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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    Nitrous oxide-induced neurological disorders: an increasing public health concern.
    Redmond, J ; Cruse, B ; Kiers, L (Wiley, 2022-05)
    BACKGROUND: Neurological presentations resulting from nitrous oxide (N2 O) abuse are increasing in Australia and worldwide. Despite known neuropsychiatric sequelae, N2 O canisters remain readily available and its use unregulated. AIMS: To examine the demographics, clinical and electrophysiological findings of patients presenting with neurological complications of N2 O abuse, and thus inform clinicians and public health decision-makers of the significant public health concerns of this increasing practice. METHODS: Consecutive patients presenting to a tertiary referral metropolitan hospital were included in this series. Patients were identified by a search of discharge summaries of patients admitted with acute or subacute neuropathy or myelopathy and a history of N2 O abuse, and from the electrophysiology database. RESULTS: Thirteen patients were identified, most presenting with subacute paraesthesia, sensory ataxia and lower limb weakness. Eleven had low serum vitamin B12 . Spinal magnetic resonance imaging was consistent with subacute combined degeneration in eight. Nerve conduction studies revealed a motor or sensorimotor axonal neuropathy (three with motor predominance). There was a bimodal demographic distribution consisting of socially isolated, international university students and local residents with a history of mental illness and polydrug abuse. CONCLUSIONS: Recreational N2 O use is an emerging health problem in Australia. International university students and patients with pre-existing mental illness or polydrug use appear to be at increased risk. A severe motor neuropathy may emerge following vitamin B12 replacement. Public health measures are required to limit the availability of N2 O and to educate adolescents and young adults about the potential for significant harm.
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    Regulation of the endosomal SNARE protein syntaxin 7 by colony-stimulating factor 1 in macrophages
    Achuthan, A ; Masendycz, P ; Lopez, JA ; Nguyen, T ; James, DE ; Sweet, MJ ; Hamilton, JA ; Scholz, GM (AMER SOC MICROBIOLOGY, 2008-10)
    Colony-stimulating factor 1 (CSF-1) is the main growth factor controlling the development of macrophages from myeloid progenitor cells. However, CSF-1 also regulates some of the key effector functions of macrophages (e.g., phagocytosis and cytokine secretion). The endosomal SNARE protein syntaxin 7 (Stx7) regulates vesicle trafficking events involved in phagocytosis and cytokine secretion. Therefore, we investigated the ability of CSF-1 to regulate Stx7. CSF-1 upregulated Stx7 expression in primary mouse macrophages; it also upregulated expression of its SNARE partners Vti1b and VAMP8 but not Stx8. Additionally, CSF-1 induced the rapid serine phosphorylation of Stx7 and enhanced its binding to Vti1b, Stx8, and VAMP8. Bioinformatics analysis and results from experiments with kinase inhibitors suggested the CSF-1-induced phosphorylation of Stx7 was mediated by protein kinase C and Akt in response to phosphatidylinositol 3-kinase activation. Based on mutagenesis studies, CSF-1 appeared to increase the binding of Stx7 to its SNARE partners by inducing the phosphorylation of serine residues in the Habc domain and/or "linker" region of Stx7. Thus, CSF-1 is a key regulator of Stx7 expression and function in macrophages. Furthermore, the effects of CSF-1 on Stx7 may provide a mechanism for the regulation of macrophage effector functions by CSF-1.
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    Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14
    Asselin-Labat, M-L ; Sutherland, KD ; Vaillant, F ; Gyorki, DE ; Wu, D ; Holroyd, S ; Breslin, K ; Ward, T ; Shi, W ; Bath, ML ; Deb, S ; Fox, SB ; Smyth, GK ; Lindeman, GJ ; Visvader, JE (AMER SOC MICROBIOLOGY, 2011-11)
    The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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    Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years
    Kalincik, T ; Diouf, I ; Sharmin, S ; Malpas, C ; Spelman, T ; Horakova, D ; Havrdova, EK ; Trojano, M ; Izquierdo, G ; Lugaresi, A ; Prat, A ; Girard, M ; Duquette, P ; Grammond, P ; Jokubaitis, V ; Van der Walt, A ; Grand'Maison, F ; Sola, P ; Ferraro, D ; Shaygannejad, V ; Alroughani, R ; Hupperts, R ; Terzi, M ; Boz, C ; Lechner-Scott, J ; Pucci, E ; Van Pesch, V ; Granella, F ; Bergamaschi, R ; Spitaleri, D ; Slee, M ; Vucic, S ; Ampapa, R ; McCombe, P ; Ramo-Tello, C ; Prevost, J ; Olascoaga, J ; Cristiano, E ; Barnett, M ; Saladino, ML ; Sanchez-Menoyo, JL ; Hodgkinson, S ; Rozsa, C ; Hughes, S ; Moore, F ; Shaw, C ; Butler, E ; Skibina, O ; Gray, O ; Kermode, A ; Csepany, T ; Singhal, B ; Shuey, N ; Piroska, I ; Taylor, B ; Simo, M ; Sirbu, C-A ; Sas, A ; Butzkueven, H (LIPPINCOTT WILLIAMS & WILKINS, 2021-02-02)
    OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. METHODS: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). CONCLUSION: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
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    Minimum technical standards and recommendations for traumatic brain injury specialist rehabilitation teams in sudden-onset disasters (for Disaster Rehabilitation Committee special session) (Abstract)
    Vasudevan, V ; Amatya, B ; Chopra, S ; Zhang, N ; Astrakhantseva, I ; Khan, F (Elsevier BV, 2018-07)
    Introduction/Background: Sudden-onset disasters (SODs) result in increased number of survivors with complex and long-term disabling injuries, including traumatic brain injury (TBI) that warrants comprehensive specialist rehabilitation. This presentation highlights the minimum technical standards required for specialised TBI rehabilitation teams and their integration into WHO Emergency Medical Teams (EMTs) to facilitate comprehensive management of TBI survivors in disaster settings. Material and method: A team of medical rehabilitation physicians from the Royal Melbourne Hospital conducted a comprehensive review of literature for TBI management, based on the WHO core-guidelines for ‘Minimum technical standards and recommendations for rehabilitation for EMTs’. These were endorsed by a specialist TBI expert panel in the Asia-Pacific region. Results: Comprehensive rehabilitation programs improve functional outcomes and quality of life of TBI survivors. It is recommended that specialised TBI care teams need to be embedded into EMTs for disaster response and management for early diagnosis, management and social reintegration. This guidance documents the minimum standards for deployment of TBI specialist rehabilitation teams in the context of SODs, including: skill requirements, team configuration and profile, professional competencies for management of TBI and complications, list of required equipment and consumables, information management/dissemination. Conclusion: TBI rehabilitation should commence from the early response phase in SODs by accredited rehabilitation professionals to minimise complications and disability. Integration of specialised TBI rehabilitation professionals into EMTs for disaster response will improve functional outcomes of survivors.
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    Efficacy and Safety of the Awake Prone Positioning in Patients with COVID-19 Related Respiratory Distress: A Scoping Review.
    Uddin, T ; Siddiquee, N ; Khandaker, MN ; Bashar, MS ; Rahim, HR ; Islam, S ; Rahman, MA ; Amatya, B ( 2022-01)
    Prone positioning (PP) is becoming an important treatment modality for the management of COVID-19 related respiratory distress syndrome. The aim of this scoping review was to evaluate effectiveness and safety of awake PP in non-intubated patients with COVID-19 related acute respiratory distress at different care settings. The study was conducted during December 1, 2019 to August 30, 2020 using health science electronic databases and grey literature. A PRISMA flow diagram was used and finally 06 studies with 187 patients were included for review. Male patients were predominating with the mean age of approximately 55 years. Oxygenation was improved in 79.14% patients. One hundred fifty seven (83.95%) patients with COVID-19-related hypoxemic respiratory distress tolerated the procedure. Intubations required 25.41% of the patients or mechanical ventilation and 6(3.2%) patients expired. Number of patients in the reported studies could tolerate more than 3 hours of PP without a major side effect. Awake proning improved oxygenation of the patients suffering from COVID-19 related respiratory hypoxia in different care settings. Early instituted prone positioning may be an effective alternative method of treating COVID-19 related respiratory distress. Patient compliance and small size cohort studies are the limitations of this review. Multicenter controlled studies are warranted before conclusions are made about safety and the settings.
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    Another line of defence
    Steinfort, DP ; Johnson, DF (WILEY, 2022-10)
    See related article
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    Social media usage in family communication about genetic information: 'I no longer speak with my sister but she needed to know'
    Leighton, S ; Forrest, LE ; Young, M-A ; Delatycki, MB ; Lynch, E (WILEY, 2021-02)
    The use of social media has become a ubiquitous form of communication. Little is known about whether social media is used in families to assist with the communication of genetic information. This study aimed to understand if and why individuals use social media to communicate genetic information to at-risk relatives. Individuals with either a pathogenic variant in a cancer-predisposing gene or a heterozygous pathogenic variant in an autosomal or X-linked recessive gene were surveyed about communicating genetic information to their at-risk relatives and their use of social media to assist this process. Surveys were sent to 323 individuals from a reproductive carrier screening program and 250 individuals from a familial cancer center. The 128 responses (response rate 25.2%) showed that while most participants (79.0%) did not use social media to communicate genetic information, those that did use social media (21.0%) found it to be helpful as it was easy, accessible and allowed individuals to overcome communication barriers. Genetic professionals should be aware that social media is being used by individuals to assist family communication about genetic information and should discuss this method of communication with individuals who are faced with communicating genetic information with their family.
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    Influence of lived experience on risk perception among women who received a breast cancer polygenic risk score: 'Another piece of the pie'
    Willis, AM ; Smith, SK ; Meiser, B ; James, PA ; Ballinger, ML ; Thomas, DM ; Yanes, T ; Young, M-A (WILEY, 2021-06)
    Polygenic risk scores (PRS) are personalized assessments of disease risk based on the cumulative effect of common low-risk genetic variants. PRS have been shown to accurately predict women's breast cancer risk and are likely to be incorporated into personalized breast cancer risk management programs. However, there are few studies investigating the individual impact of receiving a breast cancer PRS. Existing studies have not demonstrated significant changes in perceived risk or risk management behaviors after receipt of polygenic risk information. The aim of this qualitative study was to explore how women with a family history of breast cancer construct breast cancer risk perceptions after receipt of a breast cancer PRS. Unaffected women with a family history of breast cancer who had not previously received genetic counseling regarding their breast cancer risk were invited to participate in this study. In-depth, semi-structured interviews were conducted with 20 women who attended a familial cancer clinic in the Australian states of Victoria and Tasmania. Data were analyzed using an inductive thematic approach. Women's lived experience played a significant role in the construction and maintenance of their breast cancer risk perception. Women's pre-existing risk perceptions were informed by their family history and their knowledge that breast cancer is a multifactorial disease. Knowing that breast cancer is a multifactorial disease enabled most women to integrate genetic information with their pre-existing notions of risk. Women reported that the information they received was consistent with their existing notions of personal risk and screening advice. Therefore, the PRS did not lead to a change in perceived risk or risk management behaviors for most women. The results of this study provide insight into how polygenic risk information is integrated with pre-existing notions of risk, which will inform its implementation into clinical practice.