Medicine (St Vincent's) - Research Publications

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    Impact of COVID-19 lockdown restrictions on hepatitis C testing in Australian primary care services providing care for people who inject drugs
    Traeger, MW ; van Santen, DK ; Sacks-Davis, R ; Asselin, J ; Carter, A ; Doyle, JS ; Pedrana, A ; Wilkinson, AL ; Howell, J ; Thatcher, R ; Didlick, J ; Donovan, B ; Guy, R ; Hellard, ME ; Stoove, MA (WILEY, 2022-07-05)
    In 2020, the Australian state of Victoria experienced the longest COVID-19 lockdowns of any jurisdiction, with two lockdowns starting in March and July, respectively. Lockdowns may impact progress towards eliminating hepatitis C through reductions in hepatitis C testing. To examine the impact of lockdowns on hepatitis C testing in Victoria, de-identified data were extracted from a network of 11 services that specialize in the care of people who inject drugs (PWID). Interrupted time-series analyses estimated weekly changes in hepatitis C antibody and RNA testing from 1 January 2019 to 14 May 2021 and described temporal changes in testing associated with lockdowns. Interruptions were defined at the weeks corresponding to the start of the first lockdown (week 14) and the start (week 80) and end (week 95) of the second lockdown. Pre-COVID, an average of 80.6 antibody and 25.7 RNA tests were performed each week. Following the first lockdown in Victoria, there was an immediate drop of 23.2 antibody tests and 8.6 RNA tests per week (equivalent to a 31% and 46% drop, respectively). Following the second lockdown, there was an immediate drop of 17.2 antibody tests and 4.6 RNA tests per week (equivalent to a 26% and 33% drop, respectively). With testing and case finding identified as a key challenge to Australia achieving hepatitis C elimination targets, the cumulative number of testing opportunities missed during lockdowns may prolong efforts to find, diagnose and engage or reengage in care of the remaining population of PWID living with hepatitis C.
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    Feedback of aggregate patient-reported outcomes (PROs) data to clinicians and hospital end users: findings from an Australian codesign workshop process
    Ryan, OF ; Hancock, SL ; Marion, V ; Kelly, P ; Kilkenny, MF ; Clissold, B ; Gunzburg, P ; Cooke, S ; Guy, L ; Sanders, L ; Breen, S ; Cadilhac, DA (BMJ PUBLISHING GROUP, 2022-07-01)
    OBJECTIVES: Patient-reported outcomes (PROs) are increasingly used to measure the patient's perspective of their outcomes following healthcare interventions. The aim of this study was to determine the preferred formats for reporting service-level PROs data to clinicians, researchers and managers to support greater utility of these data to improve healthcare and patient outcomes. SETTING: Healthcare professionals receiving PRO data feedback at the health service level. PARTICIPANTS: An interdisciplinary Project Working Group comprised of clinicians participated in three workshops to codesign reporting templates of summarised PRO data (modified Rankin Scale, EuroQol Five Dimension Descriptive System, EuroQol Visual Analogue Scale and Hospital Anxiety and Depression Scale) using a modified Delphi process. An electronic survey was then distributed to short list the preferred templates among a broad sample of clinical end users. A final workshop was undertaken with the Project Working Group to review results and reach consensus on the final templates. PRIMARY AND SECONDARY OUTCOME MEASURES: The recommendation of preferred PRO summary data feedback templates and guiding principles for reporting aggregate PRO data to clinicians was the primary outcome. A secondary outcome was the identification of perceived barriers and enablers to the use of PRO data in hospitals. For each outcome measure, quantitative and qualitative data were summarised. RESULTS: 31 Working Group members (19 stroke, 2 psychology, 1 pharmacy, 9 researchers) participated in the workshops, where 25/55 templates were shortlisted for wider assessment. The survey was completed by 114 end users. Strongest preferences were identified for bar charts (37/82 votes, 45%) and stacked bar charts (37/91 votes, 41%). At the final workshop, recommendations to enhance communication of PROs data for comparing health service performance were made including tailoring feedback to professional roles and use of case-mix adjustment to ensure fair comparisons. CONCLUSIONS: Our research provides guidance on PROs reporting for optimising data interpretation and comparing hospital performance.
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    Cystathionine-beta-synthase is essential for AKT-induced senescence and suppresses the development of gastric cancers with PI3K/AKT activation
    Zhu, H ; Chan, KT ; Huang, X ; Cerra, C ; Blake, S ; Trigos, AS ; Anderson, D ; Creek, DJ ; De Souza, DP ; Wang, X ; Fu, C ; Jana, M ; Sanij, E ; Pearson, RB ; Kang, J (eLIFE SCIENCES PUBL LTD, 2022-06-27)
    Hyperactivation of oncogenic pathways downstream of RAS and PI3K/AKT in normal cells induces a senescence-like phenotype that acts as a tumor-suppressive mechanism that must be overcome during transformation. We previously demonstrated that AKT-induced senescence (AIS) is associated with profound transcriptional and metabolic changes. Here, we demonstrate that human fibroblasts undergoing AIS display upregulated cystathionine-β-synthase (CBS) expression and enhanced uptake of exogenous cysteine, which lead to increased hydrogen sulfide (H2S) and glutathione (GSH) production, consequently protecting senescent cells from oxidative stress-induced cell death. CBS depletion allows AIS cells to escape senescence and re-enter the cell cycle, indicating the importance of CBS activity in maintaining AIS. Mechanistically, we show this restoration of proliferation is mediated through suppressing mitochondrial respiration and reactive oxygen species (ROS) production by reducing mitochondrial localized CBS while retaining antioxidant capacity of transsulfuration pathway. These findings implicate a potential tumor-suppressive role for CBS in cells with aberrant PI3K/AKT pathway activation. Consistent with this concept, in human gastric cancer cells with activated PI3K/AKT signaling, we demonstrate that CBS expression is suppressed due to promoter hypermethylation. CBS loss cooperates with activated PI3K/AKT signaling in promoting anchorage-independent growth of gastric epithelial cells, while CBS restoration suppresses the growth of gastric tumors in vivo. Taken together, we find that CBS is a novel regulator of AIS and a potential tumor suppressor in PI3K/AKT-driven gastric cancers, providing a new exploitable metabolic vulnerability in these cancers.
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    Systemic Ablation of Camkk2 Impairs Metastatic Colonization and Improves Insulin Sensitivity in TRAMP Mice: Evidence for Cancer Cell-Extrinsic CAMKK2 Functions in Prostate Cancer
    Pulliam, TL ; Awad, D ; Han, JJ ; Murray, MM ; Ackroyd, JJ ; Goli, P ; Oakhill, JS ; Scott, JW ; Ittmann, MM ; Frigo, DE (MDPI, 2022-06-01)
    Despite early studies linking calcium-calmodulin protein kinase kinase 2 (CAMKK2) to prostate cancer cell migration and invasion, the role of CAMKK2 in metastasis in vivo remains unclear. Moreover, while CAMKK2 is known to regulate systemic metabolism, whether CAMKK2's effects on whole-body metabolism would impact prostate cancer progression and/or related comorbidities is not known. Here, we demonstrate that germline ablation of Camkk2 slows, but does not stop, primary prostate tumorigenesis in the TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) genetic mouse model. Consistent with prior epidemiological reports supporting a link between obesity and prostate cancer aggressiveness, TRAMP mice fed a high-fat diet exhibited a pronounced increase in the colonization of lung metastases. We demonstrated that this effect on the metastatic spread was dependent on CAMKK2. Notably, diet-induced lung metastases exhibited a highly aggressive neuroendocrine phenotype. Concurrently, Camkk2 deletion improved insulin sensitivity in the same mice. Histological analyses revealed that cancer cells were smaller in the TRAMP;Camkk2-/- mice compared to TRAMP;Camkk2+/+ controls. Given the differences in circulating insulin levels, a known regulator of cell growth, we hypothesized that systemic CAMKK2 could promote prostate cancer cell growth and disease progression in part through cancer cell-extrinsic mechanisms. Accordingly, host deletion of Camkk2 impaired the growth of syngeneic murine prostate tumors in vivo, confirming nonautonomous roles for CAMKK2 in prostate cancer. Cancer cell size and mTOR signaling was diminished in tumors propagated in Camkk2-null mice. Together, these data indicate that, in addition to cancer cell-intrinsic roles, CAMKK2 mediates prostate cancer progression via tumor-extrinsic mechanisms. Further, we propose that CAMKK2 inhibition may also help combat common metabolic comorbidities in men with advanced prostate cancer.
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    Association of clinic setting with quality indicator performance in systemic lupus erythematosus: a cross-sectional study
    Sreedharan, S ; Li, N ; Littlejohn, G ; Buchanan, R ; Nikpour, M ; Morand, E ; Hoi, A ; Golder, V (BMC, 2022-06-22)
    BACKGROUND: Healthcare quality for systemic lupus erythematosus (SLE) is a modifiable target for improving patient outcomes. We aimed to assess the quality of care processes in different clinic settings, comparing a subspecialty lupus clinic with hospital-based and private general rheumatology clinics. METHODS: Patients with SLE (n = 258) were recruited in 2016 from a subspecialty lupus clinic (n = 147), two hospital general rheumatology clinics (n = 56) and two private rheumatology clinics (n = 55). Data were collected from medical records and patient questionnaires. Quality of care was assessed using 31 validated SLE quality indicators (QI) encompassing diagnostic work-up, disease and comorbidity assessments, drug monitoring, preventative care and reproductive health. Per-QI performance was measured as a percentage of patients that met the QI relative to the number of patients eligible. Per-patient QI performance was calculated as a percentage of QIs met relative to the number of eligible QIs for each patient. Per-QI and per-patient QI performance were compared between the three clinic settings, and multiple regression performed to adjust for sociodemographic, disease and healthcare factors. RESULTS: Per-QI performance was generally high across all clinic settings for diagnostic work-up, comorbidity assessment, lupus nephritis, drug monitoring, prednisolone taper, osteoporosis and pregnancy care. Median [IQR] per-patient performance on eligible QIs was higher in the subspeciality lupus clinic (66.7% [57.1-74.1]) than the hospital general rheumatology (52.7% [47.5-58.1]) and private rheumatology (50.0% [42.9-60.9]) clinics (p <0.001) and the difference remained significant after multivariable adjustment. The subspecialty lupus clinic recorded higher per-QI performance for documentation of disease activity, disease damage, cardiovascular risk factor and drug toxicity assessments, pre-immunosuppression hepatitis and tuberculosis screening, new medication counselling, vaccinations, sun avoidance education and contraception counselling. CONCLUSIONS: SLE patients managed in a subspecialty lupus clinic recorded higher per-patient QI performance compared to hospital general rheumatology and private rheumatology clinics, in part related to better documentation on certain QIs.
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    The Impact of Ethnicity on Athlete ECG Interpretation: A Systematic Review.
    Davis, AJ ; Semsarian, C ; Orchard, JW ; La Gerche, A ; Orchard, JJ (MDPI AG, 2022-06-08)
    Athlete ECG interpretation criteria have been developed and refined from research in athlete populations; however, current guidelines are based on available data primarily from Caucasian and Black athletes. This study aimed to assess the impact of ethnicity on ECG interpretation in athletes. A systematic review was conducted of the MEDLINE, EMBASE, Scopus, SPORTDiscus, and Web of Science databases, for papers that assessed athlete screening ECGs and compared findings on the basis of ethnicity. Fifty-one papers which compared ECGs from various ethnicities were included. Most studies assessed Black athletes against Caucasian athletes and found a greater prevalence of T-wave inversion (TWI) (2.6-22.8% vs. 0-5.0%) and anterior TWI (3.7-14.3% vs. 0.6-2.0%). Black athlete subgroups in Africa had TWI (20-40%) and anterior TWI (4.3-18.7%) at a higher prevalence than other Black athletes. Athletes who were defined as mixed-race, Asian, and Pacific Islander are potentially more like Black athletes than Caucasian athletes. Black ethnicity is known to have an impact on the accurate interpretation of athlete ECGs; however, there is nuance related to origin of both parents. Asian and Pacific Islander origin also may impact athlete ECG interpretation. Further research is required to assist in distinguishing abnormal and normal athlete ECGs in different ethnic populations.
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    Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes.
    Hanson, AL ; Sahhar, J ; Ngian, G-S ; Roddy, J ; Walker, J ; Stevens, W ; Nikpour, M ; Assassi, S ; Proudman, S ; Mayes, MD ; Kenna, TJ ; Brown, MA (Frontiers Media SA, 2022)
    Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual's underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.
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    Corrigendum to 'A transcriptomic dataset evaluating the effect of radiotherapy injury on cells of skin and soft tissue' Data in Brief 41 (2022) 107828.
    Shuka, L ; Lee, SA ; Du, MRM ; Karnezis, T ; Ritchie, ME ; Shayan, R (Elsevier BV, 2022-08)
    [This corrects the article DOI: 10.1016/j.dib.2022.107828.].
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    A survey of knowledge, attitudes, barriers and support needs in providing hepatitis B care among GPs practising in Australia
    Xiao, Y ; van Gemert, C ; Howell, J ; Wallace, J ; Richmond, J ; Adamson, E ; Thompson, A ; Hellard, M (BMC, 2022-06-02)
    BACKGROUND: In Australia, only 22% of people with chronic hepatitis B (CHB) are clinically managed; and a national effort is engaging primary care workforce in providing CHB-related care. This study explored CHB-related knowledge, attitudes, barriers and support needs of general practitioners (GPs). METHODS: A survey was sent to a random sample of 1,000 Australian GPs in April- October 2018; 134 of 978 eligible GPs completed the questionnaire (14%). RESULTS: Respondents had high knowledge of at-risk populations (> 79%) and hepatitis B serology (82%), and most saw hepatitis B testing and monitoring as part of their work (95% and 86%, respectively). However, the survey revealed low knowledge, awareness and intention with respect to hepatitis B treatment: 23% correctly understood treatment initiation; 40% were aware that treatment for CHB could be dispensed in the community; 23% agreed that prescribing was part of their work. Lack of time was considered the greatest barrier (38%) and clear guidelines was the most important facilitator to providing care (72%). CONCLUSION: Interventions are needed to generate interest and skills to provide CHB-related care by GPs.
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    Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination
    Lew, TE ; Seymour, JF (BMC, 2022-06-03)
    BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.