No improvement in AUDIT-C screening and brief intervention rates among wait-list controls following support of Aboriginal Community Controlled Health Services: evidence from a cluster randomised trial.

BACKGROUND: While Aboriginal and Torres Strait Islander Australians are less likely to drink any alcohol than other Australians, those who drink are more likely to experience adverse alcohol-related health consequences. In a previous study, providing Aboriginal Community Controlled Health Services (ACCHSs) with training and support increased the odds of clients receiving AUDIT-C alcohol screening. A follow-up study found that these results were maintained for at least two years, but there was large variability in the effectiveness of the intervention between services. In this study, we use services that previously received support as a comparison group to test whether training and support can improve alcohol screening and brief intervention rates among wait-list control ACCHSs. METHODS: Design: Cluster randomised trial using routinely collected health data. SETTING: Australia. CASES: Twenty-two ACCHSs that see at least 1000 clients a year and use Communicare as their practice management software. Intervention and comparator: After initiating support, we compare changes in screening and brief intervention between wait-list control services and services that had previously received support. MEASUREMENT: Records of AUDIT-C screening and brief intervention activity in routinely collected data. RESULTS: During the reference period we observed 357,257 instances where one of 74,568 clients attended services at least once during a two-monthly data extraction period. Following the start of support, the odds of screening (OR = 0.94 [95% CI 0.67, 1.32], p = 0.74, [Formula: see text]≈ 0.002) and brief intervention (OR = 1.43 [95% CI 0.69, 2.95], p = 0.34, [Formula: see text]≈ 0.002) did not improve for the wait-list control group, relative to comparison services. CONCLUSIONS: We did not replicate the finding that support and training improves AUDIT-C screening rates with wait-list control data. The benefits of support are likely context dependent. Coincidental policy changes may have sensitised services to the effects of support in the earlier phase of the study. Then the COVID-19 pandemic may have made services less open to change in this latest phase. Future efforts could include practice software prompts to alcohol screening and brief intervention, which are less reliant on individual staff time or resources. TRIAL REGISTRATION: Retrospectively registered on 2018-11-21: ACTRN12618001892202.

Research priorities on microplastics in marine and coastal environments: An Australian perspective to advance global action.

Plastic and microplastic contamination in the environment receive global attention, with calls for the synthesis of scientific evidence to inform actionable strategies and policy-relevant practices. We provide a systematic literature review on microplastic research across Australian coastal environments in water, sediment and biota, highlighting the main research foci and gaps in information. At the same time, we conducted surveys and workshops to gather expert opinions from multiple stakeholders (including researchers, industry, and government) to identify critical research directions to meet stakeholder needs across sectors. Through this consultation and engagement process, we created a platform for knowledge exchange and identified three major priorities to support evidence-based policy, regulation, and management. These include a need for (i) method harmonisation in microplastic assessments, (ii) information on the presence, sources, and pathways of plastic pollution, and (iii) advancing our understanding of the risk of harm to individuals and ecosystems.

Countering stereotypes: Exploring the characteristics of Aboriginal Australians who do not drink alcohol in a community representative sample.

INTRODUCTION: Contrary to stereotypes, Aboriginal and Torres Strait Islander Australians are more likely to abstain from drinking than other Australians. We explored characteristics and experiences of Aboriginal and Torres Strait Islander Australians who do not drink alcohol. METHOD: We conducted a cross-sectional, representative survey of 775 Aboriginal and Torres Strait Islander Australians (16+ years) in remote and urban South Australia. We explore correlates of not drinking alcohol using multi-level logistic regression. We describe reasons for non-drinking and harms participants experienced in past 12 months from others' drinking. RESULTS: Non-drinking participants were more likely to be older (OR 1.35 [95% CI 1.21, 1.50] per decade) and unemployed (OR 2.72 [95% CI 1.77, 4.20]). Participants who spoke Aboriginal Australian languages at home were three times more likely to be lifetime abstainers from drinking (OR 3.07 [95% CI 1.52, 6.21]). Common reasons for not drinking alcohol were health and family. Most did not report harms from others' alcohol consumption (79.6%, 76.9%, urban and remote respectively). Stress from others' alcohol consumption was the most reported harm by non-drinkers (14.5% and 23.1%, urban and remote, respectively). DISCUSSION AND CONCLUSIONS: Culture such as speaking Aboriginal Australian languages might have protective effects that promote abstaining but was rarely explicitly cited as a reason for not drinking. A greater understanding of local values held by people who do not drink alcohol could help inform health messaging and other interventions to reduce alcohol-related harms. Understanding local reasons for abstaining can help tailor health messaging to suit local contexts.

Excitoprotective effects of conditional tau reduction in excitatory neurons and in adulthood.

Tau reduction is a promising therapeutic strategy for Alzheimer's disease. In numerous models, tau reduction via genetic knockout is beneficial, at least in part due to protection against hyperexcitability and seizures, but the underlying mechanisms are unclear. Here we describe the generation and initial study of a new conditional Tau flox model to address these mechanisms. Given the protective effects of tau reduction against hyperexcitability, we compared the effects of selective tau reduction in excitatory or inhibitory neurons. Tau reduction in excitatory neurons mimicked the protective effects of global tau reduction, while tau reduction in inhibitory neurons had the opposite effect and increased seizure susceptibility. Since most prior studies used knockout mice lacking tau throughout development, we crossed Tau flox mice with inducible Cre mice and found beneficial effects of tau reduction in adulthood. Our findings support the effectiveness of tau reduction in adulthood and indicate that excitatory neurons may be a key site for its excitoprotective effects. SUMMARY: A new conditional tau knockout model was generated to study the protective effects of tau reduction against hyperexcitability. Conditional tau reduction in excitatory, but not inhibitory, neurons was excitoprotective, and induced tau reduction in adulthood was excitoprotective without adverse effects.

Prediabetes Increases the Risk of Frailty in Prefrail Older Adults With Hypertension: Beneficial Effects of Metformin.

BACKGROUND: Prediabetes has garnered increasing attention due to its association with cardiovascular conditions, especially hypertension, which heightens the risk of prefrailty and frailty among older individuals. METHODS: We screened elders with prefrail hypertension from March 2021 to January 2023. We assessed the correlation linking cognitive dysfunction (Montreal Cognitive Assessment score), insulin resistance (triglyceride-to-glucose index), and physical impairment (5-meter gait speed). Then, we measured the risk of developing frailty after a 1-year follow-up period, adjusting the outcome using multivariable Cox regression analysis. We also investigated the impact of administering 500 mg of metformin once daily to a subset of frail subjects for an additional 6 months. RESULTS: We assessed the relationship between the triglyceride-to-glucose index and the Montreal Cognitive Assessment score, observing a significant correlation (r, 0.880; P<0.0001). Similarly, we analyzed the association between the triglyceride-to-glucose index and 5-meter gait speed, uncovering a significant link between insulin resistance and physical impairment (r, 0.809; P<0.0001). Prediabetes was found to significantly (P<0.0001) elevate the risk of frailty development compared with individuals without prediabetes by the end of the 1-year follow-up, a finding confirmed via multivariable analysis with Cox regression. Furthermore, among the subgroup of subjects who developed frailty, those who received metformin exhibited a significant decrease in frailty levels (P<0.0001). CONCLUSIONS: Insulin resistance and prediabetes play substantial roles in the development of cognitive and physical impairments, highlighting their importance in managing hypertension, even before the onset of frank diabetes. Metformin, a well-established drug for the treatment of diabetes, has shown favorable effects in mitigating frailty.

Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications.

BACKGROUND: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. METHODS: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. FINDINGS: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). INTERPRETATION: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. FUNDING: Funding acknowledgements for each cohort can be found in the Supplementary Note.

Alcohol screening in 22 Australian Aboriginal Community Controlled Health Organisations: Clinical context and who is screened.

INTRODUCTION: Alcohol screening among Indigenous Australians is important to identify individuals needing support to reduce their drinking. Understanding clinical contexts in which clients are screened, and which clients are more or less likely to be screened, could help identify areas of services and communities that might benefit from increased screening. METHODS: We analysed routinely collected data from 22 Aboriginal Community Controlled Health Organisations Australia-wide. Data collected between February 2016 and February 2021 were analysed using R, and aggregated to describe screening activity per client, within 2-monthly extraction periods. Descriptive analyses were performed to identify contexts in which clients received an Alcohol Use Disorders Identification Test consumption (AUDIT-C) screen. Multi-level logistic regression determined demographic factors associated with receiving an AUDIT-C screen. Three models are presented to examine if screening was predicted by: (i) age; (ii) age and gender; (iii) age, gender and service remoteness. RESULTS: We observed 83,931 occasions where AUDIT-C was performed at least once during a 2-monthly extraction period. Most common contexts were adult health check (55.0%), followed by pre-consult examination (18.4%) and standalone item (9.9%). For every 10 years' increase in client age, odds of being screened with AUDIT-C slightly decreased (odds ratio 0.98; 95% confidence interval [CI] 0.98, 0.99). Women were less likely to be screened with AUDIT-C (odds ratio 0.95; 95% CI 0.93, 0.96) than men. DISCUSSION AND CONCLUSIONS: This study identified areas where alcohol screening can be increased (e.g., among women). Increasing AUDIT-C screening across entire communities could help reduce or prevent alcohol-related harms. Future Indigenous-led research could help identify strategies to increase screening rates.

Local and regional-scale effects of hedgerows on grassland- and forest-associated bird populations within agroecosystems.

Linear woody features (LWFs), like hedgerows along field edges, provide wildlife habitat and support biodiversity in agroecosystems. Assessments of LWFs usually focus on community-level indices, such as species richness. However, effective conservation actions need to balance the contrasting habitat preferences of different wildlife species, necessitating a focus on population-level effects in working landscapes. We assessed associations between LWFs and abundance for 45 bird species within an intensive agroecosystem in eastern Ontario, Canada. We used distance- and removal-sampling methods across 4 years (2016-2019) to estimate local bird abundance in habitats representing a range of LWF densities. We also predicted abundance across a subset of the study region with and without LWFs to understand their contribution to regional population density. Associations between local bird abundance and LWFs were variable among species, but overall community effects were clearly positive, particularly for forest and shrubland species. At the site level, 20/45 species (44%) had higher densities associated with greater LWF presence on average, compared to 5/45 (11%) with negative associations. At the regional scale, LWFs had predicted benefits on total abundance for 31 species (69%), contributing to an estimated 20% increase on average. Positive effects were most pronounced in areas with greater agricultural land use (primarily field crops), suggesting LWFs may provide crucial habitat in heavily modified landscapes but have little to no additional benefit for the avian community in areas with greater existing heterogeneity and habitat retention. Species that responded negatively tended to be at risk with strong habitat preferences for intact forests or large, open grasslands and, thus, greater sensitivity to potential edge effects. With rapidly declining songbird populations and a global need for food security, conservation strategies that amplify biodiversity and enhance agricultural productivity through ecosystem services such as pest control, pollination, and water regulation are vital. We demonstrate the benefits of habitat heterogeneity in agroecosystems on songbird densities and highlight the need to integrate local and landscape-level assessments in conservation planning. An effective, balanced strategy includes concentrating LWFs in areas of extensive arable crops, with habitat retention patches where possible, while maintaining heterogeneity through mixtures of natural habitats and pastoral farming in less intensive regions.

Les caractéristiques d'emboisement linéaires (CEL), tels que les haies en bordure de champs, fournissent un habitat à la faune et à la flore et favorisent la biodiversité dans les agroécosystèmes. Les évaluations des caractéristiques d'emboisement linéaires se concentrent généralement sur des indices au niveau de la communauté, tels que la richesse des espèces. Cependant, pour être efficaces, les actions de conservation doivent équilibrer les préférences variables des différentes espèces sauvages en matière d'habitat, ce qui nécessite de se concentrer sur les effets au niveau de la population dans les paysages exploités. Nous avons évalué les associations entre les CEL et l'abondance de 45 espèces d'oiseaux dans un agroécosystème intensif de l'est de l'Ontario, au Canada. Nous avons utilisé des méthodes d'échantillonnage par distance et par enlèvement sur quatre ans (2016­2019) pour estimer l'abondance locale des oiseaux dans des habitats représentant une gamme de densités de CEL. Nous avons également prédit l'abondance dans un sous­ensemble de la région étudiée avec et sans CEL pour comprendre leur contribution à la densité de la population régionale. Les associations entre l'abondance des oiseaux locaux et les CEL étaient variables d'une espèce à l'autre, mais les effets globaux sur les communautés étaient clairement positifs, en particulier pour les espèces des forêts et des zones arbustives. Au niveau du site, 20/45 espèces (44%) avaient des densités plus élevées associées à une plus grande présence de CEL en moyenne, contre 5/45 (11%) avec des associations négatives. À l'échelle régionale, les CEL ont eu des effets bénéfiques sur l'abondance totale de 31 espèces (69%), contribuant à une augmentation estimée à 20% en moyenne. Les effets positifs étaient plus prononcés dans les zones où l'utilisation des terres agricoles était plus importante (principalement les grandes cultures), ce qui suggère que les CEL peuvent fournir un habitat crucial dans les paysages fortement modifiés, mais qu'elles ont peu ou pas d'avantages supplémentaires pour la communauté aviaire dans les zones où l'hétérogénéité existante et la conservation de l'habitat sont plus importantes. Les espèces qui ont répondu négativement avaient tendance à être en danger, avec de fortes préférences d'habitat pour les forêts intactes ou les grandes prairies ouvertes, et donc une plus grande sensibilité aux effets de lisière potentiels. Avec le déclin rapide des populations d'oiseaux chanteurs et le besoin mondial de sécurité alimentaire, les stratégies de conservation qui amplifient la biodiversité et améliorent la productivité agricole grâce aux services écosystémiques tels que la lutte contre les ravageurs, la pollinisation et la régulation de l'eau sont vitales. Nous démontrons les avantages de l'hétérogénéité de l'habitat dans les agroécosystèmes sur les densités de passereaux et soulignons la nécessité d'intégrer les évaluations locales et au niveau du paysage dans la planification de la conservation. Une stratégie efficace et équilibrée consiste à concentrer les CEL dans les zones de cultures arables extensives, avec des parcelles de conservation de l'habitat là où c'est possible, tout en maintenant l'hétérogénéité grâce à des mélanges d'habitats naturels et à l'agriculture pastorale dans les régions moins intensives.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

APOL1 Nephropathy Risk Variants Through the Life Course: A Review.

Two variant alleles of the gene apolipoprotein L1 (APOL1), known as risk variants (RVs), are a major contributor to kidney disease burden in those of African descent. The APOL1 protein contributes to innate immunity and may protect against Trypanosoma, HIV, Salmonella, and leishmaniasis. However, the effects of carrying 1 or more RVs contribute to a variety of disease processes starting as early as in utero and can be exacerbated by other factors (or "second hits"). Indeed, these genetic variations interact with environmental exposures, infections, and systemic disease to modify health outcomes across the life span. This review focuses on APOL1-associated diseases through the life-course perspective and discusses how early exposure to second hits can impact long-term outcomes. APOL1-related kidney disease typically presents in adolescents to young adults, and individuals harboring RVs are more likely to progress to kidney failure than are those with kidney disease who lack APOL-1 RVs. Ongoing research is aimed at elucidating the association of APOL1 RV effects with adverse donor and recipient kidney transplant outcomes. Unfortunately, there is currently no established treatment for APOL1-associated nephropathy. Long-term research is needed to evaluate the risk and protective factors associated with APOL1 RVs at different stages of life.

Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.

Background: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion: This study shows the importance of examining patient's family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister's unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.

The role of species ecology in predicting Toxoplasma gondii prevalence in wild and domesticated mammals globally.

Macroecological approaches can provide valuable insight into the epidemiology of globally distributed, multi-host pathogens. Toxoplasma gondii is a protozoan that infects any warm-blooded animal, including humans, in almost every habitat worldwide. Toxoplasma gondii infects its hosts through oocysts in the environment, carnivory of tissue cysts within intermediate host prey and vertical transmission. These routes of infection enable specific predictions regarding the ecological and life history traits that should predispose specific taxa to higher exposure and, thus infection rates of T. gondii. Using T. gondii prevalence data compiled from 485 studies representing 533 free-ranging wild mammalian species, we examined how ecological (habitat type, trophic level) and life history (longevity, vagility, gestation duration and torpor) traits influence T. gondii infection globally. We also compared T. gondii prevalence between wild and domesticated species from the same taxonomic families using data compiled from 540 studies of domestic cattle, sheep, and pigs. Across free-ranging wildlife, we found the average T. gondii prevalence was 22%, which is comparable to the global human estimate. Among ecological guilds, terrestrial species had lower T. gondii prevalence than aquatic species, with freshwater aquatic taxa having an increased prevalence compared to marine aquatic species. Dietary niches were also influential, with carnivores having an increased risk compared to other trophic feeding groups that have reduced tissue cyst exposure in their diet. With respect to influential life history traits, we found that more vagile wildlife species had higher T. gondii infection rates, perhaps because of the higher cumulative risk of infection during movement through areas with varying T. gondii environmental loads. Domestic farmed species had a higher T. gondii prevalence compared to free-ranging confamilial wildlife species. Through a macroecological approach, we determined the relative significance of transmission routes of a generalist pathogen, demonstrating an increased infection risk for aquatic and carnivorous species and highlighting the importance of preventing pathogen pollution into aquatic environments. Toxoplasma gondii is increasingly understood to be primarily an anthropogenically-associated pathogen whose dissemination is enhanced by ecosystem degradation and human subsidisation of free-roaming domestic cats. Adopting an ecosystem restoration approach to reduce one of the world's most common parasites would synergistically contribute to other initiatives in conservation, feline and wildlife welfare, climate change, food security and public health.