Three-dimensional instability in flow over a backward-facing step

Results are reported from a three-dimensional computational stability analysis of flow over a backward-facing step with an expansion ratio (outlet to inlet height) of 2 at Reynolds numbers between 450 and 1050. The analysis shows that the first absolute linear instability of the steady two-dimensional flow is a steady three-dimensional bifurcation at a critical Reynolds number of 748. The critical eigenmode is localized to the primary separation bubble and has a flat roll structure with a spanwise wavelength of 6.9 step heights. The system is further shown to be absolutely stable to two-dimensional perturbations up to a Reynolds number of 1500. Stability spectra and visualizations of the global modes of the system are presented for representative Reynolds numbers

Herd immunity under individual variation and reinfection

We study a SEIR model considered by Gomes et al. \cite{Gomes2020} and Aguas et al. \cite{Aguas2020} where different individuals are assumed to have different levels of susceptibility or exposure to infection. Under this heterogeneity assumption, epidemic growth is effectively suppressed when the percentage of population having acquired immunity surpasses a critical level - the herd immunity threshold - that is lower than in homogeneous populations. We find explicit formulas to calculate herd immunity thresholds and stable configuration, and explore extensions of the model

Heterogeneity in disease risk induces falling vaccine protection with rising disease incidence

This paper is concerned with the analysis of phase 3 vaccine trials. In a randomized controlled trial, a representative sample of a population is given a vaccine and a matched sample is given a placebo. These individuals are followed for a stipulated length of time, while infection (or disease) occurrences are registered. Vaccine efficacy is then calculated to measure the reduction in disease rate (or risk) attributed to the vaccine. Seemingly very reasonable, this procedure often results in the most disparate estimates when conducted in different parts of the world. Here, we argue that this is due to cohort selection acting on the trial participants as follows. The more susceptible individuals are infected first, leaving behind a pool whose mean susceptibility decreases over time. As a result, infection rates decrease, and this effect is stronger in the control group, provided that the vaccine reduces susceptibility. Therefore, any direct measure of vaccine efficacy is expected to decrease as the trial progresses, and this happens faster in settings where the intensity of pathogen exposure is higher. We propose an analytical scheme that takes this phenomenon into account while estimating efficacy more consistently across settings. We provide analytical results concerning the dependence of vaccine efficacy on the intensity of pathogen exposure as well as on the mean and variance of the distribution of disease risk

Modelling the epidemiology of residual Plasmodium vivax malaria in a heterogeneous host population : a case study in the Amazon Basin

The overall malaria burden in the Americas has decreased dramatically over the past two decades, but residual transmission pockets persist across the Amazon Basin, where Plasmodium vivax is the predominant infecting species. Current elimination efforts require a better quantitative understanding of malaria transmission dynamics for planning, monitoring, and evaluating interventions at the community level. This can be achieved with mathematical models that properly account for risk heterogeneity in communities approaching elimination, where few individuals disproportionately contribute to overall malaria prevalence, morbidity, and onwards transmission. Here we analyse demographic information combined with routinely collected malaria morbidity data from the town of Mâncio Lima, the main urban transmission hotspot of Brazil. We estimate the proportion of high-risk subjects in the host population by fitting compartmental susceptible-infected-susceptible (SIS) transmission models simultaneously to age-stratified vivax malaria incidence densities and the frequency distribution of P. vivax malaria attacks experienced by each individual over 12 months. Simulations with the best-fitting SIS model indicate that 20% of the hosts contribute 86% of the overall vivax malaria burden. Despite the low overall force of infection typically found in the Amazon, about one order of magnitude lower than that in rural Africa, high-risk individuals gradually develop clinical immunity following repeated infections and eventually constitute a substantial infectious reservoir comprised of asymptomatic parasite carriers that is overlooked by routine surveillance but likely fuels onwards malaria transmission. High-risk individuals therefore represent a priority target for more intensive and effective interventions that may not be readily delivered to the entire community

Modeling the Effects of Relapse in the Transmission Dynamics of Malaria Parasites

Often regarded as “benign,” Plasmodium vivax infections lay in the shadows of the much more virulent P. falciparum infections. However, about 1.98 billion people are at risk of both parasites worldwide, stressing the need to understand the epidemiology of Plasmodium vivax, particularly under the scope of decreasing P. falciparum prevalence and ecological interactions between both species. Two epidemiological observations put the dynamics of both species into perspective: (1) ACT campaigns have had a greater impact on P. falciparum prevalence. (2) Complete clinical immunity is attained at younger ages for P. vivax, under similar infection rates. We systematically compared two mathematical models of transmission for both Plasmodium species. Simulations suggest that an ACT therapy combined with a hypnozoite killing drug would eliminate both species. However, P. vivax elimination is predicted to be unstable. Differences in age profiles of clinical malaria can be explained solely by P. vivax's ability to relapse, which accelerates the acquisition of clinical immunity and serves as an immunity boosting mechanism. P. vivax transmission can subsist in areas of low mosquito abundance and is robust to drug administration initiatives due to relapse, making it an inconvenient and cumbersome, yet less lethal alternative to P. falciparum

Remodelling selection to optimise disease forecasts and policies

Funding Information: This paper benefited from supportive discussions with numerous colleagues, especially Mauricio Barreto, Maxine Caws, Andrea Doeschl-Wilson, Nicholas Feasey, Marcelo Ferreira, Philippe Glaziou, Stephen Gordon, Jessica King, James LaCourse, Christian Lienhardt, Paul McKeigue, Penelope Phillips-Howard, Lisa Reimer, Meta Roestenberg, Jamie Rylance, Bertel Squire, Russell Stothard, Miriam Taegtmeyer, Dianne Terlouw, Rachel Tolhurst, Tom Wingfield. This work is funded by national funds through the FCT – Fundação para a Ciência e a Tecnologia, I.P., under the scope of the projects UIDB/00297/2020 ( https://doi.org/10.54499/UIDB/00297/2020 ) and UIDP/00297/2020 ( https://doi.org/10.54499/UIDP/00297/2020 ) (Center for Mathematics and Applications) MGMG has received additional funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No 101007799 (Inno4Vac). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This communication reflects the author’s view and that neither IMI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained therein. Publisher Copyright: © 2024 The Author(s). Published by IOP Publishing Ltd.Mathematical models are increasingly adopted for setting disease prevention and control targets. As model-informed policies are implemented, however, the inaccuracies of some forecasts become apparent, for example overprediction of infection burdens and intervention impacts. Here, we attribute these discrepancies to methodological limitations in capturing the heterogeneities of real-world systems. The mechanisms underpinning risk factors of infection and their interactions determine individual propensities to acquire disease. These factors are potentially so numerous and complex that to attain a full mechanistic description is likely unfeasible. To contribute constructively to the development of health policies, model developers either leave factors out (reductionism) or adopt a broader but coarse description (holism). In our view, predictive capacity requires holistic descriptions of heterogeneity which are currently underutilised in infectious disease epidemiology, in comparison to other population disciplines, such as non-communicable disease epidemiology, demography, ecology and evolution.publishersversionpublishe

Migration to middle-income countries and tuberculosis-global policies for global economies.

BACKGROUND: International migration to middle-income countries is increasing and its health consequences, in particular increasing transmission rates of tuberculosis (TB), deserve consideration. Migration and TB are a matter of concern in high-income countries and targeted screening of migrants for active and latent TB infection is a main strategy to manage risk and minimize transmission. In this paper, we discuss some aspects of TB control and migration in the context of middle-income countries, together with the prospect of responding with equitable and comprehensive policies. MAIN BODY: TB rates in middle-income countries remain disproportionally high among the poorest and most vulnerable groups in large cities where most migrant populations are concentrated. Policies that tackle migrant TB in high-income countries may be inadequate for middle-income countries because of their different socio-economic and cultural scenarios. Strategies to control TB in these settings must take into account the characteristics of middle-income countries and the complexity of TB as a disease of poverty. Intersectoral policies of social protection such as cash-transfer programs help reducing poverty and improving health in vulnerable populations. We address the development of new approaches to improve well-established strategies including contact tracing and active and latent TB screening as an 'add on' to the existing health care guidelines of conditional cash transfer programs. In addition, we discuss how it might improve health and welfare among both poor migrants and locally-born populations. Authorities from middle-income countries should recognise that migrants are a vulnerable social group and promote cooperation efforts between sending and receiving countries for mitigation of poverty and prevention of disease in this group. CONCLUSIONS: Middle-income countries have long sent migrants overseas. However, the influx of large migrant populations into their societies is relatively new and a growing phenomenon and it is time to set comprehensive goals to improve health among these communities. Conditional cash transfer policies with TB screening and strengthening of DOTS are some strategies that deserve attention. Reduction of social and health inequality among migrants should be incorporated into concerted actions to meet TB control targets

Immunocompetent human 3D brain cell cultures to advance ATMP development

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Leishmania infantum released proteins specifically regulate cytokine expression and production patterns by CD4+ and CD8+ T cells

Funding Information: The authors thank J.M. Cristóvão and J. Ramada for technical assistance. Funding for this work was provided by the project research grant POCTI/CVT/37759/2001 by the Fundação para a Ciência e Tecnologia (FCT), Portugal partially supported by the European Union Fund (FEDER), and grant SFRH/BD/997/2000 from FCT.Specific immune responses by CD4+ and CD8+ T cells, from two infected mice strains (BALB/c and C57BL/6), induced by High, Inter and Low protein fractions released by Leishmania infantum, were assessed through the evaluation of IL-12, IFN-γ and IL-10 mRNA by real-time PCR and respective protein production by ELISA. During infection establishment, High and Inter fractions directed both mice strains T cells subsets to increase the production of IFN-γ, associated to IL-12 release. Later on, parasite replication augmented in BALB/c and stabilised in C57BL/6 mice. Inter fraction induced CD4+ T cells to maintain IFN-γ production, with the simultaneous release of IL-12 by both cell subsets in BALB/c mice and by CD8+ T cells in C57BL/6 mice. These observations suggested a prophylactic potential for Inter fraction which was able to induce Th1 response with IL-12 involvement, required for the maintenance of memory cells, in mice strains with different parasitic evolution.publishersversionpublishe

Controlling malaria using livestock-based interventions: a one health approach.

Where malaria is transmitted by zoophilic vectors, two types of malaria control strategies have been proposed based on animals: using livestock to divert vector biting from people (zooprophylaxis) or as baits to attract vectors to insecticide sources (insecticide-treated livestock). Opposing findings have been obtained on malaria zooprophylaxis, and despite the success of an insecticide-treated livestock trial in Pakistan, where malaria vectors are highly zoophilic, its effectiveness is yet to be formally tested in Africa where vectors are more anthropophilic. This study aims to clarify the different effects of livestock on malaria and to understand under what circumstances livestock-based interventions could play a role in malaria control programmes. This was explored by developing a mathematical model and combining it with data from Pakistan and Ethiopia. Consistent with previous work, a zooprophylactic effect of untreated livestock is predicted in two situations: if vector population density does not increase with livestock introduction, or if livestock numbers and availability to vectors are sufficiently high such that the increase in vector density is counteracted by the diversion of bites from humans to animals. Although, as expected, insecticide-treatment of livestock is predicted to be more beneficial in settings with highly zoophilic vectors, like South Asia, we find that the intervention could also considerably decrease malaria transmission in regions with more anthropophilic vectors, like Anopheles arabiensis in Africa, under specific circumstances: high treatment coverage of the livestock population, using a product with stronger or longer lasting insecticidal effect than in the Pakistan trial, and with small (ideally null) repellency effect, or if increasing the attractiveness of treated livestock to malaria vectors. The results suggest these are the most appropriate conditions for field testing insecticide-treated livestock in an Africa region with moderately zoophilic vectors, where this intervention could contribute to the integrated control of malaria and livestock diseases