Model evaluation of target product profiles of an infant vaccine against respiratory syncytial virus (RSV) in a developed country setting

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in children worldwide and is a significant cause of hospital admissions in young children in England. No RSV vaccine has been licensed but a number are under development. In this work, we present two structurally distinct mathematical models, parameterized using RSV data from the UK, which have been used to explore the effect of introducing an RSV paediatric vaccine to the National programme. We have explored different vaccine properties, and dosing regimens combined with a range of implementation strategies for RSV control. The results suggest that vaccine properties that confer indirect protection have the greatest effect in reducing the burden of disease in children under 5 years. The findings are reinforced by the concurrence of predictions from the two models with very different epidemiological structure. The approach described has general application in evaluating vaccine target product profiles

Artemisinin Antimalarials: Preserving the “Magic Bullet”

The artemisinins are the most effective antimalarial drugs known. They possess a remarkably wide therapeutic index. These agents have been used in traditional Chinese herbal medicine for more than 2,000 years but were not subjected to scientific scrutiny until the 1970s. The first formal clinical trials of the artemisinins, and the development of methods for their industrial scale production, followed rapidly. A decade later, Chinese scientists shared their findings with the rest of the world; since then, a significant body of international trial evidence has confirmed these drugs to be far superior to any available alternatives. In particular, they have the ability to rapidly kill a broad range of asexual parasite stages at safe concentrations that are consistently achievable via standard dosing regimens. As their half-life is very short, there was also thought to be a low risk of resistance. These discoveries coincided with the appearance and spread of resistance to all the other major classes of antimalarials. As a result, the artemisinins now form an essential element of recommended first-line antimalarial treatment regimens worldwide. To minimize the risk of artemisinin resistance, they are recommended to be used to treat uncomplicated malaria in combination with other antimalarials as artemisinin combination therapies (ACTs). Their rollout has resulted in documented reductions in malaria prevalence in a number of African and Asian countries. Unfortunately, there are already worrisome early signs of artemisinin resistance appearing in western Cambodia. If this resistance were to spread, it would be disastrous for malaria control efforts worldwide. The enormous challenge for the international community is how to avert this catastrophe and preserve the effectiveness of this antimalarial “magic bullet”. Drug Dev Res 71: 12–19, 2010. © 2009 Wiley-Liss, Inc

Tools and Strategies for Documenting Educational Connection with Diverse Audiences

How does an educator ensure that an audience is receiving an intended message? Further complicating this matter, what happens if the audience members\u27 primary language differs from that of the presenter and the use of an interpreter is not feasible? We explore these questions through a case study based on our experience as three Extension professionals from the U.S. mainland who led a 2-day training of Extension/4-H professionals from the greater Micronesia area in the western Pacific Ocean. The instrument and educational concepts we describe could be valuable tools as Extension educators work with audiences having diverse backgrounds and languages

Infectivity of Chronic Malaria Infections and Its Consequences for Control and Elimination

Assessing the importance of targeting the chronic Plasmodium falciparum malaria reservoir is pivotal as the world moves toward malaria eradication. Through the lens of a mathematical model, we show how, for a given malaria prevalence, the relative infectivity of chronic individuals determines what intervention tools are predicted be the most effective. Crucially, in a large part of the parameter space where elimination is theoretically possible, it can be achieved solely through improved case management. However, there are a significant number of settings where malaria elimination requires not only good vector control but also a mass drug administration campaign. Quantifying the relative infectiousness of chronic malaria across a range of epidemiological settings would provide essential information for the design of effective malaria elimination strategies. Given the difficulties obtaining this information, we also provide a set of epidemiological metrics that can be used to guide policy in the absence of such data

Assessment of the limitations on the seismic detectability of injected CO2 within a deep geological reservoir

Aquistore is a deep saline CO2 storage research and demonstration project located near Estevan, Saskatchewan where CO2 is transported via pipeline and injected into a sandstone reservoir ∼3200 m below the surface. A pre-injection time-lapse analysis performed on two sparse 3D seismic datasets was used to characterise the background time-lapse signal-to-noise level at the storage site. The time-lapse analysis revealed that the lowest global nRMS was 0.07 which was taken to represent the level above which CO2 would be detectable in the reservoir. We investigate the conditions under which the injected CO2 can be detected above the defined minimum noise level through Gassmann fluid substitution and 3D seismic forward modelling. Additionally, Wave Unix was used to simulate the seismic response of the reservoir due to the injected CO2 by generating the synthetic surface reflection seismic data from an explosive surface P-wave source. We generated noise-free synthetic seismograms for the baseline model as well as for the 2-phase fluid replacement of brine with CO2 for CO2 concentrations up to 100% within the target zone – the monitors. The baseline and monitor traces from the 3D seismic survey at Aquistore are used as the noise traces in this study, and were added to their respective baseline and monitor synthetic traces. The nRMS within the reservoir was then computed for the noisy baseline and various noisy monitor surveys and was used in the assessment of the limitation to the detection of the injected CO2 in the reservoir under the background noise level at the site. We are able to conclude that the time-lapse repeatability will not limit the ability to monitor the CO2 induced changes in the reservoir at the Aquistore storage site

Maize Provisioning of Ontario Late Woodland Turkeys: Isotopic Evidence of Seasonal, Cultural, Spatial and Temporal Variation

The isotopic composition (δ13C, δ15N) of bone collagen from Ontario Late Woodland archaeological turkeys was compared with that of modern Ontario wild turkeys, and archaeological turkeys from American Southwestern, Mexican and other Woodland sites to determine whether Late Woodland Ontario peoples managed wild turkeys by provisioning them with maize, the only isotopically distinct horticultural plant at that time. Despite the fact that humans from Late Woodland Western Basin and Iroquoian traditions consumed equal amounts of maize, wild turkeys utilized by the two groups exhibit different diets. Western Basin turkeys reflect a C3-only diet, whereas Iroquoian turkeys were consuming significant quantities of maize (a C4 plant). Both groups of archaeological turkey consumed less maize than modern wild turkeys with access to waste left in fields by mechanized agriculture, but because ancient crop yields were much lower, we suggest that Iroquoian turkeys must have been provisioned, probably to create a reliable and nearby hunting niche (Linares 1976). Archaeological and isotopic evidence supports ethnohistoric accounts that turkeys were hunted after the fall harvest. Iroquoian archaeological turkey diets, in general, reflect the seasonal consumption of maize that would have been created by cold weather maize provisioning, with the major exception of one turkey from an Attawandaron (Neutral) site that appears to have been fed maize year round. Motivations for provisioning by Middle Ontario Iroquoian people likely included climate change and ritual/ceremonial activity as well as a reliable food supply. Because Iroquoian women controlled the harvest, it is likely that they were instrumental in altering this human/animal interaction, creating a position on the wild/domesticated continuum that is unique in the North American archaeological literature

Imaging and spectroscopy of galaxies associated with two z~0.7 damped Lyman-alpha absorption systems

We have identified galaxies near two quasars which are at the redshift of damped Lyman-alpha (DLA) systems in the UV spectra of the quasars. Both galaxies are actively forming stars. One galaxy has a luminosity close to the break in the local galaxy luminosity function, L*, the other is significantly fainter than L* and appears to be interacting with a nearby companion. Despite the strong selection effects favoring spectroscopic identification of the most luminous DLA galaxies, many of the spectroscopically-identified DLA galaxies in the literature are sub-L*, suggesting that the majority of the DLA population is probably sub-L*, in contrast to MgII absorbers at similar redshifts whose mean luminosity is close to L*.Comment: 9 pages, to appear in AJ, November 2003 issu

Artemisinin resistance--modelling the potential human and economic costs.

BACKGROUND: Artemisinin combination therapy is recommended as first-line treatment for falciparum malaria across the endemic world and is increasingly relied upon for treating vivax malaria where chloroquine is failing. Artemisinin resistance was first detected in western Cambodia in 2007, and is now confirmed in the Greater Mekong region, raising the spectre of a malaria resurgence that could undo a decade of progress in control, and threaten the feasibility of elimination. The magnitude of this threat has not been quantified. METHODS: This analysis compares the health and economic consequences of two future scenarios occurring once artemisinin-based treatments are available with high coverage. In the first scenario, artemisinin combination therapy (ACT) is largely effective in the management of uncomplicated malaria and severe malaria is treated with artesunate, while in the second scenario ACT are failing at a rate of 30%, and treatment of severe malaria reverts to quinine. The model is applied to all malaria-endemic countries using their specific estimates for malaria incidence, transmission intensity and GDP. The model describes the direct medical costs for repeated diagnosis and retreatment of clinical failures as well as admission costs for severe malaria. For productivity losses, the conservative friction costing method is used, which assumes a limited economic impact for individuals that are no longer economically active until they are replaced from the unemployment pool. RESULTS: Using conservative assumptions and parameter estimates, the model projects an excess of 116,000 deaths annually in the scenario of widespread artemisinin resistance. The predicted medical costs for retreatment of clinical failures and for management of severe malaria exceed US$32 million per year. Productivity losses resulting from excess morbidity and mortality were estimated at US$385 million for each year during which failing ACT remained in use as first-line treatment. CONCLUSIONS: These 'ballpark' figures for the magnitude of the health and economic threat posed by artemisinin resistance add weight to the call for urgent action to detect the emergence of resistance as early as possible and contain its spread from known locations in the Mekong region to elsewhere in the endemic world

An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria.

Background: The artemisinins are potent and widely used antimalarial drugs that are eliminated rapidly. A simple concentration–effect pharmacometric model does not explain why dosing more frequently than once daily fails to augment parasite clearance and improve therapeutic responses in vivo. Artemisinins can induce a temporary non-replicative or ‘dormant’ drug refractory state in Plasmodium falciparum malaria parasites which may explain recrudescences observed in clinical trials despite full drug susceptibility, but whether it explains the dosing–response relationship is uncertain. Objectives: To propose a revised model of antimalarial pharmacodynamics that incorporates reversible asexual parasite injury and temporary drug refractoriness in order to explain the failure of frequent dosing to augment therapeutic efficacy in falciparum malaria. Methods: The model was fitted using a Bayesian Markov Chain Monte Carlo approach with the parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from western Cambodia and 40 patients from northwestern Thailand reported previously. Results: The revised model captured the dynamics of parasite clearance data. Its predictions are consistent with observed therapeutic responses. Conclusions: A within-host pharmacometric model is proposed in which it is hypothesized that some malaria parasites enter a temporary drug refractory state after exposure to artemisinin antimalarials, which is followed by delayed parasite death or reactivation. The model fitted the observed sequential parasite density data from patients with acute P. falciparum malaria, and it supported reduced ring stage activity in artemisinin-resistant infections