Medicine (RMH) - Research Publications

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    Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study
    Dhiman, K ; Villemagne, VL ; Fowler, C ; Bourgeat, P ; Li, Q-X ; Collins, S ; Bush, A ; Rowe, CC ; Masters, CL ; Ames, D ; Blennow, K ; Zetterberg, H ; Martins, RN ; Gupta, V (MDPI, 2022-05-01)
    BACKGROUND: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer's disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). METHODS: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. RESULTS: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03-2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31-17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. CONCLUSION: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.
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    Differences in psychosocial distress among rural and metropolitan health care workers during the COVID-19 pandemic
    Tham, R ; Pascoe, A ; Willis, K ; Kay, M ; Smallwood, N (WILEY, 2022-05-05)
    OBJECTIVE: The Australian COVID-19 Frontline Healthcare Workers study examined the prevalence and severity of mental health symptoms during the second wave of the COVID-19 pandemic. This substudy examined the differences in psychological well-being between rural and metropolitan health care workers (HCWs). DESIGN: A nationwide survey conducted between August and October 2020. SETTING AND PARTICIPANTS: Australian HCWs were recruited through multiple strategies. MAIN OUTCOME MEASURES: Demographics, mental health outcomes (anxiety, depression, post-traumatic stress disorder [PTSD] and burnout). RESULTS: Complete responses were included from 7846 participants, with 1473 (18.8%) in regional or remote ('rural') areas and 81.2% in metropolitan areas. Rural participants were older, more likely to work in allied health, nursing or in health administration, and had worked longer in their profession than metropolitan participants. Levels of resilience were similar (p = 0.132), but there was significantly higher prevalence of pre-COVID-19 pandemic mental illness in the rural workforce (p < 0.001). There were high levels of current mental health issues: moderate-severe PTSD (rural 38.0%; metropolitan 41.0% p = 0.031); high depersonalisation (rural 18.1%; metropolitan 20.7% p = 0.047); and high emotional exhaustion (rural 46.5%; metropolitan 43.3% p = 0.002). Among rural participants, mental health symptoms were associated with younger age, worry about being blamed if they contracted COVID-19, fear of transmitting COVID-19 to their family, experiencing worsening relationships and working in primary care or allied health. CONCLUSION: Despite having low COVID-19 case numbers in rural Australian health services compared with metropolitan counterparts over the course of 2020, there were widespread mental health impacts on the workforce. Rural health services need specific and flexible training, education, work policies and practices that support psychological well-being now in preparedness for ongoing or future crises.
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    Molecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens
    Yuen, KC ; Tran, B ; Anton, A ; Hamidi, H ; Costello, AJ ; Corcoran, NM ; Lawrentschuk, N ; Rainey, N ; Semira, MCG ; Gibbs, P ; Mariathasan, S ; Sandhu, S ; Kadel, EE (WILEY, 2022-04-18)
    BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor β (TGFβ) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFβ signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFβ and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.
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    A general practice intervention for people at risk of poor health outcomes: the Flinders QUEST cluster randomised controlled trial and economic evaluation.
    Reed, RL ; Roeger, L ; Kwok, YH ; Kaambwa, B ; Allison, S ; Osborne, RH (Wiley, 2022-05-16)
    OBJECTIVE: To determine whether a multicomponent general practice intervention cost-effectively improves health outcomes and reduces health service use for patients at high risk of poor health outcomes. DESIGN, SETTING: Clustered randomised controlled trial in general practices in metropolitan Adelaide. PARTICIPANTS: Three age-based groups of patients identified by their general practitioners as being at high risk of poor health outcomes: children and young people (under 18 years), adults (18-64 years) with two or more chronic diseases, and older people (65 years or more). INTERVENTION: Enrolment of patients with a preferred GP, longer general practice appointments, and general practice follow-up within seven days of emergency department and hospital care episodes. Intervention practices received payment of $1000 per enrolled participant. MAIN OUTCOME MEASURES: Primary outcome: change in self-rated health between baseline and 12-month follow-up for control (usual care) and intervention groups. SECONDARY OUTCOMES: numbers of emergency department presentations and hospital admissions, Medicare specialist claims and Pharmaceutical Benefits Scheme (PBS) items supplied, Health Literacy Questionnaire scores, and cost-effectiveness of the intervention (based on the number of quality-adjusted life-years [QALYs] gained over 12 months, derived from EQ-5D-5L utility scores for the two adult groups). RESULTS: Twenty practices with a total of 92 GPs were recruited, and 1044 eligible patients participated. The intervention did not improve self-rated health (coefficient, -0.29; 95% CI, -2.32 to 1.73), nor did it have significant effects on the numbers of emergency department presentations (incidence rate ratio [IRR], 0.90; 95% CI, 0.69-1.17), hospital admissions (IRR, 0.90; 95% CI, 0.66-1.22), Medicare specialist claims (IRR, 1.00; 95% CI, 0.91-1.09), or PBS items supplied (IRR, 0.99; 95% CI, 0.96-1.03), nor on Health Literacy Questionnaire scores. The intervention was effective in terms of QALYs gained (v usual care: difference, 0.032 QALYs; 95% CI, 0.001-0.063), but the incremental cost-effectiveness ratio was $69 585 (95% CI, $22 968-$116 201) per QALY gained, beyond the willingness-to-pay threshold. CONCLUSIONS: Our multicomponent intervention did not improve self-rated health, health service use, or health literacy. It achieved greater improvement in quality of life than usual care, but not cost-effectively. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617001589370 (prospective).
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    Toward transmural healing: Sonographic healing is associated with improved long-term outcomes in patients with Crohn's disease
    Vaughan, R ; Tjandra, D ; Patwardhan, A ; Mingos, N ; Gibson, R ; Boussioutas, A ; Ardalan, Z ; Al-Ani, A ; Gibson, PR ; Christensen, B (WILEY, 2022-03-28)
    BACKGROUND AND AIMS: Transmural healing has emerged as a treatment target in Crohn's disease (CD). We investigated whether transmural healing assessed with intestinal ultrasound (IUS) is associated with improved clinical outcomes in patients with CD in clinical remission. METHODS: Patients with CD in clinical remission at baseline (HBI <4) having IUS between August 2017 and June 2020 with at least 6-months' follow-up were retrospectively studied. Time to medication escalation, corticosteroid use and CD-related hospitalisation or surgery were compared by the presence or absence of sonographic healing, defined as bowel wall thickness ≤3 mm without hyperemia on color Doppler, inflammatory fat, or disrupted bowel wall stratification. Factors associated with survival were analyzed by Kaplan-Meier analysis using Cox proportional-hazard model. RESULTS: Of 202 consecutive patients (50% male), sonographic inflammation was present in 61%. During median follow-up of 19 (IQR 13-27) months, medication escalation occurred in 52%, corticosteroid use in 23%, hospitalisation in 21%, and CD-related surgery in 13%. Sonographic healing was significantly associated with a reduced risk of medication escalation (p = 0.0018), corticosteroid use (p = 0.0247), hospitalisation (p = 0.0102), and surgery (p = 0.083). On multivariable analysis, sonographic healing was significantly associated with an increased odds of medication escalation-free survival (hazard ratio [HR]:1.94; 95% CI 1.23-3.06; p = 0.004) and corticosteroid-free survival (HR:2.41; 95% CI 1.24-4.67; p = 0.009), but not with hospitalisation or surgery. CONCLUSION: In patients with CD in clinical remission, sonographic healing is associated with improved clinical outcomes. Further studies are needed to determine whether sonographic healing should be a treatment target.
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    Population DNA screening for medically actionable disease risk in adults.
    Lacaze, PA ; Tiller, J ; Winship, I ; DNA Screen Investigator Group, (Wiley, 2022-04-04)
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    The workplace and psychosocial experiences of Australian junior doctors during the COVID-19 pandemic.
    Hunter, R ; Willis, K ; Smallwood, N (Wiley, 2022-05)
    BACKGROUND: Junior doctors experience high levels of psychological distress and emotional exhaustion. The current Coronavirus disease 2019 (COVID-19) pandemic has resulted in significant changes to healthcare globally, with quantitative studies demonstrating increased fatigue, depression and burnout in junior doctors. However, there has been limited qualitative research to examine junior doctors' experiences, challenges and beliefs regarding management of future crises. AIMS: To investigate the workplace and psychosocial experiences of Australian junior doctors working during the second wave of the COVID-19 pandemic. METHODS: Australian healthcare workers were invited to participate in a nationwide, voluntary, anonymous, single time point, online survey between 27 August and 23 October 2020. A qualitative descriptive study of responses to four free-text questions from 621 junior doctors was undertaken, with responses analysed using inductive content analysis. RESULTS: Participants were predominantly female (73.2%), aged 31-40 years (48.0%) and most frequently reported working in medical specialties (48.4%), emergency medicine (21.7%) or intensive care medicine (11.4%). Most (51.9%) participants had 0-5 years of clinical experience since medical graduation. Junior doctors described experiences related to four key themes: a hierarchical, difficult workplace culture; challenging working conditions; disrupted training and career trajectories; and broader psychosocial impacts. The COVID-19 pandemic exacerbated longstanding, workplace issues and stressors for junior doctors and highlighted the threat that crises pose to medical workforce retention. There is an urgent need for authentic, positive workplace cultural interventions to engage, validate and empower junior doctors. CONCLUSIONS: Challenging workplace cultures and conditions, which have worsened during the COVID-19 pandemic, are associated with poor psychological well-being in junior doctors. There exists a need for long-term, widespread improvements in workplace culture and working conditions to ensure junior doctors' well-being, facilitate workforce retention and enhance the safety and quality of patient care in Australia.
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    Composite endpoint to evaluate complement inhibition therapy in patients with paroxysmal nocturnal hemoglobinuria
    Kulasekararaj, A ; Glasmacher, A ; Liu, P ; Szer, J ; Araten, D ; Rauch, G ; Gwaltney, C ; Sierra, JR ; Lee, JW (WILEY, 2022-03-01)
    This study developed and explored a novel composite endpoint to assess the overall impact that treatment can have on patients living with paroxysmal nocturnal hemoglobinuria (PNH). Candidate composite endpoint variables were selected by a group of experts and included: lactate dehydrogenase levels as a measure of intravascular hemolysis; complete terminal complement inhibition; absence of major adverse vascular events, including thrombosis; absence of any adverse events leading to death or discontinuation of study treatment; transfusion avoidance; and improvements in fatigue-related quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. From these variables, a novel composite endpoint was constructed and explored using data collected in the ravulizumab PNH Study 301 (NCT02946463). Thresholds were defined and reported for each candidate variable. Five of the six candidate variables were included in the final composite endpoint; the FACIT-Fatigue score was excluded. Composite endpoint criterion was defined as patients meeting all five selected individual component thresholds. All patients in the ravulizumab arm achieved complete terminal complement inhibition and a reduction in lactate dehydrogenase levels; 51.2% and 41.3% of patients in the ravulizumab arm and eculizumab arm, respectively, achieved all composite endpoint component thresholds (treatment difference: 9.4%; 95% confidence interval: -3.0, 21.5). The composite endpoint provided a single and simultaneous measurement of overall benefit for patients receiving treatment for PNH. Use of the composite endpoint in future PNH research is recommended to determine clinical benefit, and its use in health technology assessments should be evaluated.