Medicine (St Vincent's) - Research Publications

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    Proximal weakness and creatine kinase elevation in systemic sclerosis: Clinical correlates, prognosis and functional implications
    Fairley, JL ; Hansen, D ; Day, J ; Proudman, S ; Sahhar, J ; Ngian, G-S ; Walker, J ; Morrisroe, K ; Stevens, W ; Ross, L ; Nikpour, M ; V. Host, L (W B SAUNDERS CO-ELSEVIER INC, 2024-04)
    OBJECTIVES: To determine the frequency, clinical correlates and implications of clinical evidence of muscle disease in systemic sclerosis (SSc). METHODS: Australian Scleroderma Cohort Study participants with ≥1 creatine kinase (CK) and proximal power assessment were subdivided according to presence of proximal weakness (PW: proximal muscle power<5/5) and CK elevation(≥140IU/L). Participants were assigned to one of four groups: concurrent PW&CK elevation, PW alone, CK elevation alone or neither. Between-group comparisons were made with chi-squared, ANOVA or Kruskal-Wallis tests. Survival analysis was performed using time-varying-covariate Cox regression modelling. Longitudinal data were modelled using multinomial logistic and linear regression. RESULTS: Of 1786 participants, 4 % had concurrent PW&CK elevation, 15 % PW alone, 24 % CK elevation and 57 % neither. Participants with PW&CK elevation displayed a severe, inflammatory SSc phenotype, with more frequent dcSSc(p < 0.01), tendon friction rubs(p < 0.01), synovitis(p < 0.01) and digital ulceration(p = 0.03). Multimorbidity(p < 0.01) and cardiopulmonary disease, including ischaemic heart disease(p < 0.01) and pulmonary arterial hypertension(p < 0.01), were most common in those with PW, with and without CK elevation. Men with anti-Scl70 positivity most frequently had CK elevation alone, without other significant clinical differences. Multivariable modelling demonstrated 3.6-fold increased mortality in those with PW&CK elevation (95 %CI 1.9-6.6, p < 0.01) and 2.1-fold increased mortality in PW alone (95 %CI 1.4-3.0, p < 0.01) compared to those without PW or CK elevation. CK elevation alone conferred better survival (HR 0.7, 95 %CI 0.4-1.1, p = 0.09) compared to those with no PW or CK elevation. PW regardless of CK elevation was associated with impaired physical function, with reduced six-minute-walk-distance (p < 0.01), higher HAQ-DI scores (p < 0.01) and increased patient-reported dyspnoea (p = 0.04). CONCLUSION: Clinical features of myopathy are highly prevalent in SSc, affecting almost half of our study cohort. Detection of PW and elevated CK alone, even without imaging or histopathological identification of SSc-myopathy, identified important clinical associations and are associated with poorer function and overall prognosis.
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    Spread of activation and interaction between channels with multi-channel optogenetic stimulation in the mouse cochlea
    Azees, AA ; Thompson, AC ; Thomas, R ; Zhou, J ; Ruther, P ; Wise, AK ; Ajay, EA ; Garrett, DJ ; Quigley, A ; Fallon, JB ; Richardson, RT (ELSEVIER, 2023-12)
    For individuals with severe to profound hearing loss resulting from irreversibly damaged hair cells, cochlear implants can be used to restore hearing by delivering electrical stimulation directly to the spiral ganglion neurons. However, current spread lowers the spatial resolution of neural activation. Since light can be easily confined, optogenetics is a technique that has the potential to improve the precision of neural activation, whereby visible light is used to stimulate neurons that are modified with light-sensitive opsins. This study compares the spread of neural activity across the inferior colliculus of the auditory midbrain during electrical and optical stimulation in the cochlea of acutely deafened mice with opsin-modified spiral ganglion neurons (H134R variant of the channelrhodopsin-2). Monopolar electrical stimulation was delivered via each of four 0.2 mm wide platinum electrode rings at 0.6 mm centre-to-centre spacing, whereas 453 nm wavelength light was delivered via each of five 0.22 × 0.27 mm micro-light emitting diodes (LEDs) at 0.52 mm centre-to-centre spacing. Channel interactions were also quantified by threshold changes during simultaneous stimulation by pairs of electrodes or micro-LEDs at different distances between the electrodes (0.6, 1.2 and 1.8 mm) or micro-LEDs (0.52, 1.04, 1.56 and 2.08 mm). The spread of activation resulting from single channel optical stimulation was approximately half that of monopolar electrical stimulation as measured at two levels of discrimination above threshold (p<0.001), whereas there was no significant difference between optical stimulation in opsin-modified deafened mice and pure tone acoustic stimulation in normal-hearing mice. During simultaneous micro-LED stimulation, there were minimal channel interactions for all micro-LED spacings tested. For neighbouring micro-LEDs/electrodes, the relative influence on threshold was 13-fold less for optical stimulation compared electrical stimulation (p<0.05). The outcomes of this study show that the higher spatial precision of optogenetic stimulation results in reduced channel interaction compared to electrical stimulation, which could increase the number of independent channels in a cochlear implant. Increased spatial resolution and the ability to activate more than one channel simultaneously could lead to better speech perception in cochlear implant recipients.
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    Autoregressive models for biomedical signal processing.
    Haderlein, JF ; Peterson, ADH ; Burkitt, AN ; Mareels, IMY ; Grayden, DB (IEEE, 2023-07)
    Autoregressive models are ubiquitous tools for the analysis of time series in many domains such as computational neuroscience and biomedical engineering. In these domains, data is, for example, collected from measurements of brain activity. Crucially, this data is subject to measurement errors as well as uncertainties in the underlying system model. As a result, standard signal processing using autoregressive model estimators may be biased. We present a framework for autoregressive modelling that incorporates these uncertainties explicitly via an overparameterised loss function. To optimise this loss, we derive an algorithm that alternates between state and parameter estimation. Our work shows that the procedure is able to successfully denoise time series and successfully reconstruct system parameters.Clinical relevance- This new paradigm can be used in a multitude of applications in neuroscience such as brain-computer interface data analysis and better understanding of brain dynamics in diseases such as epilepsy.
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    Minimum clinical utility standards for wearable seizure detectors: A simulation study
    Goldenholz, DM ; Karoly, PJ ; Viana, PF ; Nurse, E ; Loddenkemper, T ; Schulze-Bonhage, A ; Vieluf, S ; Bruno, E ; Nasseri, M ; Richardson, MP ; Brinkmann, BH ; Westover, MB (WILEY, 2024-02-17)
    OBJECTIVE: Epilepsy management employs self-reported seizure diaries, despite evidence of seizure underreporting. Wearable and implantable seizure detection devices are now becoming more widely available. There are no clear guidelines about what levels of accuracy are sufficient. This study aimed to simulate clinical use cases and identify the necessary level of accuracy for each. METHODS: Using a realistic seizure simulator (CHOCOLATES), a ground truth was produced, which was then sampled to generate signals from simulated seizure detectors of various capabilities. Five use cases were evaluated: (1) randomized clinical trials (RCTs), (2) medication adjustment in clinic, (3) injury prevention, (4) sudden unexpected death in epilepsy (SUDEP) prevention, and (5) treatment of seizure clusters. We considered sensitivity (0%-100%), false alarm rate (FAR; 0-2/day), and device type (external wearable vs. implant) in each scenario. RESULTS: The RCT case was efficient for a wide range of wearable parameters, though implantable devices were preferred. Lower accuracy wearables resulted in subtle changes in the distribution of patients enrolled in RCTs, and therefore higher sensitivity and lower FAR values were preferred. In the clinic case, a wide range of sensitivity, FAR, and device type yielded similar results. For injury prevention, SUDEP prevention, and seizure cluster treatment, each scenario required high sensitivity and yet was minimally influenced by FAR. SIGNIFICANCE: The choice of use case is paramount in determining acceptable accuracy levels for a wearable seizure detection device. We offer simulation results for determining and verifying utility for specific use case and specific wearable parameters.
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    Evaluation of expression of a human T-cell depleting monoclonal antibody in islets and other tissues of transgenic pigs
    Salvaris, E ; Fisicaro, N ; Mcilfatrick, S ; Thomas, A ; Fuller, E ; Lew, AM ; Nottle, MB ; Hawthorne, WJ ; Cowan, PJ (LIPPINCOTT WILLIAMS & WILKINS, 2023-10)
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    Nuclear export of circular RNA.
    Ngo, LH ; Bert, AG ; Dredge, BK ; Williams, T ; Murphy, V ; Li, W ; Hamilton, WB ; Carey, KT ; Toubia, J ; Pillman, KA ; Liu, D ; Desogus, J ; Chao, JA ; Deans, AJ ; Goodall, GJ ; Wickramasinghe, VO (Springer Science and Business Media LLC, 2024-03)
    Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells1-5, are formed by back-splicing of precursor mRNAs in the nucleus6-10. circRNAs are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here we identify a pathway that is specific for the nuclear export of circular RNA. This pathway requires Ran-GTP, exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter CRM1 selectively increases the nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Depletion or knockout of exportin-2 specifically inhibits nuclear export of circRNA. Analysis of nuclear circRNA-binding proteins reveals that interaction between IGF2BP1 and circRNA is enhanced by Ran-GTP. The formation of circRNA export complexes in the nucleus is promoted by Ran-GTP through its interactions with exportin-2, circRNA and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Ran-GTP and exportin-2 to export circRNAs in a mechanism that is analogous to protein export, rather than mRNA export.
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    Background and Breakthrough Opioid Choice May Determine Different Pain Outcomes
    Wong, AK ; Vogrin, S ; Le, B ; Klepstad, P ; Rubio, JP ; Somogyi, AA ; Philip, J (ELSEVIER SCIENCE INC, 2024-03)
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    Point-of-care HCV RNA testing improves hepatitis C testing rates and allows rapid treatment initiation among people who inject drugs attending a medically supervised injecting facility.
    MacIsaac, MB ; Whitton, B ; Anderson, J ; Cogger, S ; Vella-Horne, D ; Penn, M ; Weeks, T ; Elmore, K ; Pemberton, D ; Winter, RJ ; Papaluca, T ; Howell, J ; Hellard, M ; Stoové, M ; Wilson, D ; Pedrana, A ; Doyle, JS ; Clark, N ; Holmes, JA ; Thompson, AJ (Elsevier BV, 2024-01-27)
    BACKGROUND: To achieve hepatitis C virus (HCV) elimination targets, simplified care engaging people who inject drugs is required. We evaluated whether fingerstick HCV RNA point-of-care testing (PoCT) increased the proportion of clients attending a supervised injecting facility who were tested for hepatitis C. METHODS: Prospective single-arm study with recruitment between 9 November 2020 and 28 January 2021 and follow-up to 31 July 2021. Clients attending the supervised injecting facility were offered HCV RNA testing using the Xpert® HCV Viral Load Fingerstick (Cepheid, Sunnyvale, CA) PoCT. Participants with a positive HCV RNA test were prescribed direct acting antiviral (DAA) therapy. The primary endpoint was the proportion of clients who engaged in HCV RNA PoCT, compared to a historical comparator group when venepuncture-based hepatitis C testing was standard of care. RESULTS: Among 1618 clients who attended the supervised injecting facility during the study period, 228 (14%) engaged in PoCT. This was significantly higher than that observed in the historical comparator group (61/1,775, 3%; p < 0.001). Sixty-five (28%) participants were HCV RNA positive, with 40/65 (62%) receiving their result on the same day as testing. Sixty-one (94%) HCV RNA positive participants were commenced on DAA therapy; 14/61 (23%) started treatment on the same day as diagnosis. There was no difference in the proportion of HCV RNA positive participants commenced on treatment with DAA therapy when compared to the historical comparator group (61/65, 94% vs 22/26, 85%; p = 0.153). However, the median time to treatment initiation was significantly shorter in the PoCT cohort (2 days (IQR 1-20) vs 41 days (IQR 22-76), p < 0.001). Among participants who commenced treatment and had complete follow-up data available, 27/36 (75%) achieved hepatitis C cure. CONCLUSIONS: HCV RNA PoCT led to a significantly higher proportion of clients attending a supervised injecting facility engaging in hepatitis C testing, whilst also reducing the time to treatment initiation.
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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.