Medicine (St Vincent's) - Research Publications

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    The effect of carbamazepine on bone structure and strength in control and osteogenesis imperfecta (Col1a2 (+/p.G610C)) mice
    Blank, M ; McGregor, NE ; Rowley, L ; Kung, LHW ; Crimeen-Irwin, B ; Poulton, IJ ; Walker, EC ; Gooi, JH ; Lamande, SR ; Sims, NA ; Bateman, JF (WILEY, 2022-06-14)
    The inherited brittle bone disease osteogenesis imperfecta (OI) is commonly caused by COL1A1 and COL1A2 mutations that disrupt the collagen I triple helix. This causes intracellular endoplasmic reticulum (ER) retention of the misfolded collagen and can result in a pathological ER stress response. A therapeutic approach to reduce this toxic mutant load could be to stimulate mutant collagen degradation by manipulating autophagy and/or ER-associated degradation. Since carbamazepine (CBZ) both stimulates autophagy of misfolded collagen X and improves skeletal pathology in a metaphyseal chondrodysplasia model, we tested the effect of CBZ on bone structure and strength in 3-week-old male OI Col1a2 +/p.G610C and control mice. Treatment for 3 or 6 weeks with CBZ, at the dose effective in metaphyseal chondrodysplasia, provided no therapeutic benefit to Col1a2 +/p.G610C mouse bone structure, strength or composition, measured by micro-computed tomography, three point bending tests and Fourier-transform infrared microspectroscopy. In control mice, however, CBZ treatment for 6 weeks impaired femur growth and led to lower femoral cortical and trabecular bone mass. These data, showing the negative impact of CBZ treatment on the developing mouse bones, raise important issues which must be considered in any human clinical applications of CBZ in growing individuals.
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    Associations between Smoking and Alcohol and Follicular Lymphoma Incidence and Survival: A Family-Based Case-Control Study in Australia
    Odutola, MK ; van Leeuwen, MT ; Turner, J ; Bruinsma, F ; Seymour, JF ; Prince, HM ; Milliken, ST ; Trotman, J ; Verner, E ; Tiley, C ; Roncolato, F ; Underhill, CR ; Opat, SS ; Harvey, M ; Hertzberg, M ; Benke, G ; Giles, GG ; Vajdic, CM (MDPI, 2022-06-01)
    The association between smoking and alcohol consumption and follicular lymphoma (FL) incidence and clinical outcome is uncertain. We conducted a population-based family case-control study (709 cases: 490 controls) in Australia. We assessed lifetime history of smoking and recent alcohol consumption and followed-up cases (median = 83 months). We examined associations with FL risk using unconditional logistic regression and with all-cause and FL-specific mortality of cases using Cox regression. FL risk was associated with ever smoking (OR = 1.38, 95%CI = 1.08-1.74), former smoking (OR = 1.36, 95%CI = 1.05-1.77), smoking initiation before age 17 (OR = 1.47, 95%CI = 1.06-2.05), the highest categories of cigarettes smoked per day (OR = 1.44, 95%CI = 1.04-2.01), smoking duration (OR = 1.53, 95%CI = 1.07-2.18) and pack-years (OR = 1.56, 95%CI = 1.10-2.22). For never smokers, FL risk increased for those exposed indoors to >2 smokers during childhood (OR = 1.84, 95%CI = 1.11-3.04). For cases, current smoking and the highest categories of smoking duration and lifetime cigarette exposure were associated with elevated all-cause mortality. The hazard ratio for current smoking and FL-specific mortality was 2.97 (95%CI = 0.91-9.72). We found no association between recent alcohol consumption and FL risk, all-cause or FL-specific mortality. Our study showed consistent evidence of an association between smoking and increased FL risk and possibly also FL-specific mortality. Strengthening anti-smoking policies and interventions may reduce the population burden of FL.
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    Risk Factors for Exercise-Associated Sudden Cardiac Death in Thoroughbred Racehorses
    Nath, L ; Stent, A ; Elliott, A ; La Gerche, A ; Franklin, S (MDPI, 2022-05-01)
    Cardiac arrhythmias resulting in sudden cardiac death (SCD) are an important cause of racehorse fatalities. The objective of this study was to determine risk factors for SCD in Thoroughbreds by evaluating a sample with a policy of mandatory post-mortem following racing or training fatalities. Risk factors were compared between case horses with SCD (n = 57) and control horses with other fatal injury (OFI, n = 188) by univariable and multivariable logistic regression. Survival in years for horses with SCD was compared to OFI using the Kaplan-Meier method with log rank test. The following variables were most important in the multiple logistic model: Horses with SCD were more likely to die during training than during racing, SCD (42/57, 74%) vs. OFI (82/188, 44%; odds ratio [OR], 95% confidence interval [CI], 2.5, 1.2-5.4; p = 0.01), had fewer lifetime starts, median (interquartile range [IQR]), SCD (3.0 [0.0-9.0]) vs. OFI (9.0 [0.0-22.8]; OR, 95% CI, 0.96, 0.9-1.0; p = 0.02 and were less likely to be entire (uncastrated) males, SCD 9/57 (16%) vs. OFI (46/188, 25%; OR, 95% CI, 0.47, 0.1-0.9; p = 0.03). Survival in years (median (IQR)) for horses with SCD was 3.6 (3.1-4.4), which was shorter than OFI (4.5 [3.1-6.0], hazard ratio, 95%CI, 1.6,1.2-2.3; p < 0.001). SCD occurs more commonly in training than racing, which suggests exercise intensity is less important in precipitating this fatality. In this study, SCD occurred early in the careers of affected horses.
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    The Global Impact of Hepatitis B Vaccination on Hepatocellular Carcinoma
    Flores, JE ; Thompson, AJ ; Ryan, M ; Howell, J (MDPI, 2022-05-01)
    Over 1.5 million preventable new hepatitis B infections continue to occur each year and there are an estimated 296 million people living with chronic hepatitis B infection worldwide, resulting in more than 820,000 deaths annually due to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B vaccination remains the cornerstone of public health policy to prevent HCC and a vital component of the global hepatitis B elimination response. The WHO has set a 90% vaccination target to achieve hepatitis B elimination by 2030; however, there is wide variability in reported birth dose coverage, with global coverage at only 42%. In this review, we outline the global trends in hepatitis B vaccination coverage and the impact of hepatitis B vaccination on HCC incidence and discuss the challenges and enabling factors for achieving WHO 2030 hepatitis B vaccination coverage targets.
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    Too much sugar does not just make us fat; it can also make us sick
    Dwyer, KM ; Robson, B ; Muecke, J (WILEY, 2022-05-22)
    The post-COVID-19 care era is likely to see a burgeoning of metabolic dysfunction and chronic kidney disease. Attention to self-care, including nutrition, will underpin the management of those affected. The damaging effects of sugar-sweetened beverages are well documented and profound and counter many accepted medical treatments. Government leadership is urgently required with explicit and strong messaging to avoid sugar-sweetened beverages.
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    Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b vaccines after temporary suspension of DMARD therapy in immune-mediated inflammatory disease (RESCUE).
    Tran, AP ; Tassone, D ; Nossent, J ; Ding, NS (BMJ, 2022-05)
    OBJECTIVE: To assess the antibody response to disease-modifying antirheumatic drug (DMARD) therapy after the first and second dose of the ChAdOx1nCov-19 (AstraZeneca (AZ)) and BNT162b (Pfizer) vaccines in patients with immune-mediated inflammatory disease (IMID) compared with controls and if withholding therapy following the first vaccination dose has any effect on seroconversion and SARS-CoV-2 antibody (Ab) levels. METHODS: A multicentre three-arm randomised controlled trial compared the immunogenicity of the Pfizer and AZ vaccines in adult patients on conventional synthetic (csDMARD), biologic (bDMARD) or targeted synthetic (tsDMARD) therapy for IMID (n=181) with a control group (n=59). Patients were randomised to continue or withhold DMARD therapy for 1-2 weeks post first dose vaccination only. Serum SARS-CoV-2 IgG detection (IgG ≥1.0 U/mL) and titres against the S1/S2 proteins were measured at baseline, 3-4 weeks post first vaccination and 4 weeks post second vaccination. RESULTS: AZ vaccination was given to 47.5%, 41.5% and 52.5% in the continue, withhold and control groups, respectively while Pfizer vaccination was given to 52.5%, 58.5% and 47.5% among the continue, withhold and control groups, respectively. Seroconversion rates following the first dose in the AZ and Pfizer groups were only 27.3% vs 79.2% (p=0.000) and 64.58% vs 100% (p=0.000), respectively in the IMID groups who continued therapy compared with the AZ and Pfizer controls, respectively. Withholding DMARD therapy following the first vaccination dose resulted in higher seroconversion to 67.7% and 84.1% in the AZ and Pfizer groups, respectively. Following the second AZ and Pfizer vaccinations when all DMARDs were continued, despite a slightly lower seroconversion rate (83.7% vs 100%, p=0.000 and 95.9% vs 100%, p=0.413), respectively, the mean SARS-CoV2 IgG Ab titres were not significantly different in the csDMARD and bDMARD groups compared with the controls regardless of hold while it was significantly lower in patients taking tsDMARD (12.88 vs 79.49 U/mL, p=0.000). CONCLUSIONS: Following the first vaccination dose, antibody responses were lower in IMID on DMARD therapy, however the final responses were excellent regardless of hold with the exception of the tsDMARD group where withholding therapy is recommended. At least 2 vaccinations are therefore recommended preferably with an messenger RNA vaccine. TRIAL REGISTRATION NUMBER: ANZCTR: 12621000661875.
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    Retinal drusen in glomerulonephritis with or without immune deposits suggest systemic complement activation in disease pathogenesis
    Harraka, P ; Mack, H ; Colville, D ; Barit, D ; Langsford, D ; Pianta, T ; Ierino, F ; Savige, J (NATURE PORTFOLIO, 2022-05-17)
    Retinal drusen are characteristic of macular degeneration and complement activation, but also occur in C3, lupus and IgA nephropathy. This cross-sectional observational study compared drusen counts in different forms of glomerulonephritis. Consecutive individuals with glomerulonephritis attending a general renal or transplant clinic underwent retinal imaging with a non-mydriatic camera. Drusen were counted in deidentified images by trained graders, compared with matched hospital patients, and correlated with clinical features. Eighty-four individuals with glomerulonephritis had a mean drusen count of 10 ± 27 compared with 3 ± 8 in hospital controls (p = 0.007). Fourteen individuals with glomerulonephritis (17%) and 4 hospital controls (4/49, 8%) had increased drusen counts (≥ 10) (p = 0.20). Increased drusen counts ≥ 10 were present in 13 (13/63, 21%)  of those with glomerulonephritis and immune deposits [membranous (n = 8), antiglomerular basement membrane nephritis (n = 6), FSGS (n = 49)], and one of the 21 (5%) with glomerulonephritis without immune deposits [ANCA-associated (n = 15), minimal change disease (n = 6)]. In antibody-mediated glomerulonephritis (n = 14), mean drusen counts were 2 ± 3 in individuals with normal kidney function, 16 ± 41 with impaired function and 5 ± 7 with kidney failure . Mean counts were 24 ± 56 in individuals with glomerular IgG deposits and 1 ± 1 in those without (p = 0.76), and 23 ± 60 with complement deposits and 4 ± 8 in those without. Drusen counts were also less in immunosuppressed individuals (p = 0.049). The demonstration of retinal drusen in some forms of glomerulonephritis is consistent with systemic complement activation, and suggests that treatment targeting the complement pathways is worthwhile.
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    Evidence-Practice Gaps in Postdischarge Initiation With Oral Anticoagulants in Patients With Atrial Fibrillation.
    Schaffer, AL ; Falster, MO ; Brieger, D ; Jorm, LR ; Wilson, A ; Hay, M ; Leeb, K ; Pearson, S ; Nasis, A (Ovid Technologies (Wolters Kluwer Health), 2019-12-17)
    Background Oral anticoagulant (OAC) therapy reduces the risk of stroke in people with atrial fibrillation (AF), and is considered best practice; however, there is little Australian evidence around the uptake of OACs in this population. Methods and Results We used linked hospital admissions, pharmaceutical dispensing claims, medical services, and mortality data for people in Australia's 2 most populous states (July 2010 to June 2015). Among OAC-naïve people hospitalized with AF, we estimated initiation of OAC therapy within 30 days of discharge, and persistence with therapy in the first year. We analyzed both outcomes using multivariable Cox regression. In 71 184 people with AF (median age 78 years, 49% female), 22.7% initiated OAC therapy. Initiation was lowest in July to December 2011 (17.0%) and highest in July to December 2014 (30.1%) after subsidy of the direct OACs. In adjusted analyses, initiation was most likely in people with a CHA2DS2-VA score ≥7 (versus 0) (hazard ratio=6.25, 95% CI 5.08-7.69), and a history of venous thromboembolism (hazard ratio=2.65, 95% CI 2.49-2.83). Of the people who initiated OAC therapy, 39.9% discontinued within 1 year; a lower risk of discontinuation was associated with a CHA2DS2-VA score ≥7 (versus 0) (hazard ratio=0.22, 95% CI 0.14-0.35), or initiation on a direct OAC (versus warfarin) (hazard ratio=0.55, 95% CI 0.50-0.60). Conclusions We found that OAC therapy was severely underutilized in people hospitalized with AF, even among high-risk individuals. Reasons for this underuse, whether patient, prescriber, or hospital related, should be identified and addressed to reduce stroke-related morbidity and mortality in people with AF.
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    Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis
    Lee, MKS ; Cooney, OD ; Lin, X ; Nadarajah, S ; Dragoljevic, D ; Huynh, K ; Onda, D-A ; Galic, S ; Meikle, PJ ; Edlund, T ; Fullerton, MD ; Kemp, BE ; Murphy, AJ ; Loh, K (ELSEVIER, 2022-07-01)
    OBJECTIVES: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. METHODS: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe-/-/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe-/- and Apoe-/-/Hmgcr KI mice. RESULTS: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe-/-/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe-/-/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe-/-/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. CONCLUSIONS: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O-3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks.
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    Development and pilot feasibility study of a health information technology tool to calculate mortality risk for patients with asymptomatic carotid stenosis: the Carotid Risk Assessment Tool (CARAT).
    Faerber, AE ; Horvath, R ; Stillman, C ; O'Connell, ML ; Hamilton, AL ; Newhall, KA ; Likosky, DS ; Goodney, PP (Springer Science and Business Media LLC, 2015-03-24)
    BACKGROUND: Patients with no history of stroke but with stenosis of the carotid arteries can reduce the risk of future stroke with surgery or stenting. At present, a physicians' ability to recommend optimal treatments based on an individual's risk profile requires estimating the likelihood that a patient will have a poor peri-operative outcomes and the likelihood that the patient will survive long enough to gain benefit from the procedure. We describe the development of the CArotid Risk Assessment Tool (CARAT) into a 2-year mortality risk calculator within the electronic medical record, integrating the tool into the clinical workflow, training the clinical team to use the tool, and assessing the feasibility and acceptability of the tool in one clinic setting. METHODS: We modified an existing clinical flowsheet with the local electronic medical record for the CARAT risk model. To understand how CARAT would fit into the existing clinical workflow, we observed the clinic and talked with the clinical staff to develop a process map for the existing clinical workflow. CARAT was completed by the clinic nurse for patients identified on the clinic schedule as having carotid narrowing. We analyzed post-implementation assessment in two ways: quantifying the proportion of eligible patients with whom CARAT was utilized, and surveying surgeons to understand the impact of CARAT on decision-making and clinical workflow. RESULTS: With minimum investment of institutional resources, we were able to produce a workable tool and pilot the tool in our clinic within a 6 month time period. Over 4 months, 287 patients were seen in the clinic with carotid narrowing, and clinic staff completed CARAT for 195 (68%). Per-surgeon completion rates ranged from 29 to 81%. Most patients (191 of 195, 98%) patients had a low 2-year calculated mortality risk. Most surgeons believed the risk assessment aligned with their expectations of patient predicted risk. CONCLUSIONS: We successfully integrated CARAT into the existing electronic medical record and have preliminary evidence that CARAT can be a valuable tool for evaluating mortality risk for patients with diseased carotid arteries. Accuracy of the risk calculations must be evaluated in larger, multi-center studies.