Medicine (Austin & Northern Health) - Research Publications

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    Peri-OPerative Pain Management, Education & De-escalation (POPPMED), a novel anaesthesiologist-led program, significantly reduces acute and long-term postoperative opioid requirements: a retrospective cohort study.
    Heldreich, C ; Meyer, I ; Dube, E ; Hu, R ; Howard, W ; Holmes, N ; Maroon, N ; Weinberg, L ; Tan, CO (Ovid Technologies (Wolters Kluwer Health), 2022-09)
    Introduction: The opioid tolerant patient requiring surgery is highly likely to be discharged on high Oral Morphine Equivalent Daily Dosages (OMEDDs), with concomitant risk of increased morbidity and mortality. Objectives: We proposed that a single anaesthesiologist-led POPPMED (Peri-Operative Pain Management, Education & De-escalation) service could reduce both short and long-term postoperative patient OMEDDs. Methods: From April 2017, our anaesthesiologist-led POPPMED service, engaged 102 perioperative patients treated with >50mg preoperative OMEDDs. We utilized behavioural interventions; acute opioid reduction and/ or rotation; and regional, multimodal and ketamine analgesia to achieve lowest possible hospital discharge and long term OMEDDs. Results: Patients' preoperative OMEDDs were [median (IQR): 115mg (114mg)], and were representative of an older [age 62 (15) years], high-risk [89% ASA status 3 or 4] patient population. 46% of patients received an acute opioid rotation; 70% received ketamine infusions; and 44% regional analgesia. OMEDDs on discharge [-25mg (82mg), p=0.003] and at 6-12 months [-55mg (105mg ), p<0.0001] were significantly reduced; 84% and 87% of patients achieved OMEDD reduction on discharge and at 6-12 months. Patients with >90mg preoperative OMEDDs achieved greater reductions [discharge: 71% of patients, -52 mg (118 mg) p<0.0001; 6-12 months: 90% of patients, -90mg (115mg), p<0.0001]. On comparison with a pre-POPPMED surgical cohort, Postoperative Day 1-3 11-point Numerical Rating Scale (NRS-11) area under the curve (AUC) measurements at rest and on movement were not significantly different (largest NRS-11:hours AUC difference [median(IQR)] 22 [13], p= 0.24). Hospital length of stay was variably increased. Conclusions: POPPMED achieved sustained OMEDD reductions safely in an older, high-risk opioid tolerant population, with analgesia comparable to a non-POPPMED cohort, and surgery specific effects on length of stay.
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    Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR)
    James, F ; Goh, MSY ; Mouhtouris, E ; Vogrin, S ; Chua, KYL ; Holmes, NE ; Awad, A ; Copaescu, A-M ; De Luca, JF ; Zubrinich, C ; Gin, D ; Cleland, H ; Douglas, A ; Kern, JS ; Katelaris, CH ; Thien, F ; Barnes, S ; Yun, J ; Tong, W ; Smith, WB ; Carr, A ; Anderson, T ; Legg, A ; Bourke, J ; Mackay, LK ; Aung, AK ; Phillips, EJ ; Trubiano, J (BMJ PUBLISHING GROUP, 2022-08-01)
    INTRODUCTION: Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand. METHODS AND ANALYSIS: Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000241134).
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    Accuracy and reproducibility of mouse cortical bone microporosity as quantified by desktop microcomputed tomography
    Hemmatian, H ; Laurent, MR ; Ghazanfari, S ; Vanderschueren, D ; Bakker, AD ; Klein-Nulend, J ; van Lenthe, GH ; Roeder, RK (PUBLIC LIBRARY SCIENCE, 2017-08-10)
    Bone's microporosity plays important roles in bone biology and bone mechanical quality. In this study, we explored the accuracy and reproducibility of nondestructive desktop μCT for 3D visualization and subsequent morphometric analysis of mouse cortical bone microporosity including the vascular canal network and osteocyte lacunae. The accuracy of measurements was evaluated in five murine fibula using confocal laser scanning microscopy (CLSM) in conjunction with Fluorescein isothiocyanate (FITC) staining as the reference method. The reproducibility of μCT-derived cortical bone microstructural indices was examined in 10 fibulae of C57Bl/6J male mice at a nominal resolution of 700 nanometer. Three repeated measurements were made on different days. An excellent correlation between μCT and CLSM was observed for both mean lacuna volume (r = 0.98, p = 0.002) and for mean lacuna orientation (r = 0.93, p = 0.02). Whereas the two techniques showed no significant differences for these parameters, the mean lacuna sphericity acquired from μCT was significantly higher than CLSM (p = 0.01). Reproducibility was high, with precision errors (PE) of 1.57-4.69% for lacuna parameters, and of 1.01-9.45% for vascular canal parameters. Intraclass correlation coefficient (ICC) showed a high reliability of the measurements, ranging from 0.998-1.000 for cortical parameters, 0.973-0.999 for vascular canal parameters and 0.755-0.991 for lacuna parameters. In conclusion, desktop μCT is a valuable tool to quantify the 3D characteristics of bone vascular canals as well as lacunae which can be applied to intact murine bones with high accuracy and reproducibility. Thus, μCT might be an important tool to improve our understanding of the physiological and biomechanical significance of these cannular and lacunar structure in cortical bone.
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    Mechanical Loading Differentially Affects Osteocytes in Fibulae from Lactating Mice Compared to Osteocytes in Virgin Mice: Possible Role for Lacuna Size
    Hemmatian, H ; Jalali, R ; Semeins, CM ; Hogervorst, JMA ; van Lenthe, GH ; Klein-Nulend, J ; Bakker, AD (SPRINGER, 2018-12-01)
    Hormonal changes during lactation are associated with profound changes in bone cell biology, such as osteocytic osteolysis, resulting in larger lacunae. Larger lacuna shape theoretically enhances the transmission of mechanical signals to osteocytes. We aimed to provide experimental evidence supporting this theory by comparing the mechanoresponse of osteocytes in the bone of lactating mice, which have enlarged lacunae due to osteocytic osteolysis, with the response of osteocytes in bone from age-matched virgin mice. The osteocyte mechanoresponse was measured in excised fibulae that were cultured in hormone-free medium for 24 h and cyclically loaded for 10 min (sinusoidal compressive load, 3000 µε, 5 Hz) by quantifying loading-related changes in Sost mRNA expression (qPCR) and sclerostin and β-catenin protein expression (immunohistochemistry). Loading decreased Sost expression by ~ threefold in fibulae of lactating mice. The loading-induced decrease in sclerostin protein expression by osteocytes was larger in lactating mice (55% decrease ± 14 (± SD), n = 8) than virgin mice (33% decrease ± 15, n = 7). Mechanical loading upregulated β-catenin expression in osteocytes in lactating mice by 3.5-fold (± 0.2, n = 6) which is significantly (p < 0.01) higher than the 1.6-fold increase in β-catenin expression by osteocytes in fibulae from virgin mice (± 0.12, n = 4). These results suggest that osteocytes in fibulae from lactating mice with large lacunae may respond stronger to mechanical loading than those from virgin mice. This could indicate that osteocytes residing in larger lacuna show a stronger response to mechanical loading.
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    Aging, Osteocytes, and Mechanotransduction
    Hemmatian, H ; Bakker, AD ; Klein-Nulend, J ; van Lenthe, GH (SPRINGER, 2017-10-01)
    PURPOSE OF REVIEW: The bone is able to adapt its structure to mechanical signals via the bone remodeling process governed by mechanosensitive osteocytes. With aging, an imbalance in bone remodeling results in osteoporosis. In this review, we hypothesized that changes in lacunar morphology underlie the decreased bone mechanoresponsiveness to mechanical loading with aging. RECENT FINDINGS: Several studies have reported considerable variations in the shape of osteocytes and their lacunae with aging. Since osteocytes can sense matrix strain directly via their cell bodies, the variations in osteocyte morphology may cause changes in osteocyte mechanosensitivity. As a consequence, the load-adaptive response of osteocytes may change with aging, even when mechanical loading would remain unchanged. Though extensive quantitative data is lacking, evidence exists that the osteocyte lacunae are becoming smaller and more spherical with aging. Future dedicated studies might reveal whether these changes would affect osteocyte mechanosensation and the subsequent biological response, and whether this is (one of) the pathways involved in age-related bone loss.
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    Multiscale bone quality analysis in osteoarthritic knee joints reveal a role of the mechanosensory osteocyte network in osteophytes
    Rabelo, GD ; vom Scheidt, A ; Klebig, F ; Hemmatian, H ; Citak, M ; Amling, M ; Busse, B ; Jaehn, K (NATURE RESEARCH, 2020-01-20)
    Osteophytes - bony outgrowths on joint structures - are found in healthy individuals but are specifically present in late osteoarthritis (OA). Osteophyte development and function is not well understood, yet biomechanical stimuli are thought to be critical. Bone adapts to mechanical forces via the cellular network of osteocytes. The involvement of osteocytes in osteophyte formation and maturation has not been unravelled. Forty-three osteophytes from tibias of 23 OA patients (65 ± 9 years) were analysed. The trabecular bone structure of osteophytes presented with fewer trabeculae of lower bone mineral density compared to subchondral bone. We identified 40% early stage and 60% late stage osteophytes that significantly differed in their trabecular bone characteristics. Osteophyte bone revealed a higher number of osteocytes and a lower number of empty osteocyte lacunae per bone area than the subchondral bone. We found that OA osteophytes consist of younger bone material comprised of woven and lamellar bone with the capacity to develop into a late stage osteophyte potentially via the involvement of the osteocyte network. Our analysis of OA osteophytes implies a transition from woven to lamellar bone as in physiological bone growth within a pathological joint. Therefore, osteophyte development and growth present a valuable research subject when aiming to investigate the osteogenic signalling cascade.
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    Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2.
    Wines, BD ; Kurtovic, L ; Trist, HM ; Esparon, S ; Lopez, E ; Chappin, K ; Chan, L-J ; Mordant, FL ; Lee, WS ; Gherardin, NA ; Patel, SK ; Hartley, GE ; Pymm, P ; Cooney, JP ; Beeson, JG ; Godfrey, DI ; Burrell, LM ; van Zelm, MC ; Wheatley, AK ; Chung, AW ; Tham, W-H ; Subbarao, K ; Kent, SJ ; Hogarth, PM (Frontiers Media SA, 2022)
    Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.
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    Use of a penicillin allergy clinical decision rule to enable direct oral penicillin provocation: an international multicentre randomised control trial in an adult population (PALACE): study protocol
    Copaescu, A-M ; James, F ; Vogrin, S ; Rose, M ; Chua, K ; Holmes, NE ; Turner, NA ; Stone, C ; Phillips, E ; Trubiano, J (BMJ PUBLISHING GROUP, 2022-08-01)
    INTRODUCTION: Penicillin allergies are highly prevalent in the healthcare setting and associated with the prescription of second-line inferior antibiotics. More than 85% of all penicillin allergy labels can be removed by skin testing and 96%-99% of low-risk penicillin allergy labels can be removed by direct oral challenge. An internally and externally validated clinical assessment tool for penicillin allergy, PEN-FAST, can identify a low-risk penicillin allergy without the need for skin testing; a score of less than 3 has a negative predictive value of 96.3% (95% CI, 94.1 to 97.8) for the presence of a penicillin allergy. It is hypothesised that PEN-FAST is a safe and effective tool for assessing penicillin allergy in an outpatient clinic setting. METHODS AND ANALYSIS: This is an international, multicentre randomised control trial using the PEN-FAST tool to risk-stratify penicillin allergy labels in adult outpatients. The study's primary objective is to evaluate the non-inferiority of using PEN-FAST score-guided management with direct oral challenge compared with standard care (defined as prick and intradermal skin testing followed by oral penicillin challenge). Participants will be randomised 1:1 to the intervention arm (direct oral penicillin challenge) or standard of care arm (skin testing followed by oral penicillin challenge, if skin testing is negative). The sample size of 380 randomised patients (190 per treatment arm) is required to demonstrate non-inferiority. ETHICS AND DISSEMINATION: The study will be performed according to the guidelines of the Helsinki Declaration and is approved by the Austin Health Human Research Ethics Committee (HREC/62425/Austin-2020) in Melbourne Australia, Vanderbilt University Institutional Review Board (IRB #202174) in Tennessee, USA, Duke University Institutional Review Board (IRB #Pro00108461) in North Carolina, USA and McGill University Health Centre Research Ethics Board in Canada (PALACE/2022-7605). The results of this study will be published and presented in various scientific forums. TRIAL REGISTRATION NUMBER: NCT04454229.
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    Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond.
    Ong, SC ; Belgi, A ; Merriman, AL ; Delaine, CA ; van Lierop, B ; Andrikopoulos, S ; Robinson, AJ ; Forbes, BE (Frontiers Media SA, 2022)
    The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6-A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 cis-dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 cis-dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.
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    Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.
    Kar, SP ; Quiros, PM ; Gu, M ; Jiang, T ; Mitchell, J ; Langdon, R ; Iyer, V ; Barcena, C ; Vijayabaskar, MS ; Fabre, MA ; Carter, P ; Petrovski, S ; Burgess, S ; Vassiliou, GS (Springer Science and Business Media LLC, 2022-08)
    Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.