Medicine (RMH) - Research Publications

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    Observational studies of treatment effectiveness in neurology
    Kalincik, T ; Roos, I ; Sharmin, S (OXFORD UNIV PRESS, 2023-12-01)
    The capacity and power of data from cohorts, registries and randomized trials to provide answers to contemporary clinical questions in neurology has increased considerably over the past two decades. Novel sophisticated statistical methods are enabling us to harness these data to guide treatment decisions, but their complexity is making appraisal of clinical evidence increasingly demanding. In this review, we discuss several methodological aspects of contemporary research of treatment effectiveness in observational data in neurology, aimed at academic neurologists and analysts specializing in outcomes research. The review discusses specifics of the sources of observational data and their key features. It focuses on the limitations of observational data and study design, as well as statistical approaches aimed to overcome these limitations. Among the examples of leading clinical themes typically studied with analyses of observational data, the review discusses methodological approaches to comparative treatment effectiveness, development of diagnostic criteria and definitions of clinical outcomes. Finally, this review provides a brief summary of key points that will help clinical audience critically evaluate design and analytical aspects of studies of disease outcomes using observational data.
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    Effect of gene variants on opioid dose, pain and adverse effect outcomes in advanced cancer: an explorative study
    Wong, AK ; Klepstad, P ; Somogyi, AA ; Vogrin, S ; Le, B ; Philip, J ; Rubio, JP (FUTURE MEDICINE LTD, 2023-12)
    Aim: Associations between gene variants and opioid net effect are unclear. We conducted an exploratory pharmacogenetic analysis of 35 gene variants and opioid response in advanced cancer. Patients & methods: This multi-center prospective cohort study included clinical data, questionnaires (pain and adverse effects) and DNA (blood). Negative binomial regression and logistic regression were used. Results: Within 54 participants, eight statistically significant associations (p = 0.002-0.038) were observed between gene variants and opioid dose, pain scores or adverse effects, the majority being within the neuroimmune TLR4 pathway (IL1B [rs1143634], IL2 [rs2069762], IL6 [rs1800795], BDNF [rs6265]) and ARRB2 pathway (ARRB2 [rs3786047], DRD2 [rs6275]). Conclusion: Neuroimmune pathway genes may contribute to differences in opioid response in cancer and may be included in future similar studies.
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    Opioid Switch Dosing in Chronic Cancer Pain: A Prospective Longitudinal Study
    Wong, AK ; Klepstad, P ; Rubio, JP ; Somogyi, AA ; Vogrin, S ; Le, B ; Philip, J (Mary Ann Liebert, 2024-03)
    Background: Opioid switching is common, however, conversion tables have limitations. Guidelines suggest postswitch dose reduction, yet, observations show opioid doses may increase postswitch. Objectives: To document the opioid conversion factor postswitch in cancer, and whether pain and adverse effect outcomes differ between switched opioid groups. Design/Setting: This multicenter prospective longitudinal study included people with advanced cancer in Australia. Clinical data (demographics, opioids) and validated instruments (pain, adverse effects) were collected twice, seven days apart. Results: Opioid switch resulted in dose increase (median oral morphine equivalent daily dose 90 mg [interquartile range {IQR} 45-184] to 150 mg [IQR 79-270]), reduced average pain (5.1 [standard deviation {SD} 1.7] to 3.8 [SD 1.6]), and reduced adverse effects. Hydromorphone dose increased 2.5 times (IQR 1.0-3.6) above the original conversion factor used. Conclusions: Opioid switching resulted in overall dose increase, particularly when switching to hydromorphone. Higher preswitch dosing may require higher dose conversion ratios. Dose reduction postswitch risks undertreatment and may not be always appropriate.
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    Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders
    Eratne, 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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    Australia and New Zealand consensus position statement: use of COVID-19 therapeutics in patients with haematological malignancies
    Campbell, A ; Teh, B ; Mulligan, S ; Ross, DM ; Weinkove, R ; Gilroy, N ; Gangatharan, S ; Prince, HM ; Szer, J ; Trotman, J ; Lane, S ; Dickinson, M ; Quach, H ; Enjeti, AK ; Ku, M ; Gregory, G ; Hapgood, G ; Ho, PJ ; Cochrane, T ; Cheah, C ; Greenwood, M ; Latimer, M ; Berkahn, L ; Wight, J ; Armytage, T ; Diamond, P ; Tam, CS ; Hamad, N (Wiley, 2023-02)
    Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines.
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    Methodological considerations for observational studies of treatment effectiveness in neurology: a clinician's guide
    Kalincik, T ; Roos, I ; Sharmin, S ; Malpas, CB (BMJ PUBLISHING GROUP, 2023-10-27)
    Data from cohorts, registries, randomised trials, electronic medical records and administrative claims databases have increasingly been used to inform the use of therapies for neurological diseases. While novel sophisticated methods are enabling us to use existing data to guide treatment decisions, the complexity of statistical methodology is making appraisal of clinical evidence increasingly demanding. In this narrative review, we provide a brief overview of the most commonly used methods for evaluation of treatment effectiveness in neurology. This primer discusses complementarity of randomised and non-randomised study designs, sources of observational data, different forms of bias and the appropriate mitigation strategies, statistical significance, Bayesian approaches and provides an overview of multivariable regression models, propensity score-based models, causal inference, mediation analysis and Mendelian randomisation.
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    Medications and cognitive risk in Aboriginal primary care: a cross-sectional study
    Holdaway, M ; Hyde, Z ; Hughson, J-A ; Malay, R ; Stafford, A ; Fulford, K ; Radford, K ; Flicker, L ; Smith, K ; Pond, D ; Russell, S ; Atkinson, D ; Blackberry, I ; LoGiudice, D (WILEY, 2023-12-30)
    BACKGROUND: Aboriginal and Torres Strait Islander people are ageing with high rates of comorbidity, yet little is known about suboptimal prescribing in this population. AIM: The prevalence of potentially suboptimal prescribing and associated risk factors were investigated among older patients attending primary care through Aboriginal Community Controlled Health Services (ACCHSs). METHODS: Medical records of 420 systematically selected patients aged ≥50 years attending urban, rural and remote health services were audited. Polypharmacy (≥ 5 prescribed medications), potentially inappropriate medications (PIMs) as per Beers Criteria and anticholinergic burden (ACB) were estimated and associated risk factors were explored with logistic regression. RESULTS: The prevalence of polypharmacy, PIMs and ACB score ≥3 was 43%, 18% and 12% respectively. In multivariable logistic regression analyses, polypharmacy was less likely in rural (odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.24-0.77) compared to urban patients, and more likely in those with heart disease (OR = 2.62, 95% CI = 1.62-4.25), atrial fibrillation (OR = 4.25, 95% CI = 1.08-16.81), hypertension (OR = 2.14, 95% CI = 1.34-3.44), diabetes (OR = 2.72, 95% CI = 1.69-4.39) or depression (OR = 1.91, 95% CI = 1.19-3.06). PIMs were more frequent in females (OR = 1.88, 95% CI = 1.03-3.42) and less frequent in rural (OR = 0.41, 95% CI = 0.19-0.85) and remote (OR = 0.58, 95% CI = 0.29-1.18) patients. Factors associated with PIMs were kidney disease (OR = 2.60, 95% CI = 1.37-4.92), urinary incontinence (OR = 3.00, 95% CI = 1.02-8.83), depression (OR = 2.67, 95% CI = 1.50-4.77), heavy alcohol use (OR = 2.83, 95% CI = 1.39-5.75) and subjective cognitive concerns (OR = 2.69, 95% CI = 1.31-5.52). High ACB was less common in rural (OR = 0.10, 95% CI = 0.03-0.34) and remote (OR = 0.51, 95% CI = 0.25-1.04) patients and more common in those with kidney disease (OR = 3.07, 95% CI = 1.50-6.30) or depression (OR = 3.32, 95% CI = 1.70-6.47). CONCLUSION: Associations between potentially suboptimal prescribing and depression or cognitive concerns highlight the importance of considering medication review and deprescribing for these patients.
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    Intratumoral presence of the genotoxic gut bacteria pks+ E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer
    Joo, JE ; Chu, YL ; Georgeson, P ; Walker, R ; Mahmood, K ; Clendenning, M ; Meyers, AL ; Como, J ; Joseland, S ; Preston, SG ; Diepenhorst, N ; Toner, J ; Ingle, DJ ; Sherry, NL ; Metz, A ; Lynch, BM ; Milne, RL ; Southey, MC ; Hopper, JL ; Win, AK ; Macrae, FA ; Winship, IM ; Rosty, C ; Jenkins, MA ; Buchanan, DD (Springer Nature, 2024)
    Background: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+ Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum). Methods: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. Results: Pks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01). Conclusion: Intratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.
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    What are the core recommendations for gout management in first line and specialist care? Systematic review of clinical practice guidelines
    Conley, B ; Bunzli, S ; Bullen, J ; O'Brien, P ; Persaud, J ; Gunatillake, T ; Dowsey, MM ; Choong, PF ; Nikpour, M ; Grainger, R ; Lin, I (SPRINGERNATURE, 2023-06-15)
    BACKGROUND: Gout is the most common inflammatory arthritis, increasing in prevalence and burden. Of the rheumatic diseases, gout is the best-understood and potentially most manageable condition. However, it frequently remains untreated or poorly managed. The purpose of this systematic review is to identify Clinical Practice Guidelines (CPG) regarding gout management, evaluate their quality, and to provide a synthesis of consistent recommendations in the high-quality CPGs. METHODS: Gout management CPGs were eligible for inclusion if they were (1) written in English and published between January 2015-February 2022; focused on adults aged ≥ 18 years of age; and met the criteria of a CPG as defined by the Institute of Medicine; and (2) were rated as high quality on the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Gout CPGs were excluded if they required additional payment to access; only addressed recommendations for the system/organisation of care and did not include interventional management recommendations; and/or included other arthritic conditions. OvidSP MEDLINE, Cochrane, CINAHL, Embase and Physiotherapy Evidence Database (PEDro) and four online guideline repositories were searched. RESULTS: Six CPGs were appraised as high quality and included in the synthesis. Clinical practice guidelines consistently recommended education, commencement of non-steroidal anti-inflammatories, colchicine or corticosteroids (unless contraindicated), and assessment of cardiovascular risk factors, renal function, and co-morbid conditions for acute gout management. Consistent recommendations for chronic gout management were urate lowering therapy (ULT) and continued prophylaxis recommended based on individual patient characteristics. Clinical practice guideline recommendations were inconsistent on when to initiate ULT and length of ULT, vitamin C intake, and use of pegloticase, fenofibrate and losartan. CONCLUSION: Management of acute gout was consistent across CPGs. Management of chronic gout was mostly consistent although there were inconsistent recommendations regarding ULT and other pharmacological therapies. This synthesis provides clear guidance that can assist health professionals to provide standardised, evidence-based gout care. TRIAL REGISTRATION: The protocol for this review was registered with Open Science Framework (DOI https://doi.org/10.17605/OSF.IO/UB3Y7 ).
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    CCL17/TARC in autoimmunity and inflammation-not just a T-cell chemokine
    Lupancu, TJ ; Eivazitork, M ; Hamilton, JA ; Achuthan, AA ; Lee, KM-C (WILEY, 2023-08)
    Chemokine (C-C) ligand 17 (CCL17) was first identified as thymus- and activation-regulated chemokine when it was found to be constitutively expressed in the thymus and identified as a T-cell chemokine. This chemoattractant molecule has subsequently been found at elevated levels in a range of autoimmune and inflammatory diseases, as well as in cancer. CCL17 is a C-C chemokine receptor type 4 (CCR4) ligand, with chemokine (C-C) ligand 22 being the other major ligand and, as CCR4 is highly expressed on helper T cells, CCL17 can play a role in T-cell-driven diseases, usually considered to be via its chemotactic activity on T helper 2 cells; however, given that CCR4 is also expressed by other cell types and there is elevated expression of CCL17 in many diseases, a broader CCL17 biology is suggested. In this review, we summarize the biology of CCL17, its regulation and its potential contribution to the pathogenesis of various preclinical models. Reference is made, for example, to recent literature indicating a role for CCL17 in the control of pain as part of a granulocyte macrophage-colony-stimulating factor/CCL17 pathway in lymphocyte-independent models and thus not as a T-cell chemokine. The review also discusses the potential for CCL17 to be a biomarker and a therapeutic target in human disorders.