Modelling to explore the potential impact of asymptomatic human infections on transmission and dynamics of African sleeping sickness.

Gambiense human African trypanosomiasis (gHAT, sleeping sickness) is one of several neglected tropical diseases (NTDs) where there is evidence of asymptomatic human infection but there is uncertainty of the role it plays in transmission and maintenance. To explore possible consequences of asymptomatic infections, particularly in the context of elimination of transmission-a goal set to be achieved by 2030-we propose a novel dynamic transmission model to account for the asymptomatic population. This extends an established framework, basing infection progression on a number of experimental and observation gHAT studies. Asymptomatic gHAT infections include those in people with blood-dwelling trypanosomes, but no discernible symptoms, or those with parasites only detectable in skin. Given current protocols, asymptomatic infection with blood parasites may be diagnosed and treated, based on observable parasitaemia, in contrast to many other diseases for which treatment (and/or diagnosis) may be based on symptomatic infection. We construct a model in which exposed people can either progress to either asymptomatic skin-only parasite infection, which would not be diagnosed through active screening algorithms, or blood-parasite infection, which is likely to be diagnosed if tested. We add extra parameters to the baseline model including different self-cure, recovery, transmission and detection rates for skin-only or blood infections. Performing sensitivity analysis suggests all the new parameters introduced in the asymptomatic model can impact the infection dynamics substantially. Among them, the proportion of exposures resulting in initial skin or blood infection appears the most influential parameter. For some plausible parameterisations, an initial fall in infection prevalence due to interventions could subsequently stagnate even under continued screening due to the formation of a new, lower endemic equilibrium. Excluding this scenario, our results still highlight the possibility for asymptomatic infection to slow down progress towards elimination of transmission. Location-specific model fitting will be needed to determine if and where this could pose a threat.

Modelling to Quantify the Likelihood that Local Elimination of Transmission has Occurred Using Routine Gambiense Human African Trypanosomiasis Surveillance Data.

BACKGROUND: The gambiense human African trypanosomiasis (gHAT) elimination programme in the Democratic Republic of Congo (DRC) routinely collects case data through passive surveillance and active screening, with several regions reporting no cases for several years, despite being endemic in the early 2000s. METHODS: We use mathematical models fitted to longitudinal data to estimate the probability that selected administrative regions have already achieved elimination of transmission (EOT) of gHAT. We examine the impact of active screening coverage on the certainty of model estimates for transmission and therefore the role of screening in the measurement of EOT. RESULTS: In 3 example health zones of Sud-Ubangi province, we find there is a moderate (>40%) probability that EOT has been achieved by 2018, based on 2000-2016 data. Budjala and Mbaya reported zero cases during 2017-18, and this further increases our respective estimates to 99.9% and 99.6% (model S) and to 87.3% and 92.1% (model W). Bominenge had recent case reporting, however, that if zero cases were found in 2021, it would substantially raise our certainty that EOT has been met there (99.0% for model S and 88.5% for model W); this could be higher with 50% coverage screening that year (99.1% for model S and 94.0% for model W). CONCLUSIONS: We demonstrate how routine surveillance data coupled with mechanistic modeling can estimate the likelihood that EOT has already been achieved. Such quantitative assessment will become increasingly important for measuring local achievement of EOT as 2030 approaches.

Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation.

Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.

Screening Strategies for a Sustainable Endpoint for Gambiense Sleeping Sickness.

BACKGROUND: Gambiense human African trypanosomiasis ([gHAT] sleeping sickness) is a vector-borne disease that is typically fatal without treatment. Intensified, mainly medical-based, interventions in endemic areas have reduced the occurrence of gHAT to historically low levels. However, persistent regions, primarily in the Democratic Republic of Congo (DRC), remain a challenge to achieving the World Health Organization's goal of global elimination of transmission (EOT). METHODS: We used stochastic models of gHAT transmission fitted to DRC case data and explored patterns of regional reporting and extinction. The time to EOT at a health zone scale (~100 000 people) and how an absence of reported cases informs about EOT was quantified. RESULTS: Regional epidemiology and level of active screening (AS) both influenced the predicted time to EOT. Different AS cessation criteria had similar expected infection dynamics, and recrudescence of infection was unlikely. However, whether EOT has been achieved when AS ends is critically dependent on the stopping criteria. Two or three consecutive years of no detected cases provided greater confidence of EOT compared with a single year (~66%-75% and ~82%-84% probability of EOT, respectively, compared with 31%-51%). CONCLUSIONS: Multiple years of AS without case detections is a valuable measure to assess the likelihood that the EOT target has been met locally.

Patterns of Polar Domains in a Spatiotemporal Model of Interacting Polarities.

Polarity fields are known to exhibit long distance patterns, in both physical and biological systems. The mechanisms behind such patterns are poorly understood. Here, we describe the dynamics of polarity fields using an original physical model that generalizes classical spin models on a lattice by incorporating effective transport of polarity molecules between neighboring sites. We account for an external field and for ferromagnetic interactions between sites and prescribe the time evolution of the system using two distinct dissipative classes for nonconserved and conserved variables representing polarity orientation and magnitude, respectively. We observe two main types of steady-state configurations-disordered configurations and patterns of highly polar spots surrounded by regions with low polarity-and we characterize patterns and transitions between configurations. Our results may provide alternative pattern-generating mechanisms for materials endowed with polarity fields.

A local difference in Hedgehog signal transduction increases mechanical cell bond tension and biases cell intercalations along the Drosophila anteroposterior compartment boundary.

Tissue organization requires the interplay between biochemical signaling and cellular force generation. The formation of straight boundaries separating cells with different fates into compartments is important for growth and patterning during tissue development. In the developing Drosophila wing disc, maintenance of the straight anteroposterior (AP) compartment boundary involves a local increase in mechanical tension at cell bonds along the boundary. The biochemical signals that regulate mechanical tension along the AP boundary, however, remain unknown. Here, we show that a local difference in Hedgehog signal transduction activity between anterior and posterior cells is necessary and sufficient to increase mechanical tension along the AP boundary. This difference in Hedgehog signal transduction is also required to bias cell rearrangements during cell intercalations to keep the characteristic straight shape of the AP boundary. Moreover, severing cell bonds along the AP boundary does not reduce tension at neighboring bonds, implying that active mechanical tension is upregulated, cell bond by cell bond. Finally, differences in the expression of the homeodomain-containing protein Engrailed also contribute to the straight shape of the AP boundary, independently of Hedgehog signal transduction and without modulating cell bond tension. Our data reveal a novel link between local differences in Hedgehog signal transduction and a local increase in active mechanical tension of cell bonds that biases junctional rearrangements. The large-scale shape of the AP boundary thus emerges from biochemical signals inducing patterns of active tension on cell bonds.

Modelling timelines to elimination of sleeping sickness in the Democratic Republic of Congo, accounting for possible cryptic human and animal transmission.

BACKGROUND: Sleeping sickness (gambiense human African trypanosomiasis, gHAT) is a vector-borne disease targeted for global elimination of transmission (EoT) by 2030. There are, however, unknowns that have the potential to hinder the achievement and measurement of this goal. These include asymptomatic gHAT infections (inclusive of the potential to self-cure or harbour skin-only infections) and whether gHAT infection in animals can contribute to the transmission cycle in humans. METHODS: Using modelling, we explore how cryptic (undetected) transmission impacts the monitoring of progress towards and the achievement of the EoT goal. We have developed gHAT models that include either asymptomatic or animal transmission, and compare these to a baseline gHAT model without either of these transmission routes, to explore the potential role of cryptic infections on the EoT goal. Each model was independently calibrated to five different health zones in the Democratic Republic of the Congo (DRC) using available historical human case data for 2000-2020 (obtained from the World Health Organization's HAT Atlas). We applied a novel Bayesian sequential updating approach for the asymptomatic model to enable us to combine statistical information about this type of transmission from each health zone. RESULTS: Our results suggest that, when matched to past case data, we estimated similar numbers of new human infections between model variants, although human infections were slightly higher in the models with cryptic infections. We simulated the continuation of screen-confirm-and-treat interventions, and found that forward projections from the animal and asymptomatic transmission models produced lower probabilities of EoT than the baseline model; however, cryptic infections did not prevent EoT from being achieved eventually under this approach. CONCLUSIONS: This study is the first to simulate an (as-yet-to-be available) screen-and-treat strategy and found that removing a parasitological confirmation step was predicted to have a more noticeable benefit to transmission reduction under the asymptomatic model compared with the others. Our simulations suggest vector control could greatly impact all transmission routes in all models, although this resource-intensive intervention should be carefully prioritised.

Predicting the impact of COVID-19 interruptions on transmission of gambiense human African trypanosomiasis in two health zones of the Democratic Republic of Congo.

Many control programmes against neglected tropical diseases have been interrupted due to the coronavirus disease 2019 (COVID-19) pandemic, including those that rely on active case finding. In this study we focus on gambiense human African trypanosomiasis (gHAT), where active screening was suspended in the Democratic Republic of Congo (DRC) due to the pandemic. We use two independent mathematical models to predict the impact of COVID-19 interruptions on transmission and reporting and achievement of the 2030 elimination of transmission (EOT) goal for gHAT in two moderate-risk regions of the DRC. We consider different interruption scenarios, including reduced passive surveillance in fixed health facilities, and whether this suspension lasts until the end of 2020 or 2021. Our models predict an increase in the number of new infections in the interruption period only if both active screening and passive surveillance were suspended, and with a slowed reduction-but no increase-if passive surveillance remains fully functional. In all scenarios, the EOT may be slightly pushed back if no mitigation, such as increased screening coverage, is put in place. However, we emphasise that the biggest challenge will remain in the higher-prevalence regions where EOT is already predicted to be behind schedule without interruptions unless interventions are bolstered.

Estimating the distribution of time to extinction of infectious diseases in mean-field approaches.

A key challenge for many infectious diseases is to predict the time to extinction under specific interventions. In general, this question requires the use of stochastic models which recognize the inherent individual-based, chance-driven nature of the dynamics; yet stochastic models are inherently computationally expensive, especially when parameter uncertainty also needs to be incorporated. Deterministic models are often used for prediction as they are more tractable; however, their inability to precisely reach zero infections makes forecasting extinction times problematic. Here, we study the extinction problem in deterministic models with the help of an effective 'birth-death' description of infection and recovery processes. We present a practical method to estimate the distribution, and therefore robust means and prediction intervals, of extinction times by calculating their different moments within the birth-death framework. We show that these predictions agree very well with the results of stochastic models by analysing the simplified susceptible-infected-susceptible (SIS) dynamics as well as studying an example of more complex and realistic dynamics accounting for the infection and control of African sleeping sickness (Trypanosoma brucei gambiense).

Mechanical properties of an adsorbed elastic polymer in contact with a rigid membrane.

A static and a dynamical model are introduced to study the physical properties of an elastic polymer adsorbed on a rigid membrane. We analyze the detailed microscopic model for the adhesion problem and show that in the force ensemble a critical force is expected. Forces smaller than the critical value are not able to peel off the filament, while larger forces will cause the filament to completely desorb from the membrane. To demonstrate the nonequilibrium properties of the moving states for forces larger than the critical value, we present the linear response of the system in the form of a force-velocity relation. In addition, we use a very simple short-range static model and obtain the equilibrium phases of the system in different cases where either a fixed force or a fixed height can be applied at the end. For the fixed force the equilibrium phases arising from the static model are in agreement with dynamical model. Forces smaller than the critical value are not able to peel off the filament while the larger forces will cause the filament to completely desorb as in the dynamical model.

The Selector Gene apterous and Notch Are Required to Locally Increase Mechanical Cell Bond Tension at the Drosophila Dorsoventral Compartment Boundary.

The separation of cells with distinct fates and functions is important for tissue and organ formation during animal development. Regions of different fates within tissues are often separated from another along straight boundaries. These compartment boundaries play a crucial role in tissue patterning and growth by stably positioning organizers. In Drosophila, the wing imaginal disc is subdivided into a dorsal and a ventral compartment. Cells of the dorsal, but not ventral, compartment express the selector gene apterous. Apterous expression sets in motion a gene regulatory cascade that leads to the activation of Notch signaling in a few cell rows on either side of the dorsoventral compartment boundary. Both Notch and apterous mutant clones disturb the separation of dorsal and ventral cells. Maintenance of the straight shape of the dorsoventral boundary involves a local increase in mechanical tension at cell bonds along the boundary. The mechanisms by which cell bond tension is locally increased however remain unknown. Here we use a combination of laser ablation of cell bonds, quantitative image analysis, and genetic mutants to show that Notch and Apterous are required to increase cell bond tension along the dorsoventral compartment boundary. Moreover, clonal expression of the Apterous target gene capricious results in cell separation and increased cell bond tension at the clone borders. Finally, using a vertex model to simulate tissue growth, we find that an increase in cell bond tension at the borders of cell clones, but not throughout the cell clone, can lead to cell separation. We conclude that Apterous and Notch maintain the characteristic straight shape of the dorsoventral compartment boundary by locally increasing cell bond tension.

Local increases in mechanical tension shape compartment boundaries by biasing cell intercalations.

Mechanical forces play important roles during tissue organization in developing animals. Many tissues are organized into adjacent, nonmixing groups of cells termed compartments. Boundaries between compartments display a straight morphology and are associated with signaling centers that are important for tissue growth and patterning. Local increases in mechanical tension at cell junctions along compartment boundaries have recently been shown to prevent cell mixing and to maintain straight boundaries. The cellular mechanisms by which local increases in mechanical tension prevent cell mixing at compartment boundaries, however, remain poorly understood. Here, we have used live imaging and quantitative image analysis to determine cellular dynamics at and near the anteroposterior compartment boundaries of the Drosophila pupal abdominal epidermis. We show that cell mixing within compartments involves multiple cell intercalations. Frequency and orientation of cell intercalations are unchanged along the compartment boundaries; rather, an asymmetry in the shrinkage of junctions during intercalation is biased, resulting in cell rearrangements that suppress cell mixing. Simulations of tissue growth show that local increases in mechanical tension can account for this bias in junctional shrinkage. We conclude that local increases in mechanical tension maintain cell populations separate by influencing junctional rearrangements during cell intercalation.

Physical mechanisms shaping the Drosophila dorsoventral compartment boundary.

BACKGROUND: Separating cells with distinct identities and fates by straight and sharp compartment boundaries is important for growth and pattern formation during animal development. The physical mechanisms shaping compartment boundaries, however, are not fully understood. RESULTS: We combine theory and quantitative experiments to investigate the roles of different mechanisms to shape compartment boundaries. Our theoretical work shows that cell elongation created by anisotropic stress, cell proliferation rate, orientation of cell division, and cell bond tension all have distinct effects on the morphology of compartment boundaries during tissue growth. Our experiments using the developing Drosophila wing reveal that the roughness of the dorsoventral compartment boundary is dynamic and that it decreases during development. By measuring tissue relaxation in response to laser ablation of cell bonds at different developmental times, we demonstrate that decreased boundary roughness correlates with increased cell bond tension along the compartment boundary. Finally, by using experimentally determined values for cell bond tension, cell elongation and bias in orientation of cell division in simulations of tissue growth, we can reproduce the main features of the time evolution of the dorsoventral compartment boundary shape. CONCLUSIONS: Local increase of cell bond tension along the boundary as well as global anisotropies in the tissue contribute to shaping boundaries in cell networks. We propose a simple scenario that combines time-dependent cell bond tension at the boundary, oriented cell division, and cell elongation in the tissue that can account for the main features of the dynamics of the shape of the dorsoventral compartment boundary.