Medicine (St Vincent's) - Research Publications
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ItemNo Preview AvailableCognition in healthy older women is a predictor of 14‐year falls risk(Wiley, 2021-12)Background: Falls are a significant cause of injuries, loss of confidence, increased morbidity, and institutionalisation in all older people, with women at 50% greater risk than men. The relationship between dementia and falls is well established and 2/3 of all dementia occurs in women. In this study we explored risk factors associated with a 14 year falls risk in a community-based cohort of women, which included validated measures across a wide range of clinical domains including neuropsychological, mood, quality of life and biomarkers (including hormonal). Method: The Australian Women’s Healthy Aging Project is an longitudinal observation study, assessments every year (1991 –1999), followed by assessments in 2002, 2004, 2012 and 2014. The assessments included cognitive (as of 2002), blood, and cardiovascular disease risk assessment, and questions related to falls. After data cleaning, the remaining cohort consisted of 180 participants (Table 1). Missing data were imputed using mice random forest. To identify key risk factors associated with a 14 year falls risk, random survival (time to event) forest (RSF) machine learning was used. Result: The RSF model, using all 290+ possible predictive variables, performed well with an Out Of Bag (OOB, withheld data) prediction error (C-index) of 32.8%. The most predictive variables in the model were identified using the variable importance measure (VIM). The initial model was refined by taking the top 30 predictive variables and retraining the RSF. This refined model resulted in an improved OOB C-index of 5.8% (27%). The top 20 predictive variables, Figure 1, include those associated with cardiovascular disease risk, cognitive performance, and hormone levels (e.g., family history of heart attack, digit symbol coding, and estradiol levels). Conclusion: Ninety percent of the top 20 predictive risk variables for the 14 year fall risk in women, were from three key domains, cognition (40%), cardiovascular (25%) and hormone-related measurements (25%). Our data suggest that for long term prevention of falls these domains may be important reducing risk of falls in the senior female population.
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ItemNo Preview AvailableDiscontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis(BMJ PUBLISHING GROUP, 2022-08)BACKGROUND AND AIMS: Sustained virological suppression and hepatitis B surface antigen (HBsAg) loss have been described after nucleot(s)ide analogue (NA) discontinuation for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We performed a meta-analysis of the clinical outcomes after NA discontinuation for HBeAg-negative CHB. METHODS: Studies involving NA cessation in HBeAg-negative CHB individuals with a median follow-up of ≥12 months were included. Participants were HBeAg-negative at the time of NA initiation. Random effects meta-analyses were performed for the following clinical outcomes: (1) virological relapse (VR) at 6 and 12 months; (2) clinical relapse (CR) at 6 and 12 months and (3) HBsAg loss. Effect of other variables was estimated using subgroup analysis and meta-regression. Studies including patients stopping entecavir (ETV) and/or tenofovir disoproxil fumarate (TDF) were considered separately to studies including patients stopping older generation NA. RESULTS: N=37 studies met inclusion criteria. Cumulative incidence of VR and CR after stopping ETV/TDF was 44% and 17% at 6 months and 63% and 35% at 12 months. Similar relapse rates were observed after stopping older NAs. Among patients stopping ETV/TDF, TDF cessation was associated with increased CR rates at 6 months versus ETV. There was an association between follow-up ≥4 years and HBsAg loss rates when stopping older NAs. Hepatic decompensation and hepatocellular carcinoma were rare but occurred more frequently in studies including cirrhotic individuals. CONCLUSION: VR is common after NA discontinuation, however, CR was only seen in one-third of patients at 12 months. Stopping NA therapy can be followed by HBsAg clearance, and rates are higher with longer follow-up.
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ItemStopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels(WILEY, 2022-07)BACKGROUND AND AIMS: Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss. METHODS: We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNA5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues. CONCLUSION: Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT <2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.
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ItemNo Preview AvailableHepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways(OXFORD UNIV PRESS INC, 2022-12-28)BACKGROUND: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.
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ItemNo Preview AvailableFactor analysis to determine relative contributions of strength, physical performance, body composition and muscle mass to disability and mobility disability outcomes in older men(PERGAMON-ELSEVIER SCIENCE LTD, 2022-05)BACKGROUND: It is not known how measures of body composition, strength and physical performance are interrelated or how empirical groupings of these measures relate to disability and mobility disability. METHODS: Muscle mass was assessed by D3-creatine dilution (D3Cr muscle mass) in 1345 men (84.1 ± 4.1 years) enrolled in the Osteoporotic Fractures in Men (MrOS) study. Participants completed anthropomorphic measures, walk speed, grip strength, chair stands, and dual x-ray absorptiometry (DXA) estimated appendicular lean mass (ALM) and body fat percentage. Men reported limitations in mobility, activities of daily living (ADLs) and instrumental ADLs at initial and over 2.2 ± 0.3 years. Factor analysis reduced variables into related groups and negative binomial models calculated relative risk (RR) of factors with mobility and disability outcomes. RESULTS: Factor analysis reduced 10 variables into four factors: Factor 1, body composition, including ALM, body fat percentage, weight and muscle mass; Factor 2, body size and lean mass, including height, weight and ALM; Factor 3, muscle mass, strength and performance, including walk speed, chair stands, grip strength, and muscle mass; and Factor 4, lean mass and weight, including ALM and weight. Only Factor 3 was significantly associated (p-value < .001) with prevalent disability (RR per standard deviation increment in factor score (reflecting higher muscle mass, strength and physical performance) 0.44, 0.35-0.56) and mobility disability (RR 0.22, 0.17 0.28), and incident mobility disability (RR 0.37, 0.27-0.50). CONCLUSION: D3Cr muscle mass was the only body composition variable that co-segregated with strength and physical performance measures, and contributed to a factor that was associated with disability outcomes in older men.
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ItemNo Preview AvailableIS QUALITY OF LIFE RECOVERY ASSOCIATED WITH LOWER MORTALITY 5 YEARS POST-FRACTURE IN COMMUNITY-DWELLING OLDER ADULTS?(SPRINGER LONDON LTD, 2022-04)
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ItemEffect of Different Anthropometric Body Indexes on Radiation Exposure in Patients Undergoing Cardiac Catheterisation and Percutaneous Coronary Intervention(MDPI, 2022-10)BACKGROUND: Patient factors, such as sex and body mass index (BMI), are known to influence patient radiation exposure. Body surface area (BSA) and its association with patient radiation exposure has not been well studied. METHODS AND RESULTS: We analysed height, weight, BMI and BSA in consecutive patients undergoing cardiac catheterisation and percutaneous coronary intervention (PCI) at a high-volume Australian centre between September 2016 and April 2020 to assess their association with dose-area product (DAP, Gycm2). The mean age of the cohort was 64.5 ± 12.3 years with males comprising 68.8% (n = 8100, 5124 diagnostic cardiac catheterisation cases and 2976 PCI cases). Median male BMI was 28.4 kg/m2 [IQR 25.2-32.1] versus 28.8 kg/m2 [24.7-33.7] for females, p = 0.01. Males had higher BSA (2.0 ± 0.2 m2) than females (1.78 ± 0.2 m2), p = 0.001. Each 0.4 m2 increase in BSA conferred a 1.32x fold change in DAP (95% CI 1.29-1.36, p ≤ 0.001). Each 5 kg/m2 increase in BMI was linked to a 1.13x DAP fold change (1.12-1.14, p ≤ 0.001). Male sex conferred a 1.23x DAP fold change (1.20-1.26, p ≤ 0.001). Multivariable modelling with BMI or BSA explained 14% of DAP variance (R2 0.67 vs. 0.53 for both, p ≤ 0.001). CONCLUSIONS: BSA is an important anthropometric measure between the sexes and a key predictor of radiation dose and radiation exposure beyond sex, BMI, and weight.
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ItemValidation of the PEN-FAST Score in a Pediatric Population(AMER MEDICAL ASSOC, 2022-09-19)This cohort study examines a clinical decision model for penicillin allergies among pediatric patients; the model considers when reactions occurred; whether patients experienced angioedema, anaphylaxis, or a severe cutaneous adverse reaction; and whether treatment was required.
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ItemThe effect of rapamycin and its analogues on age-related musculoskeletal diseases: a systematic review(SPRINGER, 2022-10)BACKGROUND: Preclinical studies have shown a therapeutic role of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin and its analogues (rapalogues) on several age-related musculoskeletal disorders (MSKD). However, the applicability to humans of these findings is unknown. OBJECTIVE: To assess the efficacy of rapalogues on age-related MSKD in humans. METHODS: We conducted a systematic review according to the PRISMA guidelines. MEDLINE, EMBase, EMCare, and Cochrane Central Registry of Controlled Trials were searched for original studies examining the effects of rapalogues on outcomes linked to the age-related MSKD in humans. This review is registered in the PROSPERO database (University of New York; registration number CRD42020208167). RESULTS: Fourteen studies met the inclusion criteria and were analyzed. The effect of rapamycin and other rapalogues, including everolimus and temsirolimus, on bone, muscle and joints have been evaluated in humans; however, considerable variability concerning the subjects' age, inclusion criteria, and drug administration protocols was identified. In bone, the use of rapamycin is associated with a decrease in bone resorption markers dependent on osteoclastic activity. In muscle, rapamycin and rapalogues are associated with a reduction in muscle protein synthesis in response to exercise. In the context of rheumatoid arthritis, rapamycin and rapalogues have been associated with clinical improvement and a decrease in inflammatory activity. CONCLUSION: Although there are studies that have evaluated the effect of rapamycin and rapalogues on MSKD in humans, the evidence supporting its use is still incipient, and the clinical implication of these results on the development of osteoporosis, sarcopenia, or osteosarcopenia has not been studied, opening an interesting field for future research.
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ItemSINFONIA study protocol: a phase II/III randomised controlled trial examining benefits of guided online group singing in people with chronic obstructive pulmonary disease and interstitial lung disease and their carers(BMC, 2022-08-16)BACKGROUND: Chronic obstructive pulmonary disease (COPD) and interstital lung disease (ILD) are incurable conditions characterised by airflow limitation, persisting respiratory symptoms, and progressive respiratory failure. People living with COPD or ILD often suffer from chronic and severe breathlessness, with limited treatment options and low engagement rates with current therapies. Group singing represents a potential community-based therapy to improve quality of life for patients with COPD or ILD and breathlessness. METHODS: This protocol papers describes SINFONIA, a parallel, double-arm, randomised, blinded-analysis, mixed-methods phase II/III trial of guided, online group singing that will be conducted over 24 months. Adults with confirmed COPD or ILD, on stable treatment for at least four weeks at time of recruitment, with a modified Medical Research Council (mMRC) dyspnoea score of two or greater, who are capable and willing to give consent, and not currently participating in pulmonary rehabilitation will be eligible to participate. Carers may optionally enrol in the trial. Data will be collected on quality of life, anxiety and depression, breathlessness, mastery of breathing, exercise tolerance, loneliness, healthcare utilisation, and carer quality of life (optional). Participants will be randomised 1:1 to intervention or control arms with intervention arm attending one 90 min, guided, online, group singing session per week for 12 weeks and control arm continuing routine care. Phase II of the trial aims to determine the feasibility and acceptability of guided, online group singing and will collect preliminary data on effectiveness. Phase III aims to determine whether guided, online group singing has an effect on quality of life with the primary outcome being a between arm difference in quality of life (36-item Short Form Survey) measured at 12 weeks. DISCUSSION: SINFONIA is the first study is the first of its kind in Australia and to our knowledge, the first to deliver the singing intervention program entirely online. Determining the feasibility, acceptability, and effectiveness of guided, online group singing is an important step towards improving low-cost, low-risk, community-based therapeutic options for patients living with COPD or ILD and breathlessness. TRIAL REGISTRATION: Phase II- ACTRN12621001274864 , registered 20th September 2021; Phase III- ACTRN12621001280897 , registered 22nd September 2021.
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