Medicine (St Vincent's) - Research Publications

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    Obesity in young sudden cardiac death: Rates, clinical features, and insights into people with body mass index >50kg/m2.
    Paratz, ED ; Ashokkumar, S ; van Heusden, A ; Smith, K ; Zentner, D ; Morgan, N ; Parsons, S ; Thompson, T ; James, P ; Connell, V ; Pflaumer, A ; Semsarian, C ; Ingles, J ; Stub, D ; Gerche, AL (Elsevier BV, 2022-09)
    Objective: To contextualize obesity rates in young sudden cardiac death (SCD) against the age-matched national population, and identify clinical and pathologic features in WHO class II and III obesity. Methods: A prospective state-wide out-of-hospital cardiac arrest registry included all SCDs in Victoria, Australia from 2019-2021. Body mass indices (BMIs) of patients 18-50 years were compared to age-referenced general population. Characteristics of SCD patients with WHO Class II obesity (BMI ≥30kg/m2) and non-obesity (BMI<30kg/m2) were compared. Clinical characteristics of people with BMI>50kg/m2 were assessed. Results: 504 patients were included. Obesity was strongly over-represented in young SCD compared to the age-matched general population (55.0% vs 28.7%, p<0.0001). Obese SCD patients more frequently had hypertension, diabetes and obstructive sleep apnoea (p<0.0001, p=0.009 and p=0.001 respectively), ventricular fibrillation as their arrest rhythm (p=0.008) and left ventricular hypertrophy (LVH) (p<0.0001). Obese patients were less likely to have toxicology positive for illicit substances (22.0% vs 32.6%, p=0.008) or history of alcohol abuse (18.8% vs 26.9%, p=0.030). Patients with BMI>50 kg/m2 represented 8.5% of young SCD. LVH (n=26, 60.5%) was their predominant cause of death and only 10 (9.3%) patients died from coronary disease. Conclusion: Over half of young Australian SCD patients are obese, with all obesity classes over-represented compared to the general population. Obese patients had more cardiac risk factors. Almost two thirds of patients with BMI>50 kg/m2 died from LVH, with fewer than 10% dying from coronary disease.
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    Use of electronic medical records to monitor the safe and effective prescribing of medicinal cannabis: is it feasible?
    Hallinan, CM ; Gunn, JM ; Bonomo, YA (CSIRO Publishing, 2022)
    General practitioners are well positioned to contribute to the pharmacovigilance of medical cannabis via the general practice electronic medical record (EMR). The aim of this research is to interrogate de-identified patient data from the Patron primary care data repository for reports of medicinal cannabis to ascertain the feasibility of using EMRs to monitor medicinal cannabis prescribing in Australia. Methods. EMR rule-based digital phenotyping of 1 164 846 active patients from 109 practices was undertaken to investigate reports of medicinal cannabis use from September 2017 to September 2020. Results. Eighty patients with 170 prescriptions of medicinal cannabis were identified in the Patron repository. Reasons for prescription included anxiety, multiple sclerosis, cancer, nausea, and Crohn’s disease. Nine patients showed symptoms of a possible adverse event, including depression, motor vehicle accident, gastrointestinal symptoms, and anxiety. Conclusions. The recording of medicinal cannabis effects in the patient EMR provides potential for medicinal cannabis monitoring in the community. This is especially feasible if monitoring were to be embedded into general practitioner workflow.
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    Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator
    Ovens, AJ ; Gee, YS ; Ling, NXY ; Yu, D ; Hardee, JP ; Chung, JD ; Ngoei, KRW ; Waters, NJ ; Hoffman, NJ ; Scott, JW ; Loh, K ; Spengler, K ; Heller, R ; Parker, MW ; Lynch, GS ; Huang, F ; Galic, S ; Kemp, BE ; Baell, JB ; Oakhill, JS ; Langendorf, CG (PORTLAND PRESS LTD, 2022-06-01)
    The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of energy homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake and provides an opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2β2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2β2-specific activators, here we perform structure/function analysis of the 2-hydroxybiphenyl group of SC4, an activator with tendency for α2-selectivity that is also capable of potently activating β2 complexes. Substitution of the LHS 2-hydroxyphenyl group with polar-substituted cyclohexene-based probes resulted in two AMPK agonists, MSG010 and MSG011, which did not display α2-selectivity when screened against a panel of AMPK complexes. By radiolabel kinase assay, MSG010 and MSG011 activated α2β2γ1 AMPK with one order of magnitude greater potency than the pan AMPK activator MK-8722. A crystal structure of MSG011 complexed to AMPK α2β1γ1 revealed a similar binding mode to SC4 and the potential importance of an interaction between the SC4 2-hydroxyl group and α2-Lys31 for directing α2-selectivity. MSG011 induced robust AMPK signalling in mouse primary hepatocytes and commonly used cell lines, and in most cases this occurred in the absence of changes in phosphorylation of the kinase activation loop residue α-Thr172, a classical marker of AMP-induced AMPK activity. These findings will guide future design of α2β2-selective AMPK activators, that we hypothesise may avoid off-target complications associated with indiscriminate activation of AMPK throughout the body.
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    Improving access to cancer information and supportive care services: A systematic review of mechanisms applied to link people with cancer to psychosocial supportive care services
    White, VM ; Pejoski, N ; Vella, E ; Skaczkowski, G ; Ugalde, A ; Yuen, EYN ; Livingston, P ; Wilson, C (WILEY, 2021-06-16)
    OBJECTIVE: Previous research has described the low uptake of psychosocial support services in people living with cancer. While characteristics of individuals using services have been examined, mechanisms applied to link individuals to support services are less frequently considered. This review aims to identify the mechanisms used to link people with cancer to support services and assess their impact. METHODS: Systematic searches of Pubmed, CINAHL, EMBASE and PsycINFO were conducted up to May 2020. Studies reporting service use associated with mechanisms to link adults with cancer to support services targeting emotional, informational, practical or social support needs were eligible. Eligible study designs included controlled trials, pre-post designs and observational studies. Study quality was assessed and a narrative synthesis of findings undertaken. RESULTS: A total of 10 papers (from 8,037 unique titles) were eligible. Testing the feasibility of the linkage mechanism was the primary aim in five (50%) studies. Three linkage mechanisms were identified: (a) outreach from the support service; (b) clinician recommendation/referral; (c) mailed invitation. Outreach was the most successful in connecting people with cancer to services (52%-90% use); clinician recommendation/referral was least successful (3%-28%). The impact of different linkage mechanisms for different demographic groups was not assessed. CONCLUSIONS: Outreach from services shows the most potential for increasing access to support services. However, the limited number of studies and limitations in the types of support services people with cancer were linked to, demonstrated the need for further work in this area. Identifying mechanisms that are effective for underserved, high-needs patient groups is also needed.
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    Vulval lichen sclerosus: An Australasian management consensus
    Yeon, J ; Oakley, A ; Olsson, A ; Drummond, C ; Veysey, E ; Marshman, G ; Saunders, H ; Opie, J ; Bradford, J ; Cole, J ; DeAmbrosis, K ; Cook, K ; Pepall, L ; Eva, LJ ; Sladden, M ; Selva-Nayagam, P ; Phillips, R ; Ball, S ; Hill, S ; Bohl, T ; Day, T ; Lee, G ; Fischer, G (WILEY, 2021-06-12)
    BACKGROUND/OBJECTIVES: Vulval lichen sclerosus (VLS) is a chronic inflammatory skin condition predominantly affecting the anogenital region in women and children. To date, there is lack of agreement amongst experts on a severity scale to aid assessment, research and treatment stratification on VLS. Furthermore, literature on best practice for long-term management of VLS is lacking. The aim of this consensus is to provide broad guidelines on the short and long-term management of VLS. METHODS: An initial focus group of Australasian experts in vulval dermatology developed a draft consensus statement for the management of VLS. Based on the results of the draft statement, a consensus panel of 22 Australasian experts, comprised of the initial and additional members, participated in an anonymous four-stage eDelphi process. Round 1 involved generation and voting on statements from the draft consensus statement developed by the focus group. In Rounds 2, 3 & 4, panel members were presented formal feedback from previous rounds and asked to indicate their level of agreement. Consensus was reached if there was ≥70% agreement on the importance of an item in the 4 (agree) to 5 (strongly agree) range. RESULTS: The expert panel, with a total of 504 collective years of experience in the field of VLS, reached consensus on a core set of 51 management statements related to diagnosis, severity, initial and long-term management, follow-up, and complications of VLS. CONCLUSIONS: This study has identified a set of management statements for VLS that may be useful in clinical practice in the Australasian population.
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    Regulation of murine B lymphopoiesis by stromal cells
    Kwang, D ; Tjin, G ; Purton, LE (WILEY, 2021-05-17)
    B lymphocytes are crucial for the body's humoral immune response, secreting antibodies generated against foreign antigens to fight infection. Adult murine B lymphopoiesis is initiated in the bone marrow and additional maturation occurs in the spleen. In both these organs, B lymphopoiesis involves interactions with numerous different non-hematopoietic cells, also known as stromal or microenvironment cells, which provide migratory, maturation, and survival signals. A variety of conditional knockout and transgenic mouse models have been used to identify the roles of distinct microenvironment cell types in the regulation of B lymphopoiesis. These studies have revealed that mesenchymal lineage cells and endothelial cells comprise the non-hematopoietic microenvironment cell types that support B lymphopoiesis in the bone marrow. In the spleen, various types of stromal cells and endothelial cells contribute to B lymphocyte maturation. More recently, comprehensive single cell RNA-seq studies have also been used to identify clusters of stromal cell types in the bone marrow and spleen, which will aid in further identifying key regulators of B lymphopoiesis. Here, we review the different types of microenvironment cells and key extrinsic regulators that are known to be involved in the regulation of murine B lymphopoiesis in the bone marrow and spleen.
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    Australian experience with total pancreatectomy with islet autotransplantation to treat chronic pancreatitis
    Bampton, TJ ; Holmes-Walker, DJ ; Drogemuller, CJ ; Radford, T ; Anderson, P ; Etherton, C ; Russell, CH ; Khurana, S ; Torpy, DJ ; Couper, JJ ; Couper, RLT ; Macintyre, P ; Neo, EL ; Benitez-Aguirre, P ; Thomas, G ; Loudovaris, T ; Thomas, HE ; Palmer, LJ ; Wu, D ; Rogers, NM ; Williams, L ; Hawthorne, WJ ; O'Connell, PJ ; Kay, TW ; Pleass, H ; Chen, JW ; Coates, PT (WILEY, 2021-05-06)
    BACKGROUND: This study aimed to describe the clinical outcomes of total pancreatectomy with islet autotransplantation (TP-IAT) in Australia. METHODS: Individuals selected for TP-IAT surgery according to the Minnesota Criteria (Appendix) without evidence of diabetes were evaluated including time to transplantation from pancreatectomy, islet numbers infused and post-transplantation HbA1c, C-peptide, total daily insulin and analgesic requirement. RESULTS: Sixteen individuals underwent TP-IAT from Australia and New Zealand between 2010 and 2020. Two recipients are deceased. The median islet equivalents/kg infused was 4244 (interquartile range (IQR) 2290-7300). The median C-peptide 1 month post-TP-IAT was 384 (IQR 210-579) pmol/L and at median 29.5 (IQR 14.5-46.5) months from transplant was 395 (IQR 139-862) pmol/L. Insulin independence was achieved in eight of 15 (53.3%) surviving recipients. A higher islet equivalents transplanted was most strongly associated with the likelihood of insulin independence (P < 0.05). Of the 15 surviving recipients, 14 demonstrated substantial reduction in analgesic requirement. CONCLUSION: The TP-IAT programme in Australia has been a successful new therapy for the management of individuals with chronic pancreatitis including hereditary forms refractory to medical treatment to improve pain management with 50% insulin independence rates.
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    Contact allergy and allergic contact dermatitis from benzalkonium chloride in a tertiary dermatology center in Melbourne, Australia.
    Dear, K ; Palmer, A ; Nixon, R (Wiley, 2021-03-03)
    BACKGROUND: Benzalkonium chloride (BAK) is a quaternary ammonium compound that is used widely as an antiseptic and preservative. It is a strong irritant and considered a weak sensitizer. OBJECTIVE: To analyze the temporal trend of BAK sensitization and the demographics of sensitized patients. METHODS: We conducted a single-center retrospective study of 7390 patients who were patch tested with BAK between January 1, 2003 and December 31, 2019. RESULTS: Of the 7390 patients who were patch tested to BAK, 108 (1.5%) had a positive reaction, with 21 reactions deemed clinically relevant (0.3% of total patch tested) and a further 5 doubtful reactions deemed clinically relevant, resulting in a total of 26 relevant reactions (0.4% of total patch tested). Common sources of exposure were ophthalmic drops (30.8%), topical antiseptic preparations (26.9%), cosmetics (15.4%), disinfectant solutions (11.5%), hand sanitizers (11.5%), and hand washes (7.7%). One fifth of patients with relevant reactions were health care workers. There has been a dramatic increase in the number of positive reactions since 2017, for reasons not totally clear. CONCLUSION: Contact allergy (CA) and allergic contact dermatitis (ACD) in response to BAK are now increasing at our center. Awareness of this trend is important, given that the coronavirus disease 2019 (COVID-19) pandemic is likely to further expose people to BAK.
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    Commercial growing up milks: usage frequency and associated child and demographic factors across four Asia Pacific countries
    Willcox, JC ; Februhartanty, J ; Satheannoppakao, W ; Hutchinson, C ; Itsiopoulos, C ; Worsley, A (WILEY, 2021-01-06)
    BACKGROUND: Commercial growing up milks (GUMs) targeted at children from 12 to 36 months of age are a rapidly growing industry, particularly across the Asia Pacific. METHODS: The present study assessed the frequency of use and socio-demographic and child associations of commercial GUM feeding in children, aged between 12 and 36 months, in capital cities in four Asia Pacific countries. Mothers of children aged between 12 and 36 months were surveyed, assessing GUM feeding frequency in the past month. A market research company database was used to survey across Asia Pacific urban cities, including Bangkok Thailand, Jakarta Indonesia, Singapore and Australian Capital Cities (ACC). RESULTS: More than 1000 women (n = 1051) were surveyed (Bangkok, n = 263; Jakarta, n = 275; ACC, n = 252; Singapore, n = 261). The mean (SD) age of mothers was 32.4 (5.3) years and that of children was 23.6 (6.7) months. In total, 62.7% of the children were fed GUMs more than once per week with significant country variance. In comparison with ACC, Asian countries were significantly more likely to feed GUMs ≥once per week: Bangkok [odds ratio (OR) = 5.7, 95% confidence interval (CI) = 3.8-8.6]; Jakarta (OR = 3.5, 95% CI = 2.3-5.5); and Singapore (OR = 7.4, 95% CI = 4.9-11.1). Associations of GUM feeding included: maternal tertiary education; mothers younger than 30 years; working full time; and feeding of commercial infant formula under 12 months. CONCLUSIONS: This is the first published study to explore commercial GUM feeding in and between countries. The incidence of GUM feeding, in contrast to international recommendations, signals the need for further research into the drivers for GUM feeding and its contribution to the diet.