Westmead Hospital

During epidemics, emergency department (ED) syndromic surveillance of patient arrivals provides timely but nonvirus-specific assessment of epidemic intensity. Surveillance of severe infection outcomes (intensive care admission or death) is less timely because outcomes can take weeks to occur. Time series models can be used to estimate the frequency of severe infection outcomes due to viruses. We developed and evaluated daily time series modeling applied to linked ED, infection, and outcomes data from Australia to better predict population and health system burden during acute respiratory virus epidemics. In retrospective daily surveillance emulation, generalized additive models nowcasted (short-term forecast) the frequency of ED arrivals attributable to each of influenza and COVID-19 that will have a severe infection outcome within 28days. Daily nowcasts spanned days -29 to -4 from each date for which surveillance was emulated. To validate the method, nowcasts were compared with subsequently observed severe infection outcome frequencies for December 2021 through February 2023. During this period, the mean daily day-4 nowcast error was 2.7 (34.2%), compared with 3.5 (43.8%) if outcomes known at day-1 were used. With increasing real-world data availability, this method could improve rapid, automated epidemic assessment for timely public health action.

BK polyomavirus (BKPyV) is a common opportunistic infection in kidney transplant recipients, typically reactivating in the context of immunosuppression. Although asymptomatic in immunocompetent individuals, reactivation in transplant recipients can cause BKPyV-associated nephropathy (BKPyVAN), a leading cause of graft dysfunction and loss. BKPyV viremia affects approximately 10%-15% of transplant recipients, and once BKPyVAN is established, the risk of graft failure can exceed 50%. The current standard of care involves immunosuppression reduction to restore virus-specific immunity, but this approach increases the risk of acute and chronic rejection. Intravenous immunoglobulin (IVIg), which contains antiviral and immunomodulatory antibodies, has been proposed as an adjunctive therapy, although evidence supporting its efficacy remains limited to small observational studies. The BEAT-BK trial is a multicenter, adaptive, randomized controlled trial comparing standard immunosuppression reduction with or without IVIg in kidney and simultaneous pancreas-kidney transplant recipients with BKPyV viremia or biopsy-confirmed BKPyVAN. The trial will enroll participants aged 2 y and older, randomizing them 1:1 to receive standard care alone or in combination with a total IVIg dose of 2 g/kg for 8 wk. An adaptive Bayesian design will permit interim analyses with the potential for early trial success or futility. The primary endpoint is a composite ordinal outcome at 12 wk, incorporating death, graft loss, estimated glomerular filtration rate decline, acute rejection, viral load, and degree of immunosuppression reduction. Secondary outcomes include viral clearance, development of BKPyVAN and donor-specific antibodies, infections, malignancy, quality of life, and cost-effectiveness. This trial will provide the first high-quality evidence on the role of IVIg in BKPyV management and inform clinical decision-making in posttransplant care.

This study evaluated the probability of pharmacokinetic/pharmacodynamic efficacy target attainment and developed a dosing interval identification nomogram to minimize toxicity risks of high-dose amikacin. Therapeutic drug monitoring was performed in critically ill patients receiving high-dose (30 mg/kg) amikacin intravenously. Population pharmacokinetic modeling and Monte Carlo simulation were performed in NONMEM® 7.5.1. The probability of target attainment and the cumulative fraction of response for the local Klebsiella pneumoniae population were assessed using maximum concentration/minimum inhibitory concentration ≥ 8 as the efficacy target. Nomograms stratified by the renal function group were established to guide dosing intervals to avoid exceeding the toxicity minimum concentration threshold of 2.5 mg/L. A total of 251 patients with 488 amikacin concentrations were included. The amikacin pharmacokinetics was best described by a two-compartment model. The creatinine clearance and adjusted body weight were significant covariates for clearance and the central volume of distribution, respectively. Amikacin 30 mg/kg achieved a probability of target attainment > 90% for minimum inhibitory concentrations < 8 mg/L and around 80% for minimum inhibitory concentrations of 8 mg/L. This regimen showed a cumulative fraction of response of 63.5% for K. pneumoniae, while attaining a cumulative fraction of response of 96.8% for susceptible isolates. The 30-mg/kg nomograms in patients with creatinine clearance < 60 and ≥ 60 mL/min showed accurate dosing intervals with around 90% of virtual patients for the post-infusion period from 20 to 32 h and from 6 to 32 h, respectively. Nomogram-aided dosing interval adjustment of high-dose amikacin (30 mg/kg) maximized the efficacy and safety target attainment for critically ill patients with infections caused by susceptible K. pneumoniae.

In the austral summer of 2021–2022, Australia experienced an unprecedented Japanese encephalitis virus (JEV) outbreak, with detections over 3000 km south of previous occurrences. Given the limited knowledge of JEV transmission ecology in Australia, we developed geospatial models of transmission risk to support the public health response. We created time-varying habitat suitability models for suspected mosquito vectors and ardeid hosts using month-scaled occurrence and covariate data from 2000–2023. Ardeid host presence-absence data were obtained from eBird and BirdLife Australia, with habitat suitability estimated using gradient-boosted regression tree models. A national dataset of Culex occurrences was compiled from mosquito surveillance records, literature, and biodiversity databases. Penalised logistic regression was used to model mosquito vector habitat suitability. Vector and host habitat predictions for the outbreak peak in February 2022 were rescaled using JEV infection locations in the public domain to create a combined habitat suitability surface. Our models aligned with detected JEV infections at the continental scale, highlighting transmission suitability across tropical northern Australia and major inland drainage basins in the East. Unlike existing models, we predicted lower suitability along the eastern seaboard, suggesting a delimiting effect of the Great Dividing Range. Our approach provides the most comprehensive and temporally dynamic models for JEV hosts and vectors in Australia, with a significantly larger vector dataset than previous studies. The novel method of rescaling host and vector outputs into a combined surface offers new insights into JEV transmission risk. Favourable conditions were repeated in 2023 with few detected infections, emphasising that JEV ecology in Australia remains poorly understood. This study’s results can support improvements in arbovirus surveillance systems, promoting earlier detection of circulating viruses. Increased focus on vector ecology and distributions is crucial for better understanding JEV transmission in Australia.

Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to treatment, with mortality rates largely unchanged despite advances in cancer therapies. For ∼80% of borderline, non-resectable, or metastatic cases, chemotherapy is predominantly palliative, underscoring the need for improved drug delivery approaches. This study presents the development, characterization and in vivo evaluation of a novel polymeric implant loaded with 5-fluorouracil, irinotecan, and oxaliplatin (FIRINOX). Scanning electron microscopy of FIRINOX implants showed internal microstructure was preserved upon drug loading, while micro-CT and X-ray imaging revealed valuable insights into the morphology and degradation of implants retrieved from in vivo experiments. In murine PDAC models, dose-escalation identified 4 × FIRINOX implants as the maximum tolerated dose, while 2 × implants achieved significant therapeutic efficacy at lower doses than IV administration, without compromising animal safety. In healthy pigs, 20 × FIRINOX implants were well-tolerated, as confirmed by histopathology and blood analysis. Finally, laser ablation-inductively coupled plasma-mass spectrometry imaging and microbiome analysis confirmed localized drug perfusion within tissues, and minimal off-target effects, including preservation of gut microbiota diversity. These findings support the potential of this implantable platform to improve outcomes in borderline or non-resectable PDAC and enhance tolerability of cytotoxic chemotherapy through localized, controlled delivery, addressing a key gap where current treatment options are limited.

Niemann-Pick disease type C (NP-C) is the fifth most prevalent lysosomal disorder in Australia. Diagnostic delay is common, impacted by disease heterogeneity, limited awareness within clinical gateway services and exclusion from state-based newborn screening programmes. A formal diagnosis, once established, places a substantial burden on the whole family, the negative impact of which is far-reaching. A clear understanding of diagnostic pathways and management objectives in NP-C is critical for optimal care. To develop an Australian standard of care for individuals diagnosed with NP-C and their families, reflecting international best practice and tailored to the Australian healthcare system. The Australian NPC Disease Foundation Inc. convened a national, multidisciplinary collaboration including NP-C treating clinicians, allied health professionals and a community advisory group. Using an iterative consensus approach, published international guidance statements were reviewed, ratified, excluded or modified to align with the Australian context. Consensus outputs included a diagnostic algorithm, a multidisciplinary care framework and management-centred management statements. The collaborative process resulted in a unified Australian standard of care for NP-C. This framework incorporates the carer perspective, emphasises shared decision-making and situates NP-C within the broader context of 'childhood dementias.' Consensus statements provide practical, evidence-aligned guidance on early recognition, diagnostic referral pathways and multidisciplinary management throughout disease progression. This initiative represents the first Australia-specific standard of care for NP-C. It is hoped that adoption of the framework will lead to improved experiences for Australians living with NP-C and their carers as they navigate the healthcare setting.

Heparin remains a foundational parenteral anticoagulant across both acute and chronic care settings. This narrative review summarizes clinical indications and dosing of unfractionated (UFH) and low-molecular-weight heparin (LMWH). It also details laboratory monitoring using activated partial thromboplastin (APTT), anti-factor Xa (anti-Xa), activated clotting time (ACT) and viscoelastic testing (VET), including common pitfalls and interferences. We provide considerations for specific populations as well as complications including heparin resistance, heparin-induced thrombocytopenia (HIT) and heparin reversal strategies. Future research directions include harmonization of therapeutic ranges, mitigation of assay interference and prospective evaluation on monitoring, particular in extracorporeal membrane oxygenation (ECMO), pregnancy and cardiac surgical settings.

Technical advancements in abdominal flap-based autologous breast reconstruction (ABR) have focussed on minimizing abdominal wall morbidity. However, no consensus exists on the technique that maximises abdominal function, particularly in cases of bilateral ABR. This systematic review critically appraises the literature to assess abdominal wall function following abdominal flap-based ABR. A literature search was performed following PRISMA guidelines. Four databases (Embase (via Ovid), Medline (via Ovid), Cochrane Library and PubMed) were searched. The primary outcome was abdominal wall function following abdominal flap-based ABR measured by sit-up performance, manual muscle function testing, isokinetic dynamometry and ultrasound. 38 studies were included comparing various types of abdominally-based autologous flaps used for breast reconstruction. Sit-up ability was highest in DIEP group (87%) when compared to free TRAM (25%) and pedicled TRAM (12%). Bilateral DIEP had higher combined mean upper rectus and lower rectus abdominis function scores (4.54) compared to bilateral free TRAM (3.87), where 5 represents normal function. Bilateral ABR demonstrated worse abdominal function compared with unilateral ABR in all flap types. DIEP flaps yield superior abdominal muscle function outcomes compared to TRAM flaps of all types, particularly when performing bilateral ABR. Future research should aim to standardise abdominal function measurement and reporting of intra-operative variables, such as the length of fascial and muscle incisions, the number of abdominal motor nerve branches sacrificed, and the use of abdominal mesh to enable more complete understanding of the impact of abdominal flap-based ABR on abdominal wall function.

Epidermal growth factor receptor inhibitors (EGFRi) commonly cause papulopustular exanthemas that may compromise the success of cancer therapy. While tetracyclines are first-line treatment, data on alternative systemic agents for refractory cases remain limited. This study compares the effectiveness and tolerability of isotretinoin and dapsone for managing tetracycline-resistant EGFRi-induced papulopustular eruptions in a tertiary dermatology service. A retrospective review was conducted of patients with EGFRi-induced papulopustular eruptions treated with isotretinoin or dapsone between 2018 and 2024. Clinical data included demographics, malignancy type, EGFRi agent, eruption severity, prior therapies, Physician's Global Assessment, treatment outcomes, time to best response, adverse events, and EGFRi dose modification. Group comparisons used one-way ANOVA and chi-square/Fisher's exact tests. Sixteen patients were identified (8 isotretinoin, 8 dapsone). Baseline severity was higher in the isotretinoin group. Time to best response was shorter with isotretinoin (mean 14.9 weeks) than dapsone (21.0 weeks). Complete resolution occurred in 62.5% of isotretinoin-treated patients and 50% of dapsone-treated patients. Both agents were well tolerated, with only mild mucocutaneous effects in the isotretinoin group and mild anemia in one dapsone patient. Survival at follow-up was higher among patients who continued EGFRi (with or without dose reduction) than among those who ceased treatment. No significant differences were observed between isotretinoin and dapsone in EGFRi dose modification patterns or overall response rates. Both isotretinoin and dapsone are effective, well-tolerated options for managing tetracycline-resistant EGFRi-induced papulopustular eruptions. Isotretinoin showed a trend toward faster improvement, while ultimate response rates were similar. Maintaining EGFRi therapy, even at reduced doses, in conjunction with dermatology treatment was associated with superior dermatological outcomes and higher survival at follow-up compared with cessation of EGFRi treatment, highlighting the importance of proactive dermatologic intervention to support oncologic treatment continuity.

Combining abdominal ultrasound with radiography improved the identification of neonates at high surgical risk from NEC, in our pilot study. A reassuring ultrasound reliably identified infants with feeding intolerance, suggesting potential to reduce unnecessary transfers and treatments. Larger multicentre studies are needed to validate these findings and inform development of a unified multimodal imaging score for NEC diagnosis.