- Medicine (Austin & Northern Health) - Research Publications
Medicine (Austin & Northern Health) - Research Publications
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ItemPlasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disordersEratne, D ; Kang, M ; Malpas, C ; Simpson-Yap, S ; Lewis, C ; Dang, C ; Grewal, J ; Coe, A ; Dobson, H ; Keem, M ; Chiu, W-H ; Kalincik, T ; Ooi, S ; Darby, D ; Brodtmann, A ; Hansson, O ; Janelidze, S ; Blennow, K ; Zetterberg, H ; Walker, A ; Dean, O ; Berk, M ; Wannan, C ; Pantelis, C ; Loi, SM ; Walterfang, M ; Berkovic, SF ; Santillo, AF ; Velakoulis, D (SAGE PUBLICATIONS LTD, 2024-01)OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
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ItemThe Importance of Sex in Preclinical Studies of BoneDavey, RA (WILEY, 2023-01)
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ItemA brief assessment of eye blink drowsiness immediately prior to or following driving detects drowsiness related driving impairmentCori, JM ; Wilkinson, VE ; Soleimanloo, SS ; Westlake, J ; Stevens, B ; Rajaratnam, SMW ; Howard, ME (Wiley, 2023-06)Drowsy driving is a major cause of fatal and serious injury motor vehicle accidents. The inability objectively to assess drowsiness has hindered the assessment of fitness to drive and the development of drowsy driving regulations. This study evaluated whether spontaneous eye blink parameters measured briefly pre- and post-drive could be used to detect drowsy driving impairment. Twelve healthy participants (6 female) drove an instrumented vehicle for 2 h on a closed-loop track during a rested (8-10 h awake) and an extended wake condition (32-34 h awake). Pre- and post-drive, the participants completed a 5 min eye blink task, a psychomotor vigilance task (PVT), and the Karolinska sleepiness scale (KSS). Whole drive impairment was defined as >3.5 lane departures per hour. Severe end of drive impairment was defined as ≥2 lane departures in the last 15 min. The pre-drive % of time with eyes closed best predicted the whole drive impairment (area under the curve [AUC] 0.87). KSS had similar prediction ability (AUC 0.85), while PVT reaction time (AUC 0.72) was less accurate. The composite eye blink parameter, the Johns drowsiness scale was the best retrospective detector of severe end of drive impairment (AUC 0.99). The PVT reaction time (AUC 0.92) and the KSS (AUC 0.93) were less accurate. Eye blink parameters detected drowsy driving impairment with an accuracy that was similar to, or marginally better than, PVT and KSS. As eye blink measures are simple to measure, are objective and have high accuracy, they present an ideal option for the assessment of fitness for duty and roadside drowsiness.
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ItemClinical characteristics of Australian treatment-naive patients with classical Hodgkin lymphoma from the lymphoma and related diseases registryNguyen, J ; Wellard, C ; Chung, E ; Cheah, CY ; Dickinson, M ; Doo, NW ; Keane, C ; Talaulikar, D ; Berkahn, L ; Morgan, S ; Hamad, N ; Cochrane, T ; Johnston, AM ; Forsyth, C ; Opat, S ; Barraclough, A ; Mutsando, H ; Ratnasingam, S ; Giri, P ; Wood, EM ; McQuilten, ZK ; Hawkes, EA (Wiley, 2023-04)Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real-world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first-line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced-stage disease, and 48% of patients with the early-stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced-stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early-stage disease, and 88% in advanced-stage disease. Early progression-free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies.
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ItemNo Preview AvailableBRINGING THE BENCH TO THE BEDSIDE: UPDATES ON THE MIND STUDY AND WHAT A ROUTINELY AVAILABLE SIMPLE BLOOD TEST FOR NEUROFILAMENT LIGHT WOULD MEAN AT THE CLINICAL COAL FACE FOR PATIENTS AND FAMILIES, PSYCHIATRISTS, NEUROLOGISTS, GERIATRICIANS AND GENERAL PRACTITIONERSEratne, D ; Lewis, C ; Cadwallader, C ; Kang, M ; Keem, M ; Santillo, A ; Li, QX ; Stehmann, C ; Loi, SM ; Walterfang, M ; Watson, R ; Yassi, N ; Blennow, K ; Zetterberg, H ; Janelidze, S ; Hansson, O ; Berry-Kravitz, E ; Brodtmann, A ; Darby, D ; Walker, A ; Dean, O ; Masters, CL ; Collins, S ; Berkovic, SF ; Velakoulis, D (SAGE PUBLICATIONS LTD, 2022-05)
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ItemNo Preview AvailableINCREASED PLASMA NEUROFILAMENT LIGHT AND CEREBRAL ATROPHY IN PATIENTS WITH TYPE 2 DIABETES AND LEFT VENTRICULAR HYPERTROPHYPatel, SK ; Restrepo, C ; Khlif, M ; Werden, E ; Ramchand, J ; Srivastava, PM ; MacIsaac, RJ ; Ekinci, EI ; Burrell, LM ; Brodtmann, A (LIPPINCOTT WILLIAMS & WILKINS, 2023-01)
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ItemNo Preview AvailableChampioning Better Care for Young People with Stroke: Australia's New Young Stroke ServiceBorschmann, KN ; Thijs, V ; Capurro, D ; Wong, D ; Power, E ; Lannin, N ; Giummarra, M ; Rose, T ; Cadilhac, D ; Parsons, B ; Murphy, L ; Hayward, KS ; Withiel, T ; Brodtmann, A ; Bladin, C ; Crotty, M ; Bernhardt, J (Sage, 2023-08)Background: The Australian Stroke Clinical Registry collects information on national acute stroke care standards. Variation in care between hospitals impacts patient outcomes. Aims: To illustrate hospital performance in four priority areas of acute stroke care (stroke unit treatment, time to neuroimaging, thrombolysis door-to-needle time (DTNT), and swallowing assessments). Methods: Across 7 states/territories, 60 adult public hospitals provided 2021 data. Adherence was determined as the percentage of eligible patients treated. Funnel plots were used identify exceptional (>3 standard deviations above national average) and poor (>3 standard deviations below national average) performance. For continuous outcomes (neuroimaging timing or DTNT), we described hospitals with performance outside of the national interquartile range. Results: Overall, 16,458 episodes of stroke were analysed (median age 75 years, 43% female, 81% ischaemic). There were 27 hospitals with exceptional adherence to stroke unit care, 13 with poor adherence and 3 with no episodes treated in a stroke unit. Stroke unit treatment was less common in regional hospitals (68% vs metropolitan 80%, p<0.001). Median time from arrival to neuroimaging was 41 minutes, 2 hospitals were above the 75th percentile (>87 minutes) and 5 hospitals were below the 25th percentile (<20 minutes). Among 1320 patients with ischaemic stroke who received intravenous thrombolysis, the median DTNT was 77 minutes. Only 5 (8%) hospitals had a median DTNT ⩽60 minutes, 4 (7%) below the 25th percentile (56.5 minutes), while 18 (30%) had DTNT above the 75th percentile (107 minutes). Only 58% of all patients had their swallowing screened/assessed prior to oral intake; and 29% within 4 hours of arrival (9 hospitals with exceptional adherence; 12 with poor adherence). Conclusion: Despite strong evidence for recommended acute stroke care practices, there remains significant variation between Australian hospitals. The standardised registry data are essential to identifying areas for improvement against national benchmarks and to support stroke unit certification.
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ItemEffect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsyMula, M ; Borghs, S ; Ferro, B ; Zaccara, G ; Dainese, F ; Ferlazzo, E ; Romigi, A ; Gambardella, A ; Perucca, E (WILEY, 2024-02)OBJECTIVE: To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy. METHODS: Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model. RESULTS: At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes. SIGNIFICANCE: Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who screen initially negative for passive suicidal ideation become positive. These changes in screening status are independent of type of ASM introduced or seizure outcomes but correlate with psychiatric status at baseline.
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ItemPharmacokinetics of d- and l-norfenfluramine following their administration as individual enantiomers in ratsErenburg, N ; Hamed, R ; Shaul, C ; Barasch, D ; Perucca, E ; Bialer, M (Wiley, 2024-02)The effect of fenfluramine and norfenfluramine enantiomers in rodent seizure models and their correlation with the pharmacokinetics of d- and l-fenfluramine in rats have been reported recently. To complement these findings, we investigated the pharmacokinetics of d- and l- norfenfluramine in rat plasma and brain. Sprague-Dawley rats were injected intraperitoneally with 20 mg/kg and 1 mg/kg l- norfenfluramine. A 1 mg/kg dose of d-norfenfluramine was used because higher doses caused severe toxicity. The concentration of each enantiomer in plasma and brain was determined at different time points by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were compared between norfenfluramine enantiomers, and with those reported previously for fenfluramine enantiomers after a 20 mg/kg, i.p., dose. All enantiomers were absorbed rapidly and eliminated, with half-lives ranging from 0.9 h (l-fenfluramine) to 6.1 h (l- norfenfluramine, 20 mg/kg) in plasma, and from 3.6 h (d-fenfluramine) to 8.0 h (l-fenfluramine) in brain. Brain-to-plasma concentration ratios ranged from 15.4 (d-fenfluramine) to 27.6 (d-norfenfluramine), indicating extensive brain penetration. The fraction of d- and l-fenfluramine metabolized to norfenfluramine was estimated to be close to unity. This work is part of ongoing investigations to determine the potential value of developing enantiomerically pure l-fenfluramine or l-norfenfluramine as follow-up compounds to the marketed racemic fenfluramine.
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ItemNo Preview AvailableHow lifestyle shapes the brain: Associations between physical activity, sleep, beta‐amyloid and cognitive function in older adultsSewell, KR ; Rainey‐Smith, SR ; Villemagne, VLL ; Peiffer, JJ ; Sohrabi, HR ; Taddei, K ; Ames, D ; Maruff, PT ; Laws, SM ; Masters, CL ; Rowe, CC ; Martins, RN ; Erickson, KI ; Brown, BM (Wiley, 2021-12)Abstract Background Lifestyle factors such as sleep and physical activity influence risk of cognitive decline and dementia. Higher habitual physical activity and optimal sleep are associated with better cognitive function and lower levels of Alzheimer’s disease biomarkers, including beta‐amyloid (Aß). There is currently a poor understanding of how physical activity may influence the relationship between sleep and cognition, and whether exercise and sleep interact to influence cognition and Aß. Developing this understanding is crucial for creating effective lifestyle interventions for dementia prevention. Method Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised to determine whether self‐reported physical activity moderates the cross‐sectional relationship between self‐reported sleep parameters (duration, efficiency, latency, disturbance, quality), cognitive function (episodic memory, attention and processing speed, executive function), and brain Aß (quantified by amyloid positron emission tomography, using the Centiloid scale). Analyses were adjusted for age, sex, APOE ε4 carriage, mood, premorbid intelligence, and collection point. Participants were 404 community‐dwelling cognitively normal older adults aged 60 and above (75.3 5.7 years). Data from a subset of participants (n = 220, aged 75.2 5.6 years) were used for analyses with AB as the outcome. Result Physical activity moderated the relationship between sleep duration and episodic memory (ß = ‐.09, SE = .03, p = .005), and sleep efficiency and episodic memory (ß = ‐.08, SE = .03, p = .016). Physical activity moderated the relationship between sleep duration and A® (ß = ‐.12, SE = .06, p = .036), and sleep quality and Aß (ß = .12, SE = .06, p = .029). Conclusion Physical activity may play an important role in the relationship between sleep and cognitive function, and sleep and brain Aß. Future longitudinal and intervention studies in this area are crucial for informing interventions for dementia prevention.