unadjusted relative risk of disease progression for each extra log10 copies per mL reduction in viral load in treated compared with placebo groups was 0·12 (95% CI 0·04-0·34; p<0·0001) on day 3, 0·20(0·08-0·50; p=0·0006) on day 5, and 0·53 (0·30-0·94; p=0·030) on day 7. The residual heterogeneity in our meta-regression was estimated as low (I2=0% [0-53] on day 3, 0% [0-71] on day 5, and 0% [0-43] on day 7). Despite the aggregation of studies with differing designs, and evidence of risk of bias in some virological outcomes, this review provides evidence that treatment-induced acceleration of viral clearance within the first 5days after treatment is a potential surrogate of clinical efficacy to prevent hospitalisation with COVID-19. This work supports the use of viral clearance as an early phase clinical trial endpoint of therapeutic efficacy. Australian Government Department of Health, Medical Research Future Fund, and Australian National Health and Medical Research Council.

Designing for Communities with Communities: A Public Library Codesign Project

ABSTRACT Codesigning public library spaces is often limited to consulting with end-users rather than giving them a role as actual co-designers. This article advocates for more genuine codesign of public library spaces and critically examines the prevalent challenges in achieving true codesign in public library developments. The article introduces a two-year Australian Research Council Linkage research project, ‘Designing for Communities with Communities’. The project aims to provide public library staff with a set of codesign tools they can adapt for their own particular projects. Using comparative case studies, the project will also identify the challenges of integrating codesign into the development of public library spaces, and key factors in the effectiveness of projects that seek their communities’ inputs and engagement. This article introduces the theory of participatory and codesign, and sets out the basic conceptual framework for the project. It also reports on its initial stages, including preliminary interviews with key protagonists and preliminary user surveys about existing spaces. Moreover, the article discusses the design of the case studies’ community workshops, where most of the actual codesigning will take place, with an extensive discussion and analysis of the activities that could be included in these workshops.

How much is invested in obesity prevention in Australia? An analysis of major research and Federal Government funding, 2013–2022

How much is invested in obesity prevention in Australia? An analysis of major research and Federal Government funding, 2013–2022

Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis

Previous meta-analyses of summary data from randomised controlled trials have shown that statin therapy increases the risk of diabetes, but less is known about the size or timing of this effect, or who is at greatest risk. We aimed to address these gaps in knowledge through analysis of individual participant data from large, long-term, randomised, double-blind trials of statin therapy. We conducted a meta-analysis of individual participant data from randomised controlled trials of statin therapy that participated in the CTT Collaboration. All double-blind randomised controlled trials of statin therapy of at least 2 years' scheduled duration and with at least 1000 participants were eligible for inclusion in this meta-analysis. All recorded diabetes-related adverse events, treatments, and measures of glycaemia were sought from eligible trials. Meta-analyses assessed the effects of allocation to statin therapy on new-onset diabetes (defined by diabetes-related adverse events, use of new glucose-lowering medications, glucose concentrations, or HbA1c values) and on worsening glycaemia in people with diabetes (defined by complications of glucose control, increased use of glucose-lowering medication, or HbA1c increase of ≥0·5%). Standard inverse-variance-weighted meta-analyses of the effects on these outcomes were conducted according to a prespecified protocol. Of the trials participating in the CTT Collaboration, 19 trials compared statin versus placebo (123 940 participants, 25 701 [21%] with diabetes; median follow-up of 4·3 years), and four trials compared more versus less intensive statin therapy (30 724 participants, 5340 [17%] with diabetes, median follow-up of 4·9 years). Compared with placebo, allocation to low-intensity or moderate-intensity statin therapy resulted in a 10% proportional increase in new-onset diabetes (2420 of 39 179 participants assigned to receive a statin [1·3% per year] vs 2214 of 39 266 participants assigned to receive placebo [1·2% per year]; rate ratio [RR] 1·10, 95% CI 1·04-1·16), and allocation to high-intensity statin therapy resulted in a 36% proportional increase (1221 of 9935 participants assigned to receive a statin [4·8% per year] vs 905 of 9859 participants assigned to receive placebo [3·5% per year]; 1·36, 1·25-1·48). For each trial, the rate of new-onset diabetes among participants allocated to receive placebo depended mostly on the proportion of participants who had at least one follow-up HbA1c measurement; this proportion was much higher in the high-intensity than the low-intensity or moderate-intensity trials. Consequently, the main determinant of the magnitude of the absolute excesses in the two types of trial was the extent of HbA1c measurement rather than the proportional increase in risk associated with statin therapy. In participants without baseline diabetes, mean glucose increased by 0·04 mmol/L with both low-intensity or moderate-intensity (95% CI 0·03-0·05) and high-intensity statins (0·02-0·06), and mean HbA1c increased by 0·06% (0·00-0·12) with low-intensity or moderate-intensity statins and 0·08% (0·07-0·09) with high-intensity statins. Among those with a baseline measure of glycaemia, approximately 62% of new-onset diabetes cases were among participants who were already in the top quarter of the baseline distribution. The relative effects of statin therapy on new-onset diabetes were similar among different types of participants and over time. Among participants with baseline diabetes, the RRs for worsening glycaemia were 1·10 (1·06-1·14) for low-intensity or moderate-intensity statin therapy and 1·24 (1·06-1·44) for high-intensity statin therapy compared with placebo. Statins cause a moderate dose-dependent increase in new diagnoses of diabetes that is consistent with a small upwards shift in glycaemia, with the majority of new diagnoses of diabetes occurring in people with baseline glycaemic markers that are close to the diagnostic threshold for diabetes. Importantly, however, any theoretical adverse effects of statins on cardiovascular risk that might arise from these small increases in glycaemia (or, indeed, from any other mechanism) are already accounted for in the overall reduction in cardiovascular risk that is seen with statin therapy in these trials. These findings should further inform clinical guidelines regarding clinical management of people taking statin therapy. British Heart Foundation, UK Medical Research Council, and Australian National Health and Medical Research Council.

Positioning theory as a framework for understanding the facilitation of professional development for educational leaders

AbstractThe article addresses the problem of providing in-service education within government-led reform initiatives yet enhancing professionalism in the Early Childhood Education and Care sector. The study was conducted during policy-mandated reform in Australia to investigate effective ways to support educational leaders in centres rated as not meeting the national quality standard. Data were derived from a larger project designed as a formative intervention and funded by the Australian Research Council. In this article, we focus on the positioning of the educational leaders over the course of the intervention as they endeavoured to develop workplace practices. We found that the participants’ status as leaders of low-rated centres was featured in the way they positioned themselves initially. How the researchers responded has been highlighted in our analysis and, we argue, repositioning these participants as professionally capable and responsible was essential to the success of the intervention for them. This article contributes an original methodological approach to researching individual learning within the collective processes of workplace practice development and provides an understanding of the reform process from the perspective of ‘working-towards’ educational leaders.

Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study

Continued SARS-CoV-2 infection among immunocompromised individuals is likely to play a role in generating genomic diversity and the emergence of novel variants. Antiviral treatments such as molnupiravir are used to mitigate severe COVID-19 outcomes, but the extended effects of these drugs on viral evolution in patients with chronic infections remain uncertain. This study investigates how molnupiravir affects SARS-CoV-2 evolution in immunocompromised patients with prolonged infections. The study included five immunocompromised patients treated with molnupiravir and four patients not treated with molnupiravir (two immunocompromised and two non-immunocompromised). We selected patients who had been infected by similar SARS-CoV-2 variants and with high-quality genomes across timepoints to allow comparison between groups. Throat and nasopharyngeal samples were collected in patients up to 44 days post treatment and were sequenced using tiled amplicon sequencing followed by variant calling. The UShER pipeline and University of California Santa Cruz genome viewer provided insights into the global context of variants. Treated and untreated patients were compared, and mutation profiles were visualised to understand the impact of molnupiravir on viral evolution. Patients treated with molnupiravir showed a large increase in low-to-mid-frequency variants in as little as 10days after treatment, whereas no such change was observed in untreated patients. Some of these variants became fixed in the viral population, including non-synonymous mutations in the spike protein. The variants were distributed across the genome and included unique mutations not commonly found in global omicron genomes. Notably, G-to-A and C-to-T mutations dominated the mutational profile of treated patients, persisting up to 44 days post treatment. Molnupiravir treatment in immunocompromised patients led to the accumulation of a distinctive pattern of mutations beyond the recommended 5 days of treatment. Treated patients maintained persistent PCR positivity for the duration of monitoring, indicating clear potential for transmission and subsequent emergence of novel variants. Australian Research Council.