Potential Impact of Intermittent Preventive Treatment (IPT) on Spread of Drug-Resistant Malaria

BACKGROUND: Treatment of asymptomatic individuals, regardless of their malaria infection status, with regularly spaced therapeutic doses of antimalarial drugs has been proposed as a method for reducing malaria morbidity and mortality. This strategy, called intermittent preventive treatment (IPT), is currently employed for pregnant women and is being studied for infants (IPTi) as well. As with any drug-based intervention strategy, it is important to understand how implementation may affect the spread of drug-resistant parasites. This is a difficult issue to address experimentally because of the limited size and duration of IPTi trials as well as the intractability of distinguishing the spread of resistance due to conventional treatment of malaria episodes versus that due to IPTi when the same drug is used in both contexts. METHODS AND FINDINGS: Using a mathematical model, we evaluated the possible impact of treating individuals with antimalarial drugs at regular intervals regardless of their infection status. We translated individual treatment strategies and drug pharmacokinetics into parasite population dynamic effects and show that immunity, treatment rate, drug decay kinetics, and presumptive treatment rate are important factors in the spread of drug-resistant parasites. Our model predicts that partially resistant parasites are more likely to spread in low-transmission areas, but fully resistant parasites are more likely to spread under conditions of high transmission, which is consistent with some epidemiological observations. We were also able to distinguish between spread of resistance due to treatment of symptomatic infections and that due to IPTi. We showed that IPTi could accelerate the spread of resistant parasites, but this effect was only likely to be significant in areas of low or unstable transmission. CONCLUSIONS: The results presented here demonstrate the importance of considering both the half-life of a drug and the existing level of resistance when choosing a drug for IPTi. Drugs to which little or no resistance exists are not advisable for IPT in high-transmission areas, but IPTi is not likely to significantly impact the spread of highly resistant parasites in areas where partial resistance is already established. IPTi is more likely to accelerate the spread of resistance in high-transmission areas than is IPT in adults (i.e., pregnant women)

The promise and potential challenges of intermittent preventive treatment for malaria in infants (IPTi)

Intermittent preventive treatment (IPT) administers a full therapeutic course of an anti-malarial drug at predetermined intervals, regardless of infection or disease status. It is recommended by the World Health Organization (WHO) for protecting pregnant women from the adverse effects of malaria (IPTp) and shows great potential as a strategy for reducing illness from malaria during infancy (IPTi). Administered concurrently with standard immunizations, IPTi is expected to reduce the frequency of clinical disease, but to allow blood-stage infections to occur between treatments, thus allowing parasite-specific immunity to develop. While wide deployment of IPTi is being considered, it is important to assess other potential effects. Transmission conditions, drug choice and administration schedule will likely affect the possibility of post-treatment rebound in child morbidity and mortality and the increased spread of parasite drug resistance and should be considered when implementing IPTi

How well do operational Numerical Weather Prediction configurations represent hydrology?

Land surface models (LSMs) have traditionally been designed to focus on providing lower boundary conditions to the atmosphere with less focus on hydrological processes. State of the art application of LSMs include land data assimilation system (LDAS) which incorporates available land surface observations to provide an improved realism of surface conditions. While improved representations of the surface variables (such as soil moisture and snow depth) make LDAS an essential component of any Numerical Weather Prediction (NWP) system, the related increments remove or add water, potentially having a negative impact on the simulated hydrological cycle by opening the water budget. This paper focuses on evaluating how well global NWP configurations are able to support hydrological applications, in addition to the traditional weather forecasting. River discharge simulations from two climatological reanalyses are compared: one ‘online’ set which includes land-atmosphere coupling and LDAS with an open water budget, and also an ‘offline’ set with a closed water budget and no LDAS. It was found that while the online version of the model largely improves temperature and snow depth conditions, it caused poorer representation of peak river flow, particularly in snowmelt-dominated areas in the high latitudes. Without addressing such issues there will never be confidence in using LSMs for hydrological forecasting applications across the globe. This type of analysis should be used to diagnose where improvements need to be made; considering the whole Earth System in the data assimilation and coupling developments is critical for moving towards the goal of holistic Earth System approaches

Statistical models for over-dispersion in the frequency of peaks over threshold data for a flow series.

In a peaks over threshold analysis of a series of river flows, a sufficiently high threshold is used to extract the peaks of independent flood events. This paper reviews existing, and proposes new, statistical models for both the annual counts of such events and the process of event peak times. The most common existing model for the process of event times is a homogeneous Poisson process. This model is motivated by asymptotic theory. However, empirical evidence suggests that it is not the most appropriate model, since it implies that the mean and variance of the annual counts are the same, whereas the counts appear to be overdispersed, i.e., have a larger variance than mean. This paper describes how the homogeneous Poisson process can be extended to incorporate time variation in the rate at which events occur and so help to account for overdispersion in annual counts through the use of regression and mixed models. The implications of these new models on the implied probability distribution of the annual maxima are also discussed. The models are illustrated using a historical flow series from the River Thames at Kingston

COST 733 - WG4: Applications of weather type classification

The main objective of the COST Action 733 is to achieve a general numerical method for assessing, comparing and classifying typical weather situations in the European regions. To accomplish this goal, different workgroups are established, each with their specific aims: WG1: Existing methods and applications (finished); WG2: Implementation and development of weather types classification methods; WG3: Comparison of selected weather types classifications; WG4: Testing methods for various applications. The main task of Workgroup 4 (WG4) in COST 733 implies the testing of the selected weather type methods for various classifications. In more detail, WG4 focuses on the following topics:• Selection of dedicated applications (using results from WG1), • Performance of the selected applications using available weather types provided by WG2, • Intercomparison of the application results as a results of different methods • Final assessment of the results and uncertainties, • Presentation and release of results to the other WGs and external interested • Recommend specifications for a new (common) method WG2 Introduction In order to address these specific aims, various applications are selected and WG4 is divided in subgroups accordingly: 1.Air quality 2. Hydrology (& Climatological mapping) 3. Forest fires 4. Climate change and variability 5. Risks and hazards Simultaneously, the special attention is paid to the several wide topics concerning some other COST Actions such as: phenology (COST725), biometeorology (COST730), agriculture (COST 734) and mesoscale modelling and air pollution (COST728). Sub-groups are established to find advantages and disadvantages of different classification methods for different applications. Focus is given to data requirements, spatial and temporal scale, domain area, specifi

Process-based modelling

The chapter describes two categories of process-based models, namely, hydrological and socio-hydrological models. It starts with an explanation of the modelling chain from climate drivers via process-based models to identification of hydrological and socio-hydrological drought characteristics. Then, the first category of process-based models is introduced, that is, hydrological models, which are divided in three types: spatially lumped, semi-distributed and spatially distributed models. Spatially distributed models are further subdivided based on whether they simulate lateral groundwater flow (GWfl) or not (nGWfl). An example model of each of these three types, including an application is given, that is, HBV (spatially lumped, semi-distributed), PCR-GLOBWB (spatially distributed model, nGWfl) and SIMGRO (spatially distributed model, GWfl). The second category of process-based models, that is, the socio-hydrological models, is also divided into three types: coupled-component, system-dynamics and agent-based models. The chapter addresses calibration and validation of process-based models and concludes with some guidance on how to select an adequate model, considering also the associated uncertainty

Reader technique as a source of variability in determining malaria parasite density by microscopy

BACKGROUND: Accurate identification and quantification of malaria parasites are critical for measuring clinical trial outcomes. Positive and negative diagnosis is usually sufficient for the assessment of therapeutic outcome, but vaccine or prophylactic drug trials require measuring density of infection as a primary endpoint. Microscopy is the most established and widely-used technique for quantifying parasite densities in the blood. METHODS: Results obtained by 24–27 expert malaria microscopists, who had independently read 895 slides from 35 donors, were analysed to understand how reader technique contributes to discrepancy in measurements of parasite density over a wide range of densities. RESULTS: Among these 35 donations, standard deviations ranged from 30% to 250% of the mean parasite density and the percent discrepancy was inversely correlated with the mean parasite density. The number of white blood cells indexed and whether parasites were counted in the thick film or thin film were shown to significantly contribute to discrepancy amongst microscopists. CONCLUSION: Errors in microscopy measurements are not widely appreciated or addressed but have serious consequences for efficacy trials, including possibly abandoning promising vaccine candidates

Pilot assessment of the sensitivity of the malaria thin film

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Modelling the impact of intermittent preventive treatment for malaria on selection pressure for drug resistance

BACKGROUND: Intermittent preventive treatment (IPT) is a promising intervention for malaria control, although there are concerns about its impact on drug resistance. METHODS: The key model inputs are age-specific values for a) baseline anti-malarial dosing rate, b) parasite prevalence, and c) proportion of those treated with anti-malarials (outside IPT) who are infected. These are used to estimate the immediate effect of IPT on the genetic coefficient of selection (s). The scenarios modelled were year round IPT to infants in rural southern Tanzania, and three doses at monthly intervals of seasonal IPT in Senegal. RESULTS: In the simulated Tanzanian setting, the model suggests a high selection pressure for drug resistance, but that IPTi would only increase this by a small amount (4.4%). The percent change in s is larger if parasites are more concentrated in infants, or if baseline drug dosing is less common or less specific. If children aged up to five years are included in the Tanzanian scenario then the predicted increase in s rises to 31%. The Senegalese seasonal IPT scenario, in children up to five years, results in a predicted increase in s of 16%. CONCLUSION: There is a risk that the useful life of drugs will be shortened if IPT is implemented over a wide childhood age range. On the other hand, IPT delivered only to infants is unlikely to appreciably shorten the useful life of the drug used