Artemisinin-induced parasite dormancy : a plausible mechanism for treatment failure

Background Artemisinin-combination therapy is a highly effective treatment for uncomplicated falciparum malaria but parasite recrudescence has been commonly reported following artemisinin (ART) monotherapy. The dormancy recovery hypothesis has been proposed to explain this phenomenon, which is different from the slower parasite clearance times reported as the first evidence of the development of ART resistance. Methods In this study, an existing P. falciparum infection model is modified to incorporate the hypothesis of dormancy. Published in vitro data describing the characteristics of dormant parasites is used to explore whether dormancy alone could be responsible for the high recrudescence rates observed in field studies using monotherapy. Several treatment regimens and dormancy rates were simulated to investigate the rate of clinical and parasitological failure following treatment. Results The model output indicates that following a single treatment with ART parasitological and clinical failures occur in up to 77% and 67% of simulations, respectively. These rates rapidly decline with repeated treatment and are sensitive to the assumed dormancy rate. The simulated parasitological and clinical treatment failure rates after 3 and 7 days of treatment are comparable to those reported from several field trials. Conclusions Although further studies are required to confirm dormancy in vivo, this theoretical study adds support for the hypothesis, highlighting the potential role of this parasite sub-population in treatment failure following monotherapy and reinforcing the importance of using ART in combination with other anti-malarials.

Interrupting malaria transmission: quantifying the impact of interventions in regions of low to moderate transmission

Malaria has been eliminated from over 40 countries with an additional 39 currently planning for, or committed to, elimination. Information on the likely impact of available interventions, and the required time, is urgently needed to help plan resource allocation. Mathematical modelling has been used to investigate the impact of various interventions; the strength of the conclusions is boosted when several models with differing formulation produce similar data. Here we predict by using an individual-based stochastic simulation model of seasonal Plasmodium falciparum transmission that transmission can be interrupted and parasite reintroductions controlled in villages of 1,000 individuals where the entomological inoculation rate is <7 infectious bites per person per year using chemotherapy and bed net strategies. Above this transmission intensity bed nets and symptomatic treatment alone were not sufficient to interrupt transmission and control the importation of malaria for at least 150 days. Our model results suggest that 1) stochastic events impact the likelihood of successfully interrupting transmission with large variability in the times required, 2) the relative reduction in morbidity caused by the interventions were age-group specific, changing over time, and 3) the post-intervention changes in morbidity were larger than the corresponding impact on transmission. These results generally agree with the conclusions from previously published models. However the model also predicted changes in parasite population structure as a result of improved treatment of symptomatic individuals; the survival probability of introduced parasites reduced leading to an increase in the prevalence of sub-patent infections in semi-immune individuals. This novel finding requires further investigation in the field because, if confirmed, such a change would have a negative impact on attempts to eliminate the disease from areas of moderate transmission.

Evaluation of the potential impact of the global economic crisis on HIV epidemics in Southeast Asia

Economic conditions around the world are likely to deteriorate in the short to medium term. The potential impact of this crisis on the spread of HIV is not clear. Government revenues and aid flows from international donors may face constraints, possibly leading to reductions in funding for HIV programs. Economic conditions (leading to increases in unemployment, for example) may also have an indirect impact on HIV epidemics by affecting the behaviour of individual people. Some behavioural changes may influence the rate of HIV transmission. This report presents findings from a study that investigates the potential impact of the economic crisis on HIV epidemics through the use of mathematical modelling. The potential epidemiological impacts of changes in the economy are explored for two distinctly characterised HIV epidemics: (i) a well-defined, established, and generalised HIV epidemic (specifically Cambodia, where incidence is declining); (ii) an HIV epidemic in its early expansion phase (specifically Papua New Guinea, where incidence has not yet peaked). Country-specific data are used for both settings and the models calibrated to accurately reflect the unique HIV epidemics in each population in terms of both incidence and prevalence. Models calibrated to describe the past and present epidemics are then used to forecast epidemic trajectories over the next few years under assumptions that behavioural or program conditions may change due to economic conditions. It should be noted that there are very limited solid data on how HIV/AIDS program funds may decrease or how social determinants related to HIV risk may change due to the economic crisis. Potential changes in key relevant factors were explored, along with sensitivity ranges around these assumptions, based on extensive discussions with in-country and international experts and stakeholders. As with all mathematical models, assumptions should be reviewed critically and results interpreted cautiously.

What impact might the economic crisis have on HIV epidemics in Southeast Asia?

Objective: To evaluate the potential impact of the current global economic crisis (GEC) on the spread of HIV. Design: To evaluate the impact of the economic downturn we studied two distinct HIV epidemics in Southeast Asia: the generalized epidemic in Cambodia where incidence is declining and the epidemic in Papua New Guinea (PNG) which is in an expansion phase. Methods: Major HIV-related risk factors that may change due to the GEC were identified and a dynamic mathematical transmission model was developed and used to forecast HIV prevalence, diagnoses, and incidence in Cambodia and PNG over the next 3 years. Results: In Cambodia, the total numbers of HIV diagnoses are not expected to be largely affected. However, an estimated increase of up to 10% in incident cases of HIV, due to potential changes in behavior, may not be observed by the surveillance system. In PNG, HIV incidence and diagnoses could be more affected by the GEC, resulting in respective increases of up to 17% and 11% over the next 3 years. Decreases in VCT and education programs are the factors that may be of greatest concern in both settings. A reduction in the rollout of antiretroviral therapy could increase the number of AIDS-related deaths (by up to 7.5% after 3 years). Conclusions: The GEC is likely to have a modest impact on HIV epidemics. However, there are plausible conditions under which the economic downturns can noticeably influence epidemic trends. This study highlights the high importance of maintaining funding for HIV programs.

The impact of incidents on macroscopic fundamental diagrams

The macroscopic fundamental diagram (MFD) traffic modelling method has been proved for large urban roads and freeway networks, but hysteresis and scatter have been found in both such networks. This paper investigates how incident variables affect the shape and scatter of the MFD using both simulated data and real data collected from the M3 Pacific motorway in Brisbane, Australia. Three key components of incidents are investigated based on the simulated data (i.e. incident location, incident duration and traffic demand). The results based on simulated data indicate that the diagram shape is a property not only of the network itself but also of the incident variables. Diagrams for three types of real incidents (crash, hazard and vehicle breakdown) are explored separately. The results based on the empirical data are consistent with the simulated results. The hysteresis phenomenon occurs both upstream and downstream of the incident location, but for opposite hysteresis loops. The gradient of the upstream diagram is greater than that downstream on the incident site, when traffic demand is for an off-peak period.

Establishing statistical foundations early : data modeling with young learners

This paper addresses research from a three-year longitudinal study that engaged children in data modeling experiences from the beginning school year through to third year (6-8 years). A data modeling approach to statistical development differs in several ways from what is typically done in early classroom experiences with data. In particular, data modeling immerses children in problems that evolve from their own questions and reasoning, with core statistical foundations established early. These foundations include a focus on posing and refining statistical questions within and across contexts, structuring and representing data, making informal inferences, and developing conceptual, representational, and metarepresentational competence. Examples are presented of how young learners developed and sustained informal inferential reasoning and metarepresentational competence across the study to become “sophisticated statisticians”.

A novel population balance model for the dilute acid hydrolysis of hemicellulose

Acid hydrolysis is a popular pretreatment for removing hemicellulose from lignocelluloses in order to produce a digestible substrate for enzymatic saccharification. In this work, a novel model for the dilute acid hydrolysis of hemicellulose within sugarcane bagasse is presented and calibrated against experimental oligomer profiles. The efficacy of mathematical models as hydrolysis yield predictors and as vehicles for investigating the mechanisms of acid hydrolysis is also examined. Experimental xylose, oligomer (degree of polymerisation 2 to 6) and furfural yield profiles were obtained for bagasse under dilute acid hydrolysis conditions at temperatures ranging from 110C to 170C. Population balance kinetics, diffusion and porosity evolution were incorporated into a mathematical model of the acid hydrolysis of sugarcane bagasse. This model was able to produce a good fit to experimental xylose yield data with only three unknown kinetic parameters ka, kb and kd. However, fitting this same model to an expanded data set of oligomeric and furfural yield profiles did not successfully reproduce the experimental results. It was found that a ``hard-to-hydrolyse'' parameter, $\alpha$, was required in the model to ensure reproducibility of the experimental oligomer profiles at 110C, 125C and 140C. The parameters obtained through the fitting exercises at lower temperatures were able to be used to predict the oligomer profiles at 155C and 170C with promising results. The interpretation of kinetic parameters obtained by fitting a model to only a single set of data may be ambiguous. Although these parameters may correctly reproduce the data, they may not be indicative of the actual rate parameters, unless some care has been taken to ensure that the model describes the true mechanisms of acid hydrolysis. It is possible to challenge the robustness of the model by expanding the experimental data set and hence limiting the parameter space for the fitting parameters. The novel combination of ``hard-to-hydrolyse'' and population balance dynamics in the model presented here appears to stand up to such rigorous fitting constraints.

Limitations of a laboratory scale model in predicting optimal pilot scale conditions for dilute acid pretreatment of sugarcane bagasse

Pilot and industrial scale dilute acid pretreatment data can be difficult to obtain due to the significant infrastructure investment required. Consequently, models of dilute acid pretreatment by necessity use laboratory scale data to determine kinetic parameters and make predictions about optimal pretreatment conditions at larger scales. In order for these recommendations to be meaningful, the ability of laboratory scale models to predict pilot and industrial scale yields must be investigated. A mathematical model of the dilute acid pretreatment of sugarcane bagasse has previously been developed by the authors. This model was able to successfully reproduce the experimental yields of xylose and short chain xylooligomers obtained at the laboratory scale. In this paper, the ability of the model to reproduce pilot scale yield and composition data is examined. It was found that in general the model over predicted the pilot scale reactor yields by a significant margin. Models that appear very promising at the laboratory scale may have limitations when predicting yields on a pilot or industrial scale. It is difficult to comment whether there are any consistent trends in optimal operating conditions between reactor scale and laboratory scale hydrolysis due to the limited reactor datasets available. Further investigation is needed to determine whether the model has some efficacy when the kinetic parameters are re-evaluated by parameter fitting to reactor scale data, however, this requires the compilation of larger datasets. Alternatively, laboratory scale mathematical models may have enhanced utility for predicting larger scale reactor performance if bulk mass transport and fluid flow considerations are incorporated into the fibre scale equations. This work reinforces the need for appropriate attention to be paid to pilot scale experimental development when moving from laboratory to pilot and industrial scales for new technologies.

Fractional models in space for diffusive processes in heterogeneous media with applications in cell motility and electrical signal propagation

This work addresses fundamental issues in the mathematical modelling of the diffusive motion of particles in biological and physiological settings. New mathematical results are proved and implemented in computer models for the colonisation of the embryonic gut by neural cells and the propagation of electrical waves in the heart, offering new insights into the relationships between structure and function. In particular, the thesis focuses on the use of non-local differential operators of non-integer order to capture the main features of diffusion processes occurring in complex spatial structures characterised by high levels of heterogeneity.

Inhaled particle surface area dose: Stationary vs personal monitoring

The aim of this paper is to determine the suitability of solely stationary measurements for exposure assessment and management applications. For this purpose, quantified inhaled particle surface area (IPSA) doses using both stationary and personal particle exposure monitors were evaluated and compared.

Human health risk of toxic chemical pollutants generated from traffic and land use activities

The research project developed a quantitative approach to assess the risk to human health from heavy metals and polycyclic aromatic hydrocarbons in urban stormwater based on traffic and land use factors. The research outcomes are expected to strengthen the scientifically robust management and reuse of urban stormwater. The innovative methodology developed can be applied to evaluate human health risk in relation to toxic chemical pollutants in urban stormwater runoff and for the development of effective risk mitigation strategies.

Flow field and traverse times for fan forced injection of fumigant via circular or annular inlet into stored grain

Fan forced injection of phosphine gas fumigant into stored grain is a common method to treat infestation by insects. For low injection velocities the transport of fumigant can be modelled as Darcy flow in a porous medium where the gas pressure satisfies Laplace's equation. Using this approach, a closed form series solution is derived for the pressure, velocity and streamlines in a cylindrically stored grain bed with either a circular or annular inlet, from which traverse times are numerically computed. A leading order closed form expression for the traverse time is also obtained and found to be reasonable for inlet configurations close to the central axis of the grain storage. Results are interpreted for the case of a representative 6m high farm wheat store, where the time to advect the phosphine to almost the entire grain bed is found to be approximately one hour.

Occupational release of engineered nanoparticles: A review

Characterising the release of different types of Engineered Nanoparticles (ENPs) from various processes is of critical importance for the assessment of human exposure, as well as understanding the possible health effects of these particles. Therefore, the main aim of this chapter is to present a comprehensive review of studies which report on the release of airborne ENPs in different nanotechnology workplaces. The chapter will cover topics of relevance to the occupational characterisation of ENP emissions, ranging from the identification of different particle release sources and scenarios, to measurement methods and working towards a more uniform approach to characterisation. Furthermore, a brief review of ENP exposure control strategies, together with the application of mathematical modelling as an effective tool for the characterisation of emissions at nanotechnology workplaces is included.