School of Mathematics and Statistics - Research Publications

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    Variational Bayesian Neural Networks via Resolution of Singularities
    Wei, S ; Lau, E (TAYLOR & FRANCIS INC, 2024-01-01)
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    Characterisation of Plasmodium vivax lactate dehydrogenase dynamics in P. vivax infections
    Cao, P ; Kho, S ; Grigg, MJ ; Barber, BE ; Piera, KA ; William, T ; Poespoprodjo, JR ; Jang, IK ; Simpson, JA ; Mccaw, JM ; Anstey, NM ; Mccarthy, JS ; Britton, S (NATURE PORTFOLIO, 2024-03-22)
    Plasmodium vivax lactate dehydrogenase (PvLDH) is an essential enzyme in the glycolytic pathway of P. vivax. It is widely used as a diagnostic biomarker and a measure of total-body parasite biomass in vivax malaria. However, the dynamics of PvLDH remains poorly understood. Here, we developed mathematical models that capture parasite and matrix PvLDH dynamics in ex vivo culture and the human host. We estimated key biological parameters characterising in vivo PvLDH dynamics based on longitudinal data of parasitemia and PvLDH concentration collected from P. vivax-infected humans, with the estimates informed by the ex vivo data as prior knowledge in a Bayesian hierarchical framework. We found that the in vivo accumulation rate of intraerythrocytic PvLDH peaks at 10-20 h post-invasion (late ring stage) with a median estimate of intraerythrocytic PvLDH mass at the end of the life cycle to be 9.4 × 10-3ng. We also found that the median estimate of in vivo PvLDH half-life was approximately 21.9 h. Our findings provide a foundation with which to advance our quantitative understanding of P. vivax biology and will facilitate the improvement of PvLDH-based diagnostic tools.
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    Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice
    Arandjelovic, P ; Kim, Y ; Cooney, JP ; Preston, SP ; Doerflinger, M ; Mcmahon, JH ; Garner, SE ; Zerbato, JM ; Roche, M ; Tumpach, C ; Ong, J ; Sheerin, D ; Smyth, GK ; Anderson, JL ; Allison, CC ; Lewin, SR ; Pellegrini, M (CELL PRESS, 2023-09-19)
    HIV-1 persists indefinitely in people living with HIV (PLWH) on antiretroviral therapy (ART). If ART is stopped, the virus rapidly rebounds from long-lived latently infected cells. Using a humanized mouse model of HIV-1 infection and CD4+ T cells from PLWH on ART, we investigate whether antagonizing host pro-survival proteins can prime latent cells to die and facilitate HIV-1 clearance. Venetoclax, a pro-apoptotic inhibitor of Bcl-2, depletes total and intact HIV-1 DNA in CD4+ T cells from PLWH ex vivo. This venetoclax-sensitive population is enriched for cells with transcriptionally higher levels of pro-apoptotic BH3-only proteins. Furthermore, venetoclax delays viral rebound in a mouse model of persistent HIV-1 infection, and the combination of venetoclax with the Mcl-1 inhibitor S63845 achieves a longer delay in rebound compared with either intervention alone. Thus, selective inhibition of pro-survival proteins can induce death of HIV-1-infected cells that persist on ART, extending time to viral rebound.
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    Optimal allocation of resources among general and species-specific tools for plant pest biosecurity surveillance
    Nguyen, H-T-M ; Chu, L ; Liebhold, AM ; Epanchin-Niell, R ; Kean, JM ; Kompas, T ; Robinson, AP ; Brockerhoff, EG ; Moore, JL (WILEY, 2024-04)
    This paper proposes a surveillance model for plant pests that can optimally allocate resources among survey tools with varying properties. While some survey tools are highly specific for the detection of a single pest species, others are more generalized. There is considerable variation in the cost and sensitivity of these tools, but there are no guidelines or frameworks for identifying which tools are most cost-effective when used in surveillance programs that target the detection of newly invaded populations. To address this gap, we applied our model to design a trapping surveillance program in New Zealand for bark- and wood-boring insects, some of the most serious forest pests worldwide. Our findings show that exclusively utilizing generalized traps (GTs) proves to be highly cost-effective across a wide range of scenarios, particularly when they are capable of capturing all pest species. Implementing surveillance programs that only employ specialized traps (ST) is cost-effective only when these traps can detect highly damaging pests. However, even in such cases, they significantly lag in cost-effectiveness compared to GT-only programs due to their restricted coverage. When both GTs and STs are used in an integrated surveillance program, the total expected cost (TEC) generally diminishes when compared to programs relying on a single type of trap. However, this relative reduction in TEC is only marginally larger than that achieved with GT-only programs, as long as highly damaging species can be detected by GTs. The proportion of STs among the optimal required traps fluctuates based on several factors, including the relative pricing of GTs and STs, pest arrival rates, potential damage, and, more prominently, the coverage capacity of GTs. Our analysis suggests that deploying GTs extensively across landscapes appears to be more cost-effective in areas with either very high or very low levels of relative risk density, potential damage, and arrival rate. Finally, STs are less likely to be required when the pests that are detected by those tools have a higher likelihood of successful eradication because delaying detection becomes less costly for these species.
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    Frugal and decentralised resolvent splittings defined by nonexpansive operators
    Tam, MK (SPRINGER HEIDELBERG, 2023-01-01)
    Abstract Frugal resolvent splittings are a class of fixed point algorithms for finding a zero in the sum of the sum of finitely many set-valued monotone operators, where the fixed point operator uses only vector addition, scalar multiplication and the resolvent of each monotone operator once per iteration. In the literature, the convergence analyses of these schemes are performed in an inefficient, algorithm-by-algorithm basis. In this work, we address this by developing a general framework for frugal resolvent splitting which simultaneously covers and extends several important schemes in the literature. The framework also yields a new resolvent splitting algorithm which is suitable for decentralised implementation on regular networks.
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    Modelling the impact of hybrid immunity on future COVID-19 epidemic waves
    Le, TP ; Abell, I ; Conway, E ; Campbell, PT ; Hogan, AB ; Lydeamore, MJ ; Mcvernon, J ; Mueller, I ; Walker, CR ; Baker, CM (BMC, 2024-04-16)
    BACKGROUND: Since the emergence of SARS-CoV-2 (COVID-19), there have been multiple waves of infection and multiple rounds of vaccination rollouts. Both prior infection and vaccination can prevent future infection and reduce severity of outcomes, combining to form hybrid immunity against COVID-19 at the individual and population level. Here, we explore how different combinations of hybrid immunity affect the size and severity of near-future Omicron waves. METHODS: To investigate the role of hybrid immunity, we use an agent-based model of COVID-19 transmission with waning immunity to simulate outbreaks in populations with varied past attack rates and past vaccine coverages, basing the demographics and past histories on the World Health Organization Western Pacific Region. RESULTS: We find that if the past infection immunity is high but vaccination levels are low, then the secondary outbreak with the same variant can occur within a few months after the first outbreak; meanwhile, high vaccination levels can suppress near-term outbreaks and delay the second wave. Additionally, hybrid immunity has limited impact on future COVID-19 waves with immune-escape variants. CONCLUSIONS: Enhanced understanding of the interplay between infection and vaccine exposure can aid anticipation of future epidemic activity due to current and emergent variants, including the likely impact of responsive vaccine interventions.
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    Four-week inhibition of the renin-angiotensin system in spontaneously hypertensive rats results in persistently lower blood pressure with reduced kidney renin and changes in expression of relevant gene networks
    Byars, SG ; Prestes, PR ; Suphapimol, V ; Takeuchi, F ; De Vries, N ; Maier, MC ; Melo, M ; Balding, D ; Samani, N ; Allen, AM ; Kato, N ; Wilkinson-Berka, JL ; Charchar, F ; Harrap, SB (OXFORD UNIV PRESS, 2024-05-29)
    AIMS: Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. METHODS AND RESULTS: In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys. CONCLUSION: Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks.
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    Spatio-temporal spread of artemisinin resistance in Southeast Asia
    Flegg, JA ; Kandanaarachchi, S ; Guerin, PJ ; Dondorp, AM ; Nosten, FH ; Otienoburu, SD ; Golding, N ; Kouyos, RD (PUBLIC LIBRARY SCIENCE, 2024-04)
    Current malaria elimination targets must withstand a colossal challenge-resistance to the current gold standard antimalarial drug, namely artemisinin derivatives. If artemisinin resistance significantly expands to Africa or India, cases and malaria-related deaths are set to increase substantially. Spatial information on the changing levels of artemisinin resistance in Southeast Asia is therefore critical for health organisations to prioritise malaria control measures, but available data on artemisinin resistance are sparse. We use a comprehensive database from the WorldWide Antimalarial Resistance Network on the prevalence of non-synonymous mutations in the Kelch 13 (K13) gene, which are known to be associated with artemisinin resistance, and a Bayesian geostatistical model to produce spatio-temporal predictions of artemisinin resistance. Our maps of estimated prevalence show an expansion of the K13 mutation across the Greater Mekong Subregion from 2000 to 2022. Moreover, the period between 2010 and 2015 demonstrated the most spatial change across the region. Our model and maps provide important insights into the spatial and temporal trends of artemisinin resistance in a way that is not possible using data alone, thereby enabling improved spatial decision support systems on an unprecedented fine-scale spatial resolution. By predicting for the first time spatio-temporal patterns and extents of artemisinin resistance at the subcontinent level, this study provides critical information for supporting malaria elimination goals in Southeast Asia.
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    Estimating measures to reduce the transmission of SARS-CoV-2 in Australia to guide a 'National Plan' to reopening
    Ryan, GE ; Shearer, FM ; Mccaw, JM ; Mcvernon, J ; Golding, N (ELSEVIER, 2024-06)
    The availability of COVID-19 vaccines promised a reduction in the severity of disease and relief from the strict public health and social measures (PHSMs) imposed in many countries to limit spread and burden of COVID-19. We were asked to define vaccine coverage thresholds for Australia's transition to easing restrictions and reopening international borders. Using evidence of vaccine effectiveness against the then-circulating Delta variant, we used a mathematical model to determine coverage targets. The absence of any COVID-19 infections in many sub-national jurisdictions in Australia posed particular methodological challenges. We used a novel metric called Transmission Potential (TP) as a proxy measure of the population-level effective reproduction number. We estimated TP of the Delta variant under a range of PHSMs, test-trace-isolate-quarantine (TTIQ) efficiencies, vaccination coverage thresholds, and age-based vaccine allocation strategies. We found that high coverage across all ages (≥70%) combined with ongoing TTIQ and minimal PHSMs was sufficient to avoid lockdowns. At lesser coverage (≤60%) rapid case escalation risked overwhelming of the health sector or the need to reimpose stricter restrictions. Maintaining low case numbers was most beneficial for health and the economy, and at higher coverage levels (≥80%) further easing of restrictions was deemed possible. These results directly informed easing of COVID-19 restrictions in Australia.
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