The South Australian Health and Medical Research Institute (SAHMRI) is an independent health and medical research institute in Adelaide, South Australia. The institute is housed in a purpose-built eponymous building with its iconic "cheese-grater" design created by architects Woods Bagot, located in South Australia's health and biomedical precinct on North Terrace, just east of the Royal Adelaide Hospital.The institute is composed of approximately 700 researchers, many of whom have links to, and work collaboratively with, other research institutes in Australia and overseas.The institute was officially incorporated in December 2009, and opened in its current location on 29 November 2013. A second building (SAHMRI 2) is under construction as of July 2020, and will house the Australian Bragg Centre for Proton Therapy & Research after its completion, scheduled in late 2023.
Despite the success of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), resistance and disease progression remain significant challenges. In this review, we summarize current understanding of BCR::ABL1 dependent and independent mechanisms of resistance, including BCR::ABL1 mutations and additional genetic abnormalities. We also discuss the current and emerging therapeutic strategies aimed at overcoming treatment failure. Recent findings have highlighted the heterogeneity of resistance in CML, suggesting that distinct BCR::ABL1 mutations confer variable sensitivity to TKIs, including mutations affecting the myristoyl binding pocket. In parallel, the acquisition of additional genetic abnormalities such as ASXL1 and RUNX1 has been increasingly linked to disease progression and poor outcomes. Together, these findings have driven the development of novel therapeutic agents such as TERN-701, ELVN-001 and Olverembatinib, as well as growing interest in combination therapy such as asciminib plus ATP-binding site TKIs. Early studies indicate that these novel agents and combination approaches show promising activity against resistant CML. Resistance in CML can be BCR::ABL1 dependent or independent, emphasising the need for molecular profiling to guide treatment decisions. Continued development of mutation-specific therapies, and combination BCR::ABL1-targeted approaches may improve outcomes for patients who develop resistance or experience disease progression. This represents an important focus for future investigations.
BACKGROUND:Primary glenohumeral osteoarthritis in young patients poses challenging treatment decisions. Arthroplasty options have different failure profiles and implant survivorship patterns. This registry study aims to analyze the cumulative per cent revision (CPR) rate of different types of arthroplasties conducted for primary osteoarthritis in patients below 55 years of age. METHODS:This comparative observational national registry study included all shoulder arthroplasty for osteoarthritis in patients below 55 years of age undertaken between January 1st, 2005, and December 31st, 2022. Partial hemi resurfacing and hemi stemless procedures were excluded. The CPR was determined using Kaplan-Meier estimates of survivorship and hazard ratios (HRs) from Cox proportional hazard models adjusted for gender. Reasons for revision of each type of arthroplasty and cumulative incidence of revision diagnoses were analyzed. RESULTS:Two thousand one-hundred eleven primary shoulder arthroplasties were compared. Glenoid erosion is the predominant cause of revision for humeral resurfacing (29.8%) and hemiarthroplasty (35.5%). Instability is the predominant cause of revision for stemmed anatomic total shoulder arthroplasty (aTSA) and reverse total shoulder arthroplasty (rTSA), while loosening is the predominant cause of revision for stemless aTSA. The 6-year CPR is 12.8% for humeral resurfacing, 14.1% for hemiarthroplasty, 12.4% for stemmed (aTSA), 7.0% for stemless aTSA, and 6.5% for rTSA. Stemmed aTSA had a higher revision rate than rTSA (entire period HR = 2.04 (95% confidence interval 1.16, 3.57), P = .012). In contrast, the revision rate of stemless aTSA was not different from rTSA (HR = 1.05 (95% confidence interval 0.51, 2.19), P = .889). Males outnumber females for all shoulder arthroplasty categories. DISCUSSION:rTSA and stemless aTSA are viable options in young patients with primary osteoarthritis. Their short-to-medium term revision rates are comparable to those of older patients and lower than those associated with humeral resurfacing, hemiarthroplasty, and stemmed aTSA. CONCLUSION:In the predominantly male patient population below the age of 55, reverse shoulder arthroplasty and stemless aTSA have a lower short-term revision risk than stemmed aTSA.
Many patients receiving frontline tyrosine kinase inhibitors (TKIs) for chronic phase chronic myeloid leukemia (CML-CP) experience inadequate disease control and/or adverse events (AEs) that impair quality of life. Treatments offering optimal efficacy, safety, and tolerability will support long-term therapy. In the primary analysis from ASC4FIRST, a phase 3 randomized trial comparing asciminib with investigator-selected TKIs (IS-TKIs) in newly diagnosed CML-CP, asciminib demonstrated superior efficacy vs all IS-TKIs and vs imatinib in the imatinib stratum, meeting both primary objectives. In the secondary analysis (2.2 years median follow-up), major molecular response (MMR) rate at week 96 was 74.1% with asciminib vs 52.0% with IS-TKIs (treatment difference, 22.4%; 95% CI, 13.6%-31.3%; 1-sided P<.001), and 76.2% with asciminib vs 47.1% with imatinib in the imatinib stratum (treatment difference, 29.7%; 95% CI, 17.6%-41.8%; 1-sided P<.001), meeting both key secondary objectives. MMR rate was 72.0% with asciminib vs 56.9% with second-generation (2G) TKIs (treatment difference, 15.1%; 95% CI, 2.3%-28.0%; 1-sided P<.05), suggesting possible clinical benefit although the study was not designed to formally confirm statistical significance for this secondary endpoint. Safety/tolerability remained favorable with asciminib vs IS-TKIs. Dose reductions and interruptions, respectively, occurred with asciminib (18.5% and 46.5%), imatinib (23.2% and 47.5%), and 2G TKIs (54.9% and 63.7%). The hazard ratio for time to discontinuation of treatment due to AEs for asciminib vs 2G TKIs was 0.46 (95% CI, 0.215%-0.997%). With longer follow-up, asciminib continued to demonstrate a favorable benefit-risk profile over IS-TKIs and imatinib, supporting its potential as a treatment option for newly diagnosed CML-CP.
OBJECTIVE:Reconstituted high-density lipoproteins (rHDL) improve wound healing in diabetes. We aimed to determine if rHDL elicit anti-inflammatory effects in diabetic wounds, as a mechanism to explain their wound healing benefits. APPROACH:Diabetes was induced using streptozotocin in C57Bl6/J mice. Two full-thickness wounds were placed on the subflanks of diabetic and nondiabetic (ND) mice. Phosphate-buffered saline (PBS) or rHDL (50 µg/wound/day) were applied topically. Wound closure was assessed daily. Inflammatory gene transcripts were measured by qPCR and proteins by Western blotting and enzyme-linked immunosorbent assay in wounds collected at baseline, 24 h, and 3 days postwounding. Wound macrophages were assessed by flow cytometry 7 days postwounding. The fate of fluorescent 3,3-dioctadecyloxacarbocyanine, perchlorate (DiO)-labeled rHDL was tracked by flow cytometry, fluorescent imaging, and microscopy. RESULTS:In diabetic mice, rHDL increased wound closure rates at days 6 (+288%, p < 0.01) and 7 (+639%, p < 0.0001) postwounding, compared with PBS controls. After 3 days, rHDL-treated diabetic wounds had lower Rela (-65%) and C-C motif chemokine ligand 2 (Ccl2) (-59%) mRNA levels and CCL2 protein (29%) than PBS controls, p < 0.05 for all. Wound macrophage content was higher in diabetic than ND wounds, but rHDL did not change macrophage content or polarity. DiO-rHDL were taken up by key wound cells including fibroblasts, macrophages, keratinocytes and endothelial cells, and retained in wounds for at least 48 h. INNOVATION:rHDL exerts anti-inflammatory effects in diabetic wounds early postwounding, which may contribute to its wound healing properties. CONCLUSION:The anti-inflammatory properties of rHDL in diabetic wounds present topical rHDL as a novel treatment option for improving healing in patients with diabetic foot ulcers. [Figure: see text].
Background: Large Language Models (LLMs) are transforming artificial intelligence applications in healthcare due to their ability to understand, generate, and summarize complex medical text. They offer valuable support to clinicians, researchers, and patients, yet their deployment in high-stakes clinical environments raises critical concerns regarding accuracy, reliability, and patient safety. Despite substantial attention in recent years, standardized benchmarking of LLMs for medical applications has been limited. Objective: This study addresses the need for a standardized comparative evaluation of LLMs in medical settings. Method: We evaluate multiple models, including ChatGPT, LLaMA, Grok, Gemini, and ChatDoctor, on core medical tasks such as patient note summarization and medical question answering, using the open-access datasets, MedMCQA, PubMedQA, and Asclepius, and assess performance through a combination of linguistic and task-specific metrics. Results: The results indicate that domain-specific models, such as ChatDoctor, excel in contextual reliability, producing medically accurate and semantically aligned text, whereas general-purpose models like Grok and LLaMA perform better in structured question-answering tasks, demonstrating higher quantitative accuracy. This highlights the complementary strengths of domain-specific and general-purpose LLMs depending on the medical task. Conclusion: Our findings suggest that LLMs can meaningfully support medical professionals and enhance clinical decision-making; however, their safe and effective deployment requires adherence to ethical standards, contextual accuracy, and human oversight in relevant cases. These results underscore the importance of task-specific evaluation and cautious integration of LLMs into healthcare workflows.
