QIMR Berghofer Medical Research Institute

Electronic Medical Records (EMRs) aim to improve efficiency, safety, and quality of care. However, the impact of EMR implementation, particularly in outpatient diabetes care, remains underexplored. This study explored clinicians' perspectives on EMR use in diabetes outpatient care. This qualitative study, conducted in line with COREQ guidelines, involved four focus groups with 22 clinicians (doctors, nurses, and allied health) at a metropolitan diabetes service in Queensland, Australia. Data were analysed using deductive content analysis, guided by the Quintuple Aim and Technology Acceptance Model/Unified Theory of Acceptance and Use of Technology frameworks. Clinicians reported mixed outcomes across the Quintuple Aim domains, shaped by technology adoption constructs. Facilitators such as improved efficiency, access to patient information, and prescribing safety reflected perceived usefulness and positive attitudes, contributing to favourable outcomes across multiple Quintuple Aim. Barriers such as navigation complexity, technical issues, alert fatigue, and overwhelming training led to negative outcomes in EMR use. Tensions around documentation practices and patient expectations of system use, resulted in mixed outcomes. Overall, clinicians viewed EMRs as essential, but sustained adoption required improved usability, tailored training, and better system integration. This study concludes that while the EMRs improved safety, efficiency, and access to information, their design and implementation also introduced burdens that negatively affected clinician experience. EMRs significantly shape the healthcare workforce, influencing workflow, wellbeing, and professional engagement. In outpatient diabetes care, specific workflow challenges such as glycaemic data integration highlight that existing EMR designs may not fully support the complexity of chronic disease management. To maximise benefits, EMR initiatives should be approached as quality improvement activities, with role-specific training, reliable infrastructure, and clinician involvement in system optimisation. Future research should address usability challenges, enhance integration, and ensure that both clinician and patient perspectives guide digital health transformation.

Chromosomal instability (CIN), a pervasive feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and metastasis. CIN stimulates the cGAS–STING pathway, typically linked to antitumor immunity. However, despite the high CIN burden in EAC, the cGAS–STING pathway remains largely intact. To address this paradox, we interrogated multiple esophageal cancer models, finding myeloid-attracting chemokines—with CXCL8 as a prominent hit—as conserved CIN-driven targets in EAC. Using multiplexed immunofluorescence microscopy, we quantified ongoing CIN in human EAC tumors by measuring cGAS-positive micronuclei, validated by whole-genome sequencing. Coupling in situ CIN detection with single-nucleus RNA sequencing and multiplex immunophenotyping of human EAC, we link CIN to tumor-intrinsic innate immune activation, CXCL8 expression, and myeloid cell–mediated immunosuppression. In patients with EAC, CINhigh, myeloid-dominated tumors correlate with poor outcomes and aberrant cGAS–STING signaling. These insights explain the counterintuitive maintenance of cGAS–STING and highlight the disruption of the CIN–cGAS–inflammation axis as a potential therapeutic strategy in EAC.

MCCS had a case/sub-cohort design, leading to a higher proportion of cases among individuals with genetic data; for individuals in the sub-cohort, there were 42 incident cases within 5 years of study baseline.

Abstract The aging population is growing, with a prevalence of cognitive decline (CD) expected to increase over the next decade, mainly affecting Latin America countries (LAC). The lack of appropriate context-based tools to detect cognitive decline (CD) may be a source of misinterpretation. The Montreal Cognitive Assessment (MoCA) is a recommended screening test to detect CD; however, it has commonly been used with a proposed cut off > 26. Our aim was to propose normative values based on a large sample from LAC to improve the detection of CD in our population. We collected data from Argentina, Brazil, Colombia, and Mexico participants who were classified as controls from the LARGE-PD consortium. A total of 781 individuals (38.54% male; mean age 55.2 ± 16.6 years), with a mean of 13.5 ± 5 years of education and a mean MoCA score of 24.2士4.1, were stratified by age and educational level (EL). DSM-V criteria were used to determine absence of CD. MoCA test v.7 was administered using a pen-and-paper format. ANOVA was used to detect differences in age and EL among countries. MoCA scores were compared using the Kruskal-Wallis test. Normative values for detecting CD were established as -1 standard deviation (SD) below the mean within each stratified group. The prevalence of CD was calculated by country and for the entire sample. Our proposed normative values adjusted for age and educational level demonstrated that the prevalence of CD decreased to 12%, compared with the 53.8% when using the cut-off of 26. Consequently, normal cognition increased to 88%. This finding improves the detection of cognitive decline through a more appropriate interpretation of MoCA score, considering the diversity of population of LAC. Working with normative values may enhance the allocation of resources to follow-up, monitoring and management in resource-limited settings.

Abstract Background Breast cancer is the most commonly diagnosed cancer globally and remains the leading cause of cancer-related death in women. HER2-positive breast cancer, comprising 15-20% of cases, is defined by overexpression of the HER2 tyrosine kinase receptor. While HER2-targeted therapies have transformed clinical outcomes, resistance, recurrence, and metastasis continue to pose significant challenges. Immunotherapy has revolutionised the treatment of several solid tumors by enhancing anti-tumor immunity; however its efficacy in HER2-positive breast cancer has been limited. There is a pressing need for biomarkers that can both track metastatic burden and identify patients most likely to benefit from immunotherapeutic strategies. In this study, we present novel preclinical data from liquid biopsy analyses and propose a biomarker-driven approach targeting the PI3K-mTOR pathway to enhance immune reinvigoration in HER2-positive metastatic breast cancer. Methods Twenty five stage IV HER2-positive metastatic breast cancer (mBC) patients underwent liquid biopsy profiling using an epigenetic biomarker targeting the PI3K-mTOR signaling pathway. We applied digital pathology, Duolink® proximity ligation assays, global immune profiling, and flow cytometry to characterize biomarker expression and immune landscape features. Ex vivo drug screening with PI3K-mTOR inhibitors, including the brain-penetrant paxalisib, was performed to evaluate their effects on mesenchymal phenotypes, disruption of circulating tumor cell (CTC) clusters, and immune reinvigoration. Results We identified a novel epigenetic switch that drives the transition to a more aggressive, drug-resistant mesenchymal phenotype in HER2-positive breast cancer, associated with activation of the nuclear chromatinised PI3K signaling pathway. This phenotype, detectable via liquid biopsy, correlates with metastatic burden and immune exhaustion. In our pilot cohort, we evaluated the interplay between PI3K mutational burden and activation of this mesenchymal epigenetic program. Functional drug response profiling of patient-derived samples demonstrated that dual PI3K-mTOR inhibition not only facilitated mesenchymal-to-epithelial transition but also suppressed key metastatic signatures, including those linked to the highly aggressive persister cell phenotype (p65, FOXQ1, NRF2, and NNMT) and cancer drug resistance (ABCB5, SNAIL, and ALDH1). Importantly, PI3K-mTOR inhibition disrupted metastatic progenitors, including circulating tumor cell (CTC) clusters, and enhanced anti-tumor immune responses, as evidenced by modulation of both progenitor-like and terminally exhausted T cell populations. Conclusions Our preclinical findings support a biomarker-driven therapeutic strategy targeting the PI3K-mTOR pathway to induce epigenetic reprogramming and immune modulation. This dual mechanism may enhance anti-tumor efficacy by converting immunologically 'cold' tumors into 'hot', more immunogenic tumors. By reshaping the tumor microenvironment, this approach has the potential to improve the clinical utility of immunotherapy and expand treatment options for patients with HER2-positive metastatic breast cancer. Citation Format: M. Melino, W. Tu, S. Goh, A. Bain, J. Friend, T. Prasanna, D. Yip, A. Ives, M. Leahy, D. Lewis, M. Nottage, S. Rao. Liquid Biopsy Tracking of PI3K-mTOR Residual Disease Signatures in Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-10-02.

The rising incidence of skin cancer places a significant burden on Australia's health workforce. To support workforce planning, we estimated the supply of dermatologists and general practitioners (GP) working in skin cancer medicine, service demand and need across Queensland in 2023. We built a supply-, demand- and needs-based health workforce model using publicly available data. We collated data on the numbers of clinicians and clinical full-time equivalents (FTE), Medicare-reported skin cancer services and melanoma incidence. We quantified health workforce supply and clinical workload, clinical FTE per 100,000 population, number of Medicare claims for skin cancer services per clinical FTE and incident cases of melanoma per clinical FTE for all of Queensland and across 19 Level 4 Statistical Areas. Queensland had 7179 GPs (852 adjusted FTE) and 124 (71 adjusted FTE) dermatologists servicing 5,527,369 residents, with an estimated 17 FTE skin cancer clinicians per 100,000 population. Ten (53%) SA4 areas had no dermatologists, with none residing in central or western Queensland. Seven of the nine SA4 levels with dermatologists were in southeast Queensland (78%), and 47% of all FTE dermatologists practised in Brisbane Inner City. GPs were well distributed relative to population size. Access to dermatology services is limited for Queensland residents living outside the southeast region, with few providers available within reasonable proximity. GPs are managing a growing skin cancer workload in Queensland. This could be eased by increased use of telemedicine, upskilling other health professionals in skin cancer medicine and improving care efficiency.

Background:Mendelian randomization (MR) is increasingly used for causal inference in nutritional epidemiology; however, dietary MR studies often rely on instruments statistically selected from genome-wide association studies of self-reported intake, which are vulnerable to pleiotropy and reverse causation and may violate core MR assumptions. We aimed to develop and evaluate a biologically informed framework for selecting valid genetic instruments for dietary exposures, based on genes encoding taste and olfactory receptors that mediate chemosensory inputs and shape food preferences and dietary behaviour.Methods:We prioritised 1,214 nonsynonymous variants in 30 taste and 295 olfactory receptor genes with minor allele frequency ≥1%. Associations with 140 food-liking traits were tested in UK Biobank participants aged 37 to 73 years. Candidate variants were evaluated using a multi-stage filtering pipeline designed to improve instrument validity. This included replication in an independent younger cohort (Avon Longitudinal Study of Parents and Children, age 25), concordance between food liking and intake, exclusion of associations with socioeconomic status, assessment of food specificity accounting for linkage disequilibrium and co-consumption patterns, and directionality testing to reduce reverse causation. Retained variants were applied as instruments in MR analyses to assess cardiometabolic outcomes.Results:We identified 268 nonsynonymous variants within 101 olfactory and 16 taste receptor genes associated with 96 food-liking traits. The filtering process yielded 28 candidate instruments for 24 foods. Among these, the instrument for onion liking uniquely satisfied all criteria for classification as high confidence. To demonstrate clinical relevance, genetically proxied onion liking was associated with lower blood pressure and a reduced risk of type 2 diabetes in MR analyses, with no evidence of effects on body mass index, glycaemic traits, or serum lipid levels.Conclusions:Guiding genetic instrument selection using chemosensory receptor genes provides a biologically informed strategy for dietary Mendelian randomization that reduces susceptibility to pleiotropy and reverse causation. This framework enables more robust causal evaluation of diet–disease relationships and strengthens inference in nutritional epidemiology and public health research.

Recent research has challenged a long-held view of the brain as an immune-privileged organ, revealing active immunosurveillance with therapeutic relevance. Using a new genetically engineered mouse model of ZFTA-RELA ependymoma, a childhood brain tumor, we characterized an immune circuit between the tumor and antigen-presenting hematopoietic stem and progenitor cells (HSPCs) in the skull bone marrow. The presentation of antigens by HSPCs to CD4+ T cells biased HSPC lineages toward myelopoiesis and polarized CD4+ T cells to regulatory T cells, culminating in tumor immunotolerance. Remarkably, normalizing hematopoiesis with a single infusion of antibodies directed against cytokines enriched in the cerebrospinal fluid of mice bearing ZFTA-RELA ependymomas, choroid plexus carcinomas or group 3 medulloblastoma-all aggressive childhood brain tumors-disrupted this process and caused profound tumor regression. These findings demonstrate the existence of a skull bone marrow-tumor immunological interface and suggest that modulating the local supply of myeloid cells could represent a less toxic therapeutic strategy for aggressive childhood brain tumors.