The Monash Health digital repository system captures, stores, indexes, preserves, and distributes digital research material. http://repository.monashhealth.org:80/monashhealthjspui 2026-09-15T14:48:22Z 2026-09-15T14:48:22Z Kebede A.M. David C.T. Rawlinson S.M. Deffrasnes C. Gooley P.R. Forster S.C. Moseley G.W. https://repository.monashhealth.org/monashhealthjspui/handle/1/60841 2026-09-10T05:27:28Z 2026-08-31T00:00:00Z

Title: The rabies virus interferon antagonist P protein selectively modulates interferon signalling to inhibit antiviral gene expression while supporting proviral gene expression. Authors: Kebede A.M.; David C.T.; Rawlinson S.M.; Deffrasnes C.; Gooley P.R.; Forster S.C.; Moseley G.W. Abstract: Type-I IFNs mediate the principle antiviral response of cells by controlling the expression of hundreds of IFN-regulated genes (IRGs), many of which have antiviral functions. The best understood mediators of IFN signalling are STAT1 and STAT2, and STAT1/2-dependent gene induction is conventionally viewed as the primary outcome of type-I IFN signalling. To overcome the IFN response, viruses express proteins called IFN-antagonists, which target IFN signalling pathways (e.g. rabies virus P-protein (RABV-P) binds and inhibits IFN-activated STAT1/2) and so are typically considered to mediate shutdown of the IFN response. However, IFN signalling is not exclusively antiviral, with many IRGs reported to be required for or to facilitate infection by certain viruses. How viruses coordinate the apparent need to suppress certain antiviral IRGs, while presumably permitting the expression of others, including 'proviral' IRGs is poorly defined. However, it has been shown that type-I IFN can activate multiple pathways other than classical STAT1/2, so discriminatory targeting of specific pathways by IFN-antagonists may enable highly selective regulation of distinct IRGs, dependent on the requirements of the specific virus. Here, we analyse the global effects of RABV-P protein on the IFN-regulated transcriptome. We confirm that IFN not only stimulates (IFN-stimulated genes, ISGs) but also represses (IFN-repressed genes, IRepGs) a large number of IRGs. Notably, our data indicate that RABV-P protein can antagonize both the IFN-dependent stimulation and repression of certain ISGs and IRepGs, without significantly impacting the expression of large proportion of IRGs. Antagonized ISGs included classical antiviral genes, while non-antagonized ISGs include genes with pro-viral effects on RABV. Transcription factor analysis indicated that RABV-P antagonizes STAT1/2-regulated IRGs, but not IRGs regulated by other pathways including MAP-kinase pathways, which are important to process such as cell survival and inflammatory response. These data indicate that selective modulation rather than global inhibition of IFN-signalling has beneficial outcomes for replication. The data also support the significance of IRepGs, and their modulation by IFN antagonists in viral infection.Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

2026-08-31T00:00:00Z Lannin N.A. Jolliffe L. Scrivener K. Ada L. Dean C. Hoffmann T. Cadilhac D.A. Lynch E. Churilov L. https://repository.monashhealth.org/monashhealthjspui/handle/1/60840 2026-09-10T05:27:28Z 2026-08-25T00:00:00Z

Title: Promoting the use of evidence (PROMOTE) in upper limb stroke rehabilitation: protocol for a multicentre, cluster-randomised, phase IV implementation trial. Authors: Lannin N.A.; Jolliffe L.; Scrivener K.; Ada L.; Dean C.; Hoffmann T.; Cadilhac D.A.; Lynch E.; Churilov L. Abstract: INTRODUCTION: Fewer than half of patients receive evidence-based upper limb rehabilitation after stroke. Implementation science interventions may improve use of guidelines by clinicians; however, it is not yet known whether they lead to evidence-based stroke rehabilitation practice. We aim to determine the effect and cost-effectiveness of a champion-led implementation package (PROMOTE) to increase adherence to best practice guidelines for upper limb rehabilitation after stroke. METHODS AND ANALYSIS: A multistate, multicentre, cluster-randomised, implementation phase IV trial with concealed allocation, blinded measurement and intention-to-treat analysis will be conducted. The PROMOTE package includes appointing an internal champion, local audit and feedback, interactive education tailored to gaps in knowledge and skill, and a decision-aid to support intervention selection. To be eligible, centres delivered rehabilitation to at least 20 stroke patients in the preceding year. Assuming 35% baseline adherence to guidelines, 14 centres (n=238) will be recruited to provide 80% power to detect a 30% absolute difference with a two-sided alpha=0.05. An embedded process evaluation and economic analysis will assess implementation and costs. The primary outcome is the proportion of people with stroke who are documented to receive guideline-recommended upper limb rehabilitation interventions by 6 months. Secondary outcomes include self-reported clinician behaviour change, upper limb therapy outcomes at the end of intervention, costs and cost effectiveness (eg, incremental cost per quality adjusted life year). Process evaluation outcomes include reach, adoption, implementation and maintenance (sustainability). ETHICS AND DISSEMINATION: Ethical approval was obtained from the Alfred Hospital Human Research Ethics Committee (approval number 89725 (NMA), 26 April 2023) with each participating site providing ethical clearance prior to the commencement of the trial. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials extended for cluster-randomised trials and in peer-reviewed journals, and communicated to stakeholders and the public. Understanding and characterising the active ingredients of effective implementation will inform scalable strategies to improve stroke rehabilitation practice, health outcomes and the equitable delivery of evidence-based care. TRIAL REGISTRATION NUMBER: The trial is currently recruiting and is registered at https://www.anzctr.org.au/.ID: ANZCTR 12623000608662 (UTN U1111-1292-8705), 2 June 2023.Copyright © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY. Published by BMJ Group.

2026-08-25T00:00:00Z Myles P.S. Klein A.A. Smith J.A. Wallace S. Forbes A. Zavarsek S. Symons J.A. Baker R.A. Wood E.M. McQuilten Z. McGiffin D. Christie-Taylor G. Soon C.K. Chan M.T.V. Martin C. Richards T. https://repository.monashhealth.org/monashhealthjspui/handle/1/60837 2026-09-10T05:27:27Z 2026-08-24T00:00:00Z

Title: Intravenous iron to treat anaemia before cardiac surgery (ITACS): international, double blind, placebo controlled randomised trial. Authors: Myles P.S.; Klein A.A.; Smith J.A.; Wallace S.; Forbes A.; Zavarsek S.; Symons J.A.; Baker R.A.; Wood E.M.; McQuilten Z.; McGiffin D.; Christie-Taylor G.; Soon C.K.; Chan M.T.V.; Martin C.; Richards T. Abstract: OBJECTIVE: To evaluate the effects of intravenous iron on red cell transfusion and recovery after cardiac surgery. DESIGN: International, multicentre, double blind, placebo controlled randomised trial (ITACS). SETTING: 33 hospitals across 10 countries. Participants were enrolled between July 2016 and December 2023. PARTICIPANTS: 955 adults with anaemia undergoing elective cardiac surgery. Exclusion criteria included haemoglobinopathy or iron storage disorder, renal dialysis, and erythropoietin or intravenous iron given in the previous four weeks. INTERVENTION: A computer generated program randomised participants to intravenous iron 1000 mg or placebo 1-26 weeks before surgery. Participants, clinicians, and data collectors were masked to the intervention. MAIN OUTCOME MEASURES: The number of days alive and at home up to 90 days after surgery (primary outcome), red cell transfusion requirements and complications (secondary outcomes). RESULT(S): Of 2993 screened participants, 955 were enrolled and 921 of the eligible 939 modified intention-to-treat participants were assessed for the primary outcome. The median number of days alive and at home up to 90 days after surgery was 81.1 (interquartile range 74.8-83.7) in patients assigned to intravenous iron and 80.0 (69.5-83.6) in those receiving placebo (adjusted median difference 1.0 day, 95.4% confidence interval 0.0 to 2.1 days, P=0.041). Red cell transfusions were given to 262 patients (61.1%) in the iron group and 302 (68.2%) in the placebo group during their hospital stay (relative risk 0.90, 95% confidence interval 0.82 to 0.99, P=0.027). No differences were observed for major complications or length of hospital stay. CONCLUSION(S): Among patients with anaemia undergoing elective cardiac surgery, preoperative intravenous iron was associated with a reduction in red cell transfusion and a small improvement in the number of days alive and at home in the first 90 days after surgery. Intravenous iron is an effective component of patient blood management in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02632760.Copyright © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

2026-08-24T00:00:00Z Le Magnen C. Brennen W.N. Aytes A. Bock N. Bristow R.G. Choo N. Chua C.W. Clark A.K. Clements J.A. Coleman I.M. Corey E. Dinevska M. Doultsinos D. Edge G. Holst J. Horvath L.G. Labanca E. Lyons S. Luna-Velez M.V. Karthaus W. Kruithof-de Julio M. Philp L.K. Prins G.S. Ranasinghe W. Selth L.A. Shepherd P. Taubenberger A. Taylor R.A. Timpson P. Waugh D.J. van Weerden W.M. Risbridger G.P. Lawrence M.G. https://repository.monashhealth.org/monashhealthjspui/handle/1/60839 2026-09-10T05:27:27Z 2026-08-25T00:00:00Z

Title: Patient-derived models of prostate cancer: Capturing tumour complexity from initiation to metastasis. Authors: Le Magnen C.; Brennen W.N.; Aytes A.; Bock N.; Bristow R.G.; Choo N.; Chua C.W.; Clark A.K.; Clements J.A.; Coleman I.M.; Corey E.; Dinevska M.; Doultsinos D.; Edge G.; Holst J.; Horvath L.G.; Labanca E.; Lyons S.; Luna-Velez M.V.; Karthaus W.; Kruithof-de Julio M.; Philp L.K.; Prins G.S.; Ranasinghe W.; Selth L.A.; Shepherd P.; Taubenberger A.; Taylor R.A.; Timpson P.; Waugh D.J.; van Weerden W.M.; Risbridger G.P.; Lawrence M.G. Abstract: Prostate cancer is a growing global health challenge. To identify new ways to improve patient care, researchers need a variety of preclinical models that faithfully recapitulate human tumours across the disease continuum, from initiation to metastasis. These complementary models include primary cultures of prostate epithelial cells (PrECs), co-cultures, patient-derived explants (PDEs), patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). Collectively, these models enable researchers to study tumour biology and therapeutic responses in clinically relevant contexts. Yet, there is still a need to improve the fidelity of preclinical models to human tumours by integrating diverse cell types from the tumour microenvironment and mimicking biomechanical features. By improving culture methods with matrix components that resemble the tumour microenvironment and new formulations of media that imitate human plasma, in vitro models will more accurately reflect human physiology, nutrient availability, and metabolism. In time this may reduce the reliance on animal testing through organ-on-chip and related techniques. These more complex models are suited to more detailed experimental readouts, including single-cell and spatial analyses. Intravital imaging also enables dynamic visualisation of cell-cell interactions and treatment responses in vivo . Collectively, these approaches are facilitating a shift towards sophisticated models that capture patients' tumour heterogeneity, different cellular niches, and provide opportunities to carefully study tumorigenesis, metastasis, lineage plasticity, and therapy resistance. In this review, we discuss the current progress and future directions for patient-derived models of prostate cancer, highlighting how they can be generated, refined, characterised and shared to accelerate the worldwide effort in translational research.Copyright © 2026 The Authors.

2026-08-25T00:00:00Z