Medicine (RMH) - Research Publications

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    BRINGING 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 PRACTITIONERS
    Eratne, 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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    INCREASED PLASMA NEUROFILAMENT LIGHT AND CEREBRAL ATROPHY IN PATIENTS WITH TYPE 2 DIABETES AND LEFT VENTRICULAR HYPERTROPHY
    Patel, 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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    Championing Better Care for Young People with Stroke: Australia's New Young Stroke Service
    Borschmann, 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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    How actionable are infection prevention and control guidelines in residential aged care? A document analysis based on a behaviour specification framework
    Tropea, J ; Francis, J ; Lim, L-L ; Bennett, N ; Lim, K ; Buising, K ; Fetherstonhaugh, D ; Peters, S (BMC, 2023-09-07)
    Background: Older people living in residential aged care are susceptible to transmissible infections such as influenza, COVID-19, and gastroenteritis. Effective infection prevention and control (IPC) practice in residential aged care is therefore imperative. To enable this, national and aged care provider-level IPC guidelines need to be specific enough to be actionable by residential aged care staff and organisations. The aim of this study was to assess the actionability of IPC national guidelines and residential aged care policies and procedures. We chose to examine the guidelines around healthcare associated infection (HAI) surveillance in residential aged care. Methods: A content analysis of the Australian IPC guidelines, and IPC policies and procedures from Victorian residential aged care facilities was conducted. Data extraction, coding and interpretation of findings were directed by the action-actor-context-target-time (AACTT) framework. Results: National guidelines did not specify recommendations related to HAI surveillance but include general statements of support for data collection on HAI and outbreaks, suggest best epidemiologic principles that should be applied in data collection, and suggest that data should be fed back to appropriate staff groups and administrators. Provider-level policies and procedures varied in specificity. Conclusions: While it is recommended that aged care providers undertake HAI surveillance, national guideline recommendations are open to interpretation and are not specific or actionable. Provider-level guidelines also need improving to facilitate actionability. To increase uptake of effective HAI surveillance in residential aged care, local policies and procedures need to be written with greater behavioural specificity.
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    Longitudinal Asthma Phenotypes from Childhood to Middle-Age A Population-based Cohort Study
    Tan, DJ ; Lodge, CJ ; Walters, EH ; Lowe, AJ ; Bui, DS ; Bowatte, G ; Pham, J ; Erbas, B ; Hui, J ; Hamilton, GS ; Thomas, PS ; Hew, M ; Washko, G ; Wood-Baker, R ; Abramson, MJ ; Perret, JL ; Dharmage, SC (AMER THORACIC SOC, 2023-07-15)
    Rationale: Asthma is a heterogeneous condition, and longitudinal phenotyping may provide new insights into the origins and outcomes of the disease. Objectives: We aimed to characterize the longitudinal phenotypes of asthma between the first and sixth decades of life in a population-based cohort study. Methods: Respiratory questionnaires were collected at seven time points in the TAHS (Tasmanian Longitudinal Health Study) when participants were aged 7, 13, 18, 32, 43, 50, and 53 years. Current-asthma and ever-asthma status was determined at each time point, and group-based trajectory modeling was used to characterize distinct longitudinal phenotypes. Linear and logistic regression models were fitted to investigate associations of the longitudinal phenotypes with childhood factors and adult outcomes. Measurements and Main Results: Of 8,583 original participants, 1,506 had reported ever asthma. Five longitudinal asthma phenotypes were identified: early-onset adolescent-remitting (40%), early-onset adult-remitting (11%), early-onset persistent (9%), late-onset remitting (13%), and late-onset persistent (27%). All phenotypes were associated with chronic obstructive pulmonary disease at age 53 years, except for late-onset remitting asthma (odds ratios: early-onset adolescent-remitting, 2.00 [95% confidence interval (CI), 1.13-3.56]; early-onset adult-remitting, 3.61 [95% CI, 1.30-10.02]; early-onset persistent, 8.73 [95% CI, 4.10-18.55]; and late-onset persistent, 6.69 [95% CI, 3.81-11.73]). Late-onset persistent asthma was associated with the greatest comorbidity at age 53 years, with increased risk of mental health disorders and cardiovascular risk factors. Conclusions: Five longitudinal asthma phenotypes were identified between the first and sixth decades of life, including two novel remitting phenotypes. We found differential effects of these phenotypes on risk of chronic obstructive pulmonary disease and nonrespiratory comorbidities in middle age.
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    The risk of secondary progressive multiple sclerosis is geographically determined but modifiable
    Sharmin, S ; Roos, I ; Simpson-Yap, S ; Malpes, C ; Sanchez, MM ; Ozakbas, S ; Horakova, D ; Havrdova, EK ; Patti, F ; Alroughani, R ; Izquierdo, G ; Eichau, S ; Boz, C ; Zakaria, M ; Onofrj, M ; Lugaresi, A ; Weinstock-Guttman, B ; Prat, A ; Girard, M ; Duquette, P ; Terzi, M ; Amato, MP ; Karabudak, R ; Grand'Maison, F ; Khoury, SJ ; Grammond, P ; Lechner-Scott, J ; Buzzard, K ; Skibina, O ; van der Walt, A ; Butzkueven, H ; Turkoglu, R ; Altintas, A ; Maimone, D ; Kermode, A ; Shalaby, N ; Pesch, VV ; Butler, E ; Sidhom, Y ; Gouider, R ; Mrabet, S ; Gerlach, O ; Soysal, A ; Barnett, M ; Kuhle, J ; Hughes, S ; Sa, MJ ; Hodgkinson, S ; Oreja-Guevara, C ; Ampapa, R ; Petersen, T ; Ramo-Tello, C ; Spitaleri, D ; McCombe, P ; Taylor, B ; Prevost, J ; Foschi, M ; Slee, M ; McGuigan, C ; Laureys, G ; Hijfte, LV ; de Gans, K ; Solaro, C ; Oh, J ; Macdonell, R ; Aguera-Morales, E ; Singhal, B ; Gray, O ; Garber, J ; Wijmeersch, BV ; Simu, M ; Castillo-Trivino, T ; Sanchez-Menoyo, JL ; Khurana, D ; Al-Asmi, A ; Al-Harbi, T ; Deri, N ; Fragoso, Y ; Lalive, PH ; Sinnige, LGF ; Shaw, C ; Shuey, N ; Csepany, T ; Sempere, AP ; Moore, F ; Decoo, D ; Willekens, B ; Gobbi, C ; Massey, J ; Hardy, T ; Parratt, J ; Kalincik, T (OXFORD UNIV PRESS, 2023-11-02)
    Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.
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    Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis
    Diouf, I ; Malpas, CB ; Sharmin, S ; Roos, I ; Horakova, D ; Havrdova, EK ; Patti, F ; Shaygannejad, V ; Ozakbas, S ; Izquierdo, G ; Eichau, S ; Onofrj, M ; Lugaresi, A ; Alroughani, R ; Prat, A ; Girard, M ; Duquette, P ; Terzi, M ; Boz, C ; Grand'Maison, F ; Hamdy, S ; Sola, P ; Ferraro, D ; Grammond, P ; Turkoglu, R ; Buzzard, K ; Skibina, O ; Yamout, B ; Altintas, A ; Gerlach, O ; van Pesch, V ; Blanco, Y ; Maimone, D ; Lechner-Scott, J ; Bergamaschi, R ; Karabudak, R ; Iuliano, G ; McGuigan, C ; Cartechini, E ; Barnett, M ; Hughes, S ; Sa, MJ ; Solaro, C ; Kappos, L ; Ramo-Tello, C ; Cristiano, E ; Hodgkinson, S ; Spitaleri, D ; Soysal, A ; Petersen, T ; Slee, M ; Butler, E ; Granella, F ; de Gans, K ; McCombe, P ; Ampapa, R ; Van Wijmeersch, B ; van der Walt, A ; Butzkueven, H ; Prevost, J ; Sinnige, LGF ; Sanchez-Menoyo, JL ; Vucic, S ; Laureys, G ; Van Hijfte, L ; Khurana, D ; Macdonell, R ; Gouider, R ; Castillo-Trivino, T ; Gray, O ; Aguera-Morales, E ; Al-Asmi, A ; Shaw, C ; Deri, N ; Al-Harbi, T ; Fragoso, Y ; Csepany, T ; Sempere, AP ; Trevino-Frenk, I ; Schepel, J ; Moore, F ; Kalincik, T (WILEY, 2023-04)
    BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
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    Sustained benefits for thrombectomy triage using the act-fast algorithm after real-world implementation
    Zhao, H ; Smith, K ; Anderson, D ; Stephenson, M ; Churilov, L ; Ng, JL ; Pesavento, L ; Weir, L ; Yassi, N ; Mitchell, P ; Davis, S ; Campbell, B (SAGE, 2022-10-01)
    Background and Aims: The severity-based ACT-FAST algorithm for pre-hospital triage of large vessel occlusion (LVO) has previously been validated in a large paramedic-led study. We examined the subsequent real-world diagnostic utility of this tool for ambulance triage in the western metropolitan region of Melbourne, Australia. Methods: A manual audit was conducted of all patients presenting to a central comprehensive center for patients in the catchment of two spoke primary centers where ACT-FAST bypass was active from April 2020 to March 2021. Diagnostic performance was determined for LVO and overall need for comprehensive center care, including and excluding concurrent mobile stroke unit (MSU) cases. Results: Of 1222 presentations screened, 182 (15%) patients were in the bypass zone. These included 15 secondary inter-hospital LVO transfers, of which 9 had high severity (NIHSS⩾10). In contrast, 23 ACTFAST- Positive LVOs were bypassed (6 MSU-facilitated) in addition to 11 ICH and 1 intracerebral tumour. There were 8 bypassed false-positives (6 infarcts, 2 mimics) of which only 1 received thrombolysis. Bypassed patients received significantly faster EVT from ambulance dispatch (median 177min vs 237 min, p=0.001) whereas there was no significant difference in thrombolysis time (113min vs 101min, p=0.486). Conclusions: Implementation of ACT-FAST triaging avoided >70% of secondary transfers for high-severity LVO with significant time savings to thrombectomy and low rates of false-positive bypass (<1/month). Thrombolysis delay was minimal in our metropolitan setting and triage benefit was complementary to that provided by an active MSU service in the area.
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    DUPILUMAB LEADS TO CLINICAL ASTHMA REMISSION INDICATIVE OF COMPREHENSIVE IMPROVEMENT IN PATIENTS WITH ASTHMA: RESULTS FROM THE LIBERTY ASTHMA QUEST AND TRAVERSE STUDIES
    Douglass, JA ; Pavord, ID ; Brusselle, GG ; Rabe, KF ; Menzies-Gow, A ; Moody, J ; Altincatal, A ; Pandit-Abid, N ; Lederer, DJ ; Zhang, Y ; Rowe, PJ ; Deniz, Y ; Radwan, A ; Jacob-Nara, JA ; Busse, WW (WILEY, 2022-10-01)
    Introduction: Asthma treatment response is ascertained by improvement in several important outcomes: exacerbations, symptom control, and lung function. A recent consensus framework defined criteria for remission in severe asthma. This post hoc analysis assessed clinical asthma remission following dupilumab treatment in the phase 3 QUEST (NCT02414854) and TRAVERSE (NCT02134028) studies using a multicomponent endpoint. Method: Patients with uncontrolled, non-OCS dependent, moderate-to-severe asthma received add-on dupilumab 200 mg or 300 mg every 2 weeks (q2w) or matched placebo for 52 weeks in QUEST, followed by add-on dupilumab 300 mg q2w for up to 96 weeks in TRAVERSE (dupilumab/dupilumab and placebo/dupilumab groups, respectively). Clinical asthma remission (no exacerbations and 5-item Asthma Control Questionnaire [ACQ-5] total score <1.5 and improvement in pre-bronchodilator forced expiratory volume in 1 second [FEV1] ≥ 100 mL [TRAVERSE] or either improvement in pre-bronchodilator FEV1 ≥ 100 mL, or post-bronchodilator percent predicted FEV1 ≥ 80% and no OCS use [QUEST]) was assessed at QUEST Week 52 and TRAVERSE Week 48 in patients with baseline eosinophils ≥150 cells/μL or FeNO ≥ 25 ppb. Results: 1519 patients from QUEST (dupilumab: n = 992; placebo: n = 527) and 1,227 QUEST patients who enrolled in TRAVERSE (dupilumab/dupilumab: n = 804; placebo/dupilumab: n = 423) were included in this post hoc analysis. At Week 52 of QUEST, 31.7% (314) dupilumab-treated vs. 17.7% (93) placebo-treated patients achieved all four criteria, meeting the requirements for clinical remission. At Week 48 of TRAVERSE, 36.4% (293) and 29.6% (125) of dupilumab/dupilumab and placebo/dupilumab patients met all criteria for clinical remission. Conclusion: Approximately 32% of patients in QUEST with elevated type 2 biomarkers and uncontrolled, moderate-to-severe asthma achieved a multicomponent endpoint representing clinical asthma remission after 1 year of dupilumab treatment. This percentage increased to 36% after an additional 48 weeks of treatment in TRAVERSE.
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    Let's CHAT (Community Health Approaches to) Dementia in Aboriginal and Torres Strait Islander Community Controlled Primary Care: Baseline audit results of a stepped-wedge cluster randomised controlled trial
    Logiudice, D ; Bradley, K ; Hughson, J-A ; Hyde, Z ; Atkinson, D ; Bessarab, D ; Flicker, L ; Radford, K ; Strivens, E ; Thompson, S ; Blackberry, I ; Belfrage, M ; Smith, R ; Malay, R ; Allan, W ; Lavrencic, L ; Russell, S ; Quigley, R ; Humphrey, T ; Smith, K (WILEY, 1/05/2021)
    Aim: This study describes baseline audit results documenting cognitive impairment not dementia (CIND) and dementia and associated risk factors in Aboriginal and Torres Strait Islander peoples aged ≥50 years attending Aboriginal Community Controlled Health Services (ACCHSs). Method: A specialised chart audit tool was designed to identify documented dementia and CIND, and relevant risk factor profiles in patient health records. The audits were conducted as part of a stepped-wedge cluster randomised controlled trial. Twelve Aboriginal Controlled Community Health Services (ACCHSs) in four states across Australia were recruited and medical records of 1,662 patients aged >50 years were audited. The primary outcome measure is documentation of CIND and dementia along with the associated risk factors. Results: The mean age was 60.2 +/-8.2 years and 56% were female. The overall prevalence of documented CIND or dementia was low, reported for only 57 (3.4%) patients audited. The prevalence of risk factors was high, with nearly two-thirds (64.1%,) having ≥4 risk factors. These included high rates of hypertension (52.5%), diabetes (44.3%), dyslipidemia (42.3%), obesity (35.3%) and current smoking (35.3%). Conclusion: Our previous work demonstrated the true prevalence of dementia was 10% and CIND was 10% in Indigenous communities. The low detection of these conditions in the primary care setting, accompanied by high prevalence of associated risk factors for cognitive impairment, demonstrates the need for dementia specific culturally responsive primary care interventions that optimise brain health and support identification of cognitive impairment and dementia, using a community wide and holistic approach across the lifespan.