Search

Horizontal gene transfer via plasmids could favour cooperation in bacteria, because transfer of a cooperative gene turns non-cooperative cheats into cooperators. This hypothesis has received support from theoretical, genomic and experimental analyses. By contrast, we show here, with a comparative analysis across 51 diverse species, that genes for extracellular proteins, which are likely to act as cooperative 'public goods', were not more likely to be carried on either: (1) plasmids compared to chromosomes; or (2) plasmids that transfer at higher rates. Our results were supported by theoretical modelling which showed that, while horizontal gene transfer can help cooperative genes initially invade a population, it has less influence on the longer-term maintenance of cooperation. Instead, we found that genes for extracellular proteins were more likely to be on plasmids when they coded for pathogenic virulence traits, in pathogenic bacteria with a broad host-range.

Abstract Background There are a lack of biomarkers which can be used to predict clinical outcomes for multiple sclerosis (MS) patients receiving interferon beta (IFN-β). Thus the objective of this study was to characterize changes in CD4+ T-lymphocyte expression in an unbiased manner following initiation of intramuscular (IM) IFN-β-1a treatment, and then to verify those findings using marker-specific assays. Methods Peripheral blood specimens were collected from twenty MS patients before and after treatment with intramuscular (IM) IFN-β-1a and were used for isolation of mononuclear cells (PBMCs). mRNA expression patterns of negatively-selected CD4+ T-cells from the PBMCs were analyzed using microarray gene expression technology. IL-12 and IL-23 receptor levels on PBMC-derived CD4+ T-cells were analyzed by flow cytometry. The phosphorylation status of Stat4 was measured by performing densitometry on western blots. Results Microarray analyses demonstrated that mRNA expression of the IL-12Rβ2 gene was uniformly up-regulated in response to IFN-β-1a treatment and was associated with an increased number of IL-12Rβ2+ CD4+ T-cells by flow cytometry in 4 of 6 patients. This finding was substantiated by demonstrating that Stat4 phosphorylation, a transcription factor for IL-12, was increased after treatment. Conversely, the number of IL-23R+ CD4+ T-cells was decreased following treatment. Conclusions The IL-12 receptor shares a common subunit, the IL-12Rβ2, with the IL-23 receptor. Both of these receptors have a probable role in regulating IL-17 and TH-17 cells, important mediators of inflammation in multiple sclerosis (MS). Thus, the changes in the numbers of CD4+ T-cells expressing these receptors in response to IFN-β-1a treatment may point to an important mechanism of action for this drug, but further large scale studies are needed to confirm these preliminary observations.

Abstract Background Vector control in the highlands of western Kenya has resulted in a significant reduction of malaria transmission and a change in the vectorial system. Climate variability as a result of events such as El Niño increases the highlands suitability for malaria transmission. Surveillance and monitoring is an important component of early transmission risk identification and management. However, below certain disease transmission thresholds, traditional tools for surveillance such as entomological inoculation rates may become insensitive. A rapid diagnostic kit comprising Plasmodium falciparum circumsporozoite surface protein and merozoite surface protein antibodies in humans was tested for early detection of transmission surges in the western Kenya highlands during an El Niño event (October 2009-February 2010). Methods Indoor resting female adult malaria vectors were collected in western Kenya highlands in four selected villages categorized into two valley systems, the U-shaped (Iguhu and Emutete) and the V-shaped valleys (Marani and Fort Ternan) for eight months. Members of the Anopheles gambiae complex were identified by PCR. Blood samples were collected from children 6-15 years old and exposure to malaria was tested using a circum-sporozoite protein and merozoite surface protein immunchromatographic rapid diagnostic test kit. Sporozoite ELISA was conducted to detect circum-sporozoite protein, later used for estimation of entomological inoculation rates. Results Among the four villages studied, an upsurge in antibody levels was first observed in October 2009. Plasmodium falciparum sporozoites were then first observed in December 2009 at Iguhu village and February 2010 at Emutete. Despite the upsurge in Marani and Fort Ternan no sporozoites were detected throughout the eight month study period. The antibody-based assay had much earlier transmission detection ability than the sporozoite-based assay. The proportion of An. arabiensis among An. gambiae s.l. ranged from 2.9-66.7% indicating a rearrangement of the sibling species of the An. gambiae s.l complex. This is possibly an adaptation to insecticide interventions and climate change. Conclusion The changing malaria transmission rates in the western Kenya highlands will lead to more unstable transmission, decreased immunity and a high vulnerability to epidemics unless surveillance tools are improved and effective vector control is sustained.

BackgroundThe COVID-19 pandemic has induced unprecedented reductions in human mobility and social contacts throughout the world. Because dengue virus (DENV) transmission is strongly driven by human mobility, behavioral changes associated with the pandemic have been hypothesized to impact dengue incidence. By discouraging human contact, COVID-19 control measures have also disrupted dengue vector control interventions, the most effective of which require entry into homes. We sought to investigate how and why dengue incidence could differ under a lockdown scenario with a proportion of the population sheltered at home.Methodology & principal findingsWe used an agent-based model with a realistic treatment of human mobility and vector control. We found that a lockdown in which 70% of the population sheltered at home and which occurred in a season when a new serotype invaded could lead to a small average increase in cumulative DENV infections of up to 10%, depending on the time of year lockdown occurred. Lockdown had a more pronounced effect on the spatial distribution of DENV infections, with higher incidence under lockdown in regions with higher mosquito abundance. Transmission was also more focused in homes following lockdown. The proportion of people infected in their own home rose from 54% under normal conditions to 66% under lockdown, and the household secondary attack rate rose from 0.109 to 0.128, a 17% increase. When we considered that lockdown measures could disrupt regular, city-wide vector control campaigns, the increase in incidence was more pronounced than with lockdown alone, especially if lockdown occurred at the optimal time for vector control.Conclusions & significanceOur results indicate that an unintended outcome of lockdown measures may be to adversely alter the epidemiology of dengue. This observation has important implications for an improved understanding of dengue epidemiology and effective application of dengue vector control. When coordinating public health responses during a syndemic, it is important to monitor multiple infections and understand that an intervention against one disease may exacerbate another.

This study describes the evolution of knockdown resistance (kdr) haplotypes in Aedes aegypti in response to pyrethroid insecticide use over the course of 18 years in Iquitos, Peru. Based on the duration and intensiveness of sampling (~10,000 samples), this is the most thorough study of kdr population genetics in Ae. aegypti to date within a city. We provide evidence for the direct connection between programmatic citywide pyrethroid spraying and the increase in frequency of specific kdr haplotypes by identifying two evolutionary events in the population. The relatively high selection coefficients, even under infrequent insecticide pressure, emphasize how quickly Ae. aegypti populations can evolve. In our examination of the literature on mosquitoes and other insect pests, we could find no cases where a pest evolved so quickly to so few exposures to low or nonresidual insecticide applications. The observed rapid increase in frequency of resistance alleles might have been aided by the incomplete dominance of resistance-conferring alleles over corresponding susceptibility alleles. In addition to dramatic temporal shifts, spatial suppression experiments reveal that genetic heterogeneity existed not only at the citywide scale, but also on a very fine scale within the city.

BackgroundHuman mobility among residential locations can drive dengue virus (DENV) transmission dynamics. Recently, it was shown that individuals with symptomatic DENV infection exhibit significant changes in their mobility patterns, spending more time at home during illness. This change in mobility is predicted to increase the risk of acquiring infection for those living with or visiting the ill individual. It has yet to be considered, however, whether social contacts are also changing their mobility, either by socially distancing themselves from the infectious individual or increasing contact to help care for them. Social, or physical, distancing and caregiving could have diverse yet important impacts on DENV transmission dynamics; therefore, it is necessary to better understand the nature and frequency of these behaviors including their effect on mobility.Methodology and principal findingsThrough community-based febrile illness surveillance and RT-PCR infection confirmation, 67 DENV positive (DENV+) residents were identified in the city of Iquitos, Peru. Using retrospective interviews, data were collected on visitors and home-based care received during the illness. While 15% of participants lost visitors during their illness, 22% gained visitors; overall, 32% of all individuals (particularly females) received visitors while symptomatic. Caregiving was common (90%), particularly caring by housemates (91%) and caring for children (98%). Twenty-eight percent of caregivers changed their behavior enough to have their work (and, likely, mobility patterns) affected. This was significantly more likely when caring for individuals with low "health-related quality of well-being" during illness (Fisher's Exact, p = 0.01).Conclusions/significanceOur study demonstrates that social contacts of individuals with dengue modify their patterns of visitation and caregiving. The observed mobility changes could impact a susceptible individual's exposure to virus or a presymptomatic/clinically inapparent individual's contribution to onward transmission. Accounting for changes in social contact mobility is imperative in order to get a more accurate understanding of DENV transmission.

Abstract Background Our understanding of the effects of human movement on dengue virus spread remains limited in part due to the lack of precise tools to monitor the time-dependent location of individuals. We determined the utility of a new, commercially available, GPS data-logger for long-term tracking of human movements in Iquitos, Peru. We conducted a series of evaluations focused on GPS device attributes key to reliable use and accuracy. GPS observations from two participants were later compared with semi-structured interview data to assess the usefulness of GPS technology to track individual mobility patterns. Results Positional point and line accuracy were 4.4 and 10.3 m, respectively. GPS wearing mode increased spatial point error by 6.9 m. Units were worn on a neck-strap by a carpenter and a moto-taxi driver for 14-16 days. The application of a clustering algorithm (I-cluster) to the raw GPS positional data allowed the identification of locations visited by each participant together with the frequency and duration of each visit. The carpenter moved less and spent more time in more fixed locations than the moto-taxi driver, who visited more locations for a shorter period of time. GPS and participants' interviews concordantly identified 6 common locations, whereas GPS alone identified 4 locations and participants alone identified 10 locations. Most (80%) of the locations identified by participants alone were places reported as visited for less than 30 minutes. Conclusion The present study demonstrates the feasibility of a novel, commercially available GPS data-logger for long-term tracking of humans and shows the potential of these units to quantify mobility patterns in relationship with dengue virus transmission risk in a tropical urban environment. Cost, battery life, size, programmability and ease of wear are unprecedented from previously tested units, proving the usefulness of GPS-dataloggers for linking movement of individuals and transmission risk of dengue virus and other infectious agents, particularly in resource-poor settings.

Abstract Background Several observations support the hypothesis that vector-driven selection plays an important role in shaping dengue virus (DENV) genetic diversity. Clustering of DENV genetic diversity at a particular location may reflect underlying genetic structure of vector populations, which combined with specific vector genotype × virus genotype (G × G) interactions may promote adaptation of viral lineages to local mosquito vector genotypes. Although spatial structure of vector polymorphism at neutral genetic loci is well-documented, existence of G × G interactions between mosquito and virus genotypes has not been formally demonstrated in natural populations. Here we measure G × G interactions in a system representative of a natural situation in Thailand by challenging three isofemale families from field-derived Aedes aegypti with three contemporaneous low-passage isolates of DENV-1. Results Among indices of vector competence examined, the proportion of mosquitoes with a midgut infection, viral RNA concentration in the body, and quantity of virus disseminated to the head/legs (but not the proportion of infected mosquitoes with a disseminated infection) strongly depended on the specific combinations of isofemale families and viral isolates, demonstrating significant G × G interactions. Conclusion Evidence for genetic specificity of interactions in our simple experimental design indicates that vector competence of Ae. aegypti for DENV is likely governed to a large extent by G × G interactions in genetically diverse, natural populations. This result challenges the general relevance of conclusions from laboratory systems that consist of a single combination of mosquito and DENV genotypes. Combined with earlier evidence for fine-scale genetic structure of natural Ae. aegypti populations, our finding indicates that the necessary conditions for local DENV adaptation to mosquito vectors are met.

Abstract Background Simple modifications of typical rural house design can be an effective and relatively inexpensive method of reducing indoor mosquito vector densities and consequently decreasing malaria transmission. Public health scientists have shown the potential for house design to protect people against malaria, yet this type of intervention remains virtually ignored. A randomized-controlled study was, therefore, undertaken to determine the effects of this method of vector control on the density of indoor resting malaria vectors in a rice irrigation scheme area in lowlands of western Kenya. Methods Ten treatment houses were modified with ceilings of papyrus mats and insecticide-treated netting (ITN) and tested against ten control houses without papyrus ceilings. To determine densities of mosquitoes resting in homes, the pyrethrum spray method was used to simultaneously collect indoor resting malaria vectors in intervention and control houses. Each house was sampled a total of eight times over a period of four months, resulting in a total of 80 sampling efforts for each treatment. Community response to such intervention was investigated by discussions with residents. Results Papyrus mats ceiling modification reduced house entry by Anopheles gambiae s.l and Anopheles funestus densities by between 78–80% and 86% respectively compared to unmodified houses. Geometric mean density of Anopheles gambiae s.l. and Anopheles funestus in modified houses were significantly lower (t18 = 7.174, P < 0.0001 and t18 = 2.52, P = 0.02, respectively) compared to controls. Unmodified houses were associated with relatively higher densities of malaria vectors. There was a 84% (OR 0.16, 95% CI 0.07–0.39, P < 0.0001) and 87% (OR 0.13, 95% CI 0.03–0.5, P = 0.0004) reduction in the odds of Anopheles gambiae s.l. and Anopheles funestus presence in modified houses, respectively, compared with unmodified houses. Residents responded favourably to this mode of vector control. Conclusion House modifications involving insect screen ceilings made from locally available materials and small ITN incorporated in house construction have the potential to reduce human exposure to malaria vectors, and thus parasite infection, in a rice irrigation scheme area of western Kenya. Ceiling modification is likely to be acceptable and is expected to be of greatest benefit when used in combination with other malaria control strategies.

Heterogeneous exposure to mosquitoes determines an individual's contribution to vector-borne pathogen transmission. Particularly for dengue virus (DENV), there is a major difficulty in quantifying human-vector contacts due to the unknown coupled effect of key heterogeneities. To test the hypothesis that the reduction of human out-of-home mobility due to dengue illness will significantly influence population-level dynamics and the structure of DENV transmission chains, we extended an existing modeling framework to include social structure, disease-driven mobility reductions, and heterogeneous transmissibility from different infectious groups. Compared to a baseline model, naïve to human pre-symptomatic infectiousness and disease-driven mobility changes, a model including both parameters predicted an increase of 37% in the probability of a DENV outbreak occurring; a model including mobility change alone predicted a 15.5% increase compared to the baseline model. At the individual level, models including mobility change led to a reduction of the importance of out-of-home onward transmission (R, the fraction of secondary cases predicted to be generated by an individual) by symptomatic individuals (up to -62%) at the expense of an increase in the relevance of their home (up to +40%). An individual's positive contribution to R could be predicted by a GAM including a non-linear interaction between an individual's biting suitability and the number of mosquitoes in their home (>10 mosquitoes and 0.6 individual attractiveness significantly increased R). We conclude that the complex fabric of social relationships and differential behavioral response to dengue illness cause the fraction of symptomatic DENV infections to concentrate transmission in specific locations, whereas asymptomatic carriers (including individuals in their pre-symptomatic period) move the virus throughout the landscape. Our findings point to the difficulty of focusing vector control interventions reactively on the home of symptomatic individuals, as this approach will fail to contain virus propagation by visitors to their house and asymptomatic carriers.

Measuring heterogeneity of dengue illness is necessary to define suitable endpoints in dengue vaccine and therapeutic trials and will help clarify behavioral responses to illness. To quantify heterogeneity in dengue illness, including milder cases, we developed the Dengue Illness Perceptions Response (IPR) survey, which captured detailed symptom data, including intensity, duration, and character, and change in routine activities caused by illness. During 2016-2019, we collected IPR data daily during the acute phase of illness for 79 persons with a positive reverse transcription PCR result for dengue virus RNA. Most participants had mild ambulatory disease. However, we measured substantial heterogeneity in illness experience, symptom duration, and maximum reported intensity of individual symptoms. Symptom intensity was a more valuable predicter of major activity change during dengue illness than symptom presence or absence alone. These data suggest that the IPR measures clinically useful heterogeneity in dengue illness experience and its relation to altered human behavior.

Measuring heterogeneity of dengue illness is necessary to define suitable endpoints in dengue vaccine and therapeutic trials and will help clarify behavioral responses to illness. To quantify heterogeneity in dengue illness, including milder cases, we developed the Dengue Illness Perceptions Response (IPR) survey, which captured detailed symptom data, including intensity, duration, and character, and change in routine activities caused by illness. During 2016-2019, we collected IPR data daily during the acute phase of illness for 79 persons with a positive reverse transcription PCR result for dengue virus RNA. Most participants had mild ambulatory disease. However, we measured substantial heterogeneity in illness experience, symptom duration, and maximum reported intensity of individual symptoms. Symptom intensity was a more valuable predicter of major activity change during dengue illness than symptom presence or absence alone. These data suggest that the IPR measures clinically useful heterogeneity in dengue illness experience and its relation to altered human behavior.

Previous studies measuring the health-related quality of life (HRQoL) of individuals with dengue focused on treatment seeking populations. However, the vast majority of global dengue cases are unlikely to be detected by health systems. Representative measurements of HRQoL should therefore include patients with disease not likely to trigger treatment-seeking behavior. This study based in Iquitos, Peru used the Quality of Wellbeing Scale-Self Administered, a survey that enquires about not only physical health, but also psychological health, self-care, mobility, and usual social activities, and rates HRQoL between 0 (death) and 1 (optimum function), to evaluate the impact of dengue on HRQoL. In order to enroll treatment and non treatment-seeking participants, three modalities of participant recruitment were used. In addition to clinic and community-based febrile surveillance, a contact-cluster methodology was also employed to identify infected individuals less likely to seek treatment. We measured changes in HRQoL and identified common areas of health impairment in 73 virologically confirmed dengue cases at 3 time points during the participant's illness; the early-acute (days 0-6 post symptom onset), late-acute (days 7-20), and convalescent illness phases (days 21 +). Participants reported HRQoL related impairments at significantly higher frequency during the early-acute versus convalescent illness phase (Fisher's exact: P

[This corrects the article DOI: 10.1371/journal.pntd.0007756.].

Mosquitoes are important vectors for pathogens that infect humans and other vertebrate animals. Some aspects of adult mosquito behavior and mosquito ecology play an important role in determining the capacity of vector populations to transmit pathogens. Here, we re-examine factors affecting the transmission of pathogens by mosquitoes using a new approach. Unlike most previous models, this framework considers the behavioral states and state transitions of adult mosquitoes through a sequence of activity bouts. We developed a new framework for individual-based simulation models called MBITES (Mosquito Bout-based and Individual-based Transmission Ecology Simulator). In MBITES, it is possible to build models that simulate the behavior and ecology of adult mosquitoes in exquisite detail on complex resource landscapes generated by spatial point processes. We also developed an ordinary differential equation model which is the Kolmogorov forward equations for models developed in MBITES under a specific set of simplifying assumptions. While mosquito infection and pathogen development are one possible part of a mosquito's state, that is not our main focus. Using extensive simulation using some models developed in MBITES, we show that vectorial capacity can be understood as an emergent property of simple behavioral algorithms interacting with complex resource landscapes, and that relative density or sparsity of resources and the need to search can have profound consequences for mosquito populations' capacity to transmit pathogens.

Recent years have seen rising incidence of dengue and large outbreaks of Zika and chikungunya, which are all caused by viruses transmitted by Aedes aegypti mosquitoes. In most settings, the primary intervention against Aedes-transmitted viruses is vector control, such as indoor, ultra-low volume (ULV) spraying. Targeted indoor residual spraying (TIRS) has the potential to more effectively impact Aedes-borne diseases, but its implementation requires careful planning and evaluation. The optimal time to deploy these interventions and their relative epidemiological effects are, however, not well understood. We used an agent-based model of dengue virus transmission calibrated to data from Iquitos, Peru to assess the epidemiological effects of these interventions under differing strategies for deploying them. Specifically, we compared strategies where spray application was initiated when incidence rose above a threshold based on incidence in recent years to strategies where spraying occurred at the same time(s) each year. In the absence of spraying, the model predicted 361,000 infections [inter-quartile range (IQR): 347,000-383,000] in the period 2000-2010. The ULV strategy with the fewest median infections was spraying twice yearly, in March and October, which led to a median of 172,000 infections [IQR: 158,000-183,000], a 52% reduction from baseline. Compared to spraying once yearly in September, the best threshold-based strategy utilizing ULV had fewer median infections (254,000 vs. 261,000), but required more spraying (351 vs. 274 days). For TIRS, the best strategy was threshold-based, which led to the fewest infections of all strategies tested (9,900; [IQR: 8,720-11,400], a 94% reduction), and required fewer days spraying than the equivalent ULV strategy (280). Although spraying twice each year is likely to avert the most infections, our results indicate that a threshold-based strategy can become an alternative to better balance the translation of spraying effort into impact, particularly if used with a residual insecticide.

Dengue is one of the most important vector-borne diseases, resulting in an estimated hundreds of millions of infections annually throughout the tropics. Control of dengue is heavily dependent upon control of its primary mosquito vector, Aedes aegypti. Innovative interventions that are effective at targeting the adult stage of the mosquito are needed to increase the options for effective control. The use of insecticide-treated curtains (ITCs) has previously been shown to significantly reduce the abundance of Ae. aegypti in and around homes, but the impact of ITCs on dengue virus (DENV) transmission has not been rigorously quantified. A parallel arm cluster-randomized controlled trial was conducted in Iquitos, Peru to quantify the impact of ITCs on DENV seroconversion as measured through plaque-reduction neutralization tests. Seroconversion data showed that individuals living in the clusters that received ITCs were at greater risk to seroconverting to DENV, with an average seroconversion rate of 50.6 per 100 person-years (PY) (CI: 29.9-71.9), while those in the control arm had an average seroconversion rate of 37.4 per 100 PY (CI: 15.2-51.7). ITCs lost their insecticidal efficacy within 6 months of deployment, necessitating re-treatment with insecticide. Entomological indicators did not show statistically significant differences between ITC and non-ITC clusters. It's unclear how the lack of protective efficacy reported here is attributable to simple failure of the intervention to protect against Ae. aegypti bites, or the presence of a faulty intervention during much of the follow-up period. The higher risk of dengue seroconversion that was detected in the ITC clusters may have arisen due to a false sense of security that inadvertently led to less routine protective behaviors on the part of households that received the ITCs. Our study provides important lessons learned for conducting cluster randomized trials for vector control interventions against Aedes-transmitted virus infections.

Vector-borne diseases (VBDs) such as malaria, dengue, and leishmaniasis exert a huge burden of morbidity and mortality worldwide, particularly affecting the poorest of the poor. The principal method by which these diseases are controlled is through vector control, which has a long and distinguished history. Vector control, to a greater extent than drugs or vaccines, has been responsible for shrinking the map of many VBDs. Here, we describe the history of vector control programmes worldwide from the late 1800s to date. Pre 1940, vector control relied on a thorough understanding of vector ecology and epidemiology, and implementation of environmental management tailored to the ecology and behaviour of local vector species. This complex understanding was replaced by a simplified dependency on a handful of insecticide-based tools, particularly for malaria control, without an adequate understanding of entomology and epidemiology and without proper monitoring and evaluation. With the rising threat from insecticide-resistant vectors, global environmental change, and the need to incorporate more vector control interventions to eliminate these diseases, we advocate for continued investment in evidence-based vector control. There is a need to return to vector control approaches based on a thorough knowledge of the determinants of pathogen transmission, which utilise a range of insecticide and non-insecticide-based approaches in a locally tailored manner for more effective and sustainable vector control.

Fields such as behavioural and evolutionary ecology are built on the assumption that natural selection leads to organisms that behave as if they are trying to maximise their fitness. However, there is considerable evidence for selfish genetic elements that change the behaviour of individuals to increase their own transmission. How can we reconcile this contradiction? Here we show that: (1) when selfish genetic elements have a greater impact at the individual level, they are more likely to be suppressed, and suppression spreads more quickly; (2) selection on selfish genetic elements leads them towards a greater impact at the individual level, making them more likely to be suppressed; (3) the majority interest within the genome generally prevails over 'cabals' of a few genes, irrespective of genome size, mutation rate and the sophistication of trait distorters. Overall, our results suggest that even when there is the potential for considerable genetic conflict, this will often have negligible impact at the individual level.

BACKGROUND:Human mobility plays a central role in shaping pathogen transmission by generating spatial and/or individual variability in potential pathogen-transmitting contacts. Recent research has shown that symptomatic infection can influence human mobility and pathogen transmission dynamics. Better understanding the complex relationship between symptom severity, infectiousness, and human mobility requires quantification of movement patterns throughout infectiousness. For dengue virus (DENV), human infectiousness peaks 0-2 days after symptom onset, making it paramount to understand human movement patterns from the beginning of illness. METHODOLOGY AND PRINCIPAL FINDINGS:Through community-based febrile surveillance and RT-PCR assays, we identified a cohort of DENV+ residents of the city of Iquitos, Peru (n = 63). Using retrospective interviews, we measured the movements of these individuals when healthy and during each day of symptomatic illness. The most dramatic changes in mobility occurred during the first three days after symptom onset; individuals visited significantly fewer locations (Wilcoxon test, p = 0.017) and spent significantly more time at home (Wilcoxon test, p = 0.005), compared to when healthy. By 7-9 days after symptom onset, mobility measures had returned to healthy levels. Throughout an individual's symptomatic period, the day of illness and their subjective sense of well-being were the most significant predictors for the number of locations and houses they visited. CONCLUSIONS/SIGNIFICANCE:Our study is one of the first to collect and analyze human mobility data at a daily scale during symptomatic infection. Accounting for the observed changes in human mobility throughout illness will improve understanding of the impact of disease on DENV transmission dynamics and the interpretation of public health-based surveillance data.

In the Americas, as in much of the rest of the world, the dengue virus vector Aedes aegypti is found in close association with human habitations, often leading to high population densities of mosquitoes in urban settings. In the Peruvian Amazon, this vector has been expanding to rural communities over the last 10-15 years, but to date, the population genetic structure of Ae. aegypti in this region has not been characterized. To investigate the relationship between Ae. aegypti gene flow and human transportation networks, we characterized mosquito population structure using a panel of 8 microsatellite markers and linked results to various potential mechanisms for long-distance dispersal. Adult and immature Ae. aegypti (>20 individuals per site) were collected from Iquitos city and from six neighboring riverine communities, i.e., Nauta, Indiana, Mazan, Barrio Florida, Tamshiaco, and Aucayo. FST statistics indicate significant, but low to moderate differentiation for the majority of study site pairs. Population structure of Ae. aegypti is not correlated with the geographic distance between towns, suggesting that human transportation networks provide a reasonable explanation for the high levels of population mixing. Our results indicate that Ae. aegypti gene flow among sub-populations is greatest between locations with heavy boat traffic, such as Iquitos-Tamshiaco and Iquitos-Indiana-Mazan, and lowest between locations with little or no boat/road traffic between them such as Barrio Florida-Iquitos. Bayesian clustering analysis showed ancestral admixture among three genetic clusters; no single cluster was exclusive to any site. Our results are consistent with the hypothesis that human transportation networks, particularly riverways, are responsible for the geographic spread of Ae. aegypti in the Peruvian Amazon. Our findings are applicable to other regions of the world characterized by networks of urban islands connected by fluvial transport routes.

Dengue is a mosquito-borne viral infection that has spread throughout the tropical world over the past 60 years and now affects over half the world's population. The geographical range of dengue is expected to further expand due to ongoing global phenomena including climate change and urbanization. We applied statistical mapping techniques to the most extensive database of case locations to date to predict global environmental suitability for the virus as of 2015. We then made use of climate, population and socioeconomic projections for the years 2020, 2050 and 2080 to project future changes in virus suitability and human population at risk. This study is the first to consider the spread of Aedes mosquito vectors to project dengue suitability. Our projections provide a key missing piece of evidence for the changing global threat of vector-borne disease and will help decision-makers worldwide to better prepare for and respond to future changes in dengue risk.

The tetravalent dengue vaccine CYD-TDV (Dengvaxia) is the first licensed vaccine against dengue, but recent findings indicate an elevated risk of severe disease among vaccinees without prior dengue virus (DENV) exposure. The World Health Organization currently recommends CYD-TDV only for individuals with serological confirmation of past DENV exposure. Our objective was to evaluate the potential health impact and cost-effectiveness of vaccination following serological screening. To do so, we used an agent-based model to simulate DENV transmission with and without vaccination over a 10-year timeframe. Across a range of values for the proportion of vaccinees with prior DENV exposure, we projected the proportion of symptomatic and hospitalized cases averted as a function of the sensitivity and specificity of serological screening. Scenarios about the cost-effectiveness of screening and vaccination were chosen to be representative of Brazil and the Philippines. We found that public health impact depended primarily on sensitivity in high-transmission settings and on specificity in low-transmission settings. Cost-effectiveness could be achievable from the perspective of a public payer provided that sensitivity and the value of a disability-adjusted life-year were both high, but only in high-transmission settings. Requirements for reducing relative risk and achieving cost-effectiveness from an individual perspective were more restricted, due to the fact that those who test negative pay for screening but receive no benefit. Our results predict that cost-effectiveness could be achieved only in high-transmission areas of dengue-endemic countries with a relatively high per capita GDP, such as Panamá (13,680 USD), Brazil (8,649 USD), México (8,201 USD), or Thailand (5,807 USD). In conclusion, vaccination with CYD-TDV following serological screening could have a positive impact in some high-transmission settings, provided that screening is highly specific (to minimize individual harm), at least moderately sensitive (to maximize population benefit), and sufficiently inexpensive (depending on the setting).

During the last 50 years, the geographic range of the mosquito Aedes aegypti has increased dramatically, in parallel with a sharp increase in the disease burden from the viruses it transmits, including Zika, chikungunya, and dengue. There is a growing consensus that vector control is essential to prevent Aedes-borne diseases, even as effective vaccines become available. What remains unclear is how effective vector control is across broad operational scales because the data and the analytical tools necessary to isolate the effect of vector-oriented interventions have not been available. We developed a statistical framework to model Ae. aegypti abundance over space and time and applied it to explore the impact of citywide vector control conducted by the Ministry of Health (MoH) in Iquitos, Peru, over a 12-year period. Citywide interventions involved multiple rounds of intradomicile insecticide space spray over large portions of urban Iquitos (up to 40% of all residences) in response to dengue outbreaks. Our model captured significant levels of spatial, temporal, and spatio-temporal variation in Ae. aegypti abundance within and between years and across the city. We estimated the shape of the relationship between the coverage of neighborhood-level vector control and reductions in female Ae. aegypti abundance; i.e., the dose-response curve. The dose-response curve, with its associated uncertainties, can be used to gauge the necessary spraying effort required to achieve a desired effect and is a critical tool currently absent from vector control programs. We found that with complete neighborhood coverage MoH intra-domicile space spray would decrease Ae. aegypti abundance on average by 67% in the treated neighborhood. Our framework can be directly translated to other interventions in other locations with geolocated mosquito abundance data. Results from our analysis can be used to inform future vector-control applications in Ae. aegypti endemic areas globally.

In the version of this Article originally published, the affiliation for author Catherine Linard was incorrectly stated as '6Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK'. The correct affiliation is '9Spatial Epidemiology Lab (SpELL), Universite Libre de Bruxelles, Brussels, Belgium'. The affiliation for author Hongjie Yu was also incorrectly stated as '11Department of Statistics, Harvard University, Cambridge, MA, USA'. The correct affiliation is '15School of Health, Fudan University, Key Laboratory of Public Health Safety, Ministry of Education, Shanghai, China'. This has now been amended in all versions of the Article.

The global population at risk from mosquito-borne diseases-including dengue, yellow fever, chikungunya and Zika-is expanding in concert with changes in the distribution of two key vectors: Aedes aegypti and Aedes albopictus. The distribution of these species is largely driven by both human movement and the presence of suitable climate. Using statistical mapping techniques, we show that human movement patterns explain the spread of both species in Europe and the United States following their introduction. We find that the spread of Ae. aegypti is characterized by long distance importations, while Ae. albopictus has expanded more along the fringes of its distribution. We describe these processes and predict the future distributions of both species in response to accelerating urbanization, connectivity and climate change. Global surveillance and control efforts that aim to mitigate the spread of chikungunya, dengue, yellow fever and Zika viruses must consider the so far unabated spread of these mosquitos. Our maps and predictions offer an opportunity to strategically target surveillance and control programmes and thereby augment efforts to reduce arbovirus burden in human populations globally.

Prophylactic vaccination is a powerful tool for reducing the burden of infectious diseases, due to a combination of direct protection of vaccinees and indirect protection of others via herd immunity. Computational models play an important role in devising strategies for vaccination by making projections of its impacts on public health. Such projections are subject to uncertainty about numerous factors, however. For example, many vaccine efficacy trials focus on measuring protection against disease rather than protection against infection, leaving the extent of breakthrough infections (i.e., disease ameliorated but infection unimpeded) among vaccinees unknown. Our goal in this study was to quantify the extent to which uncertainty about breakthrough infections results in uncertainty about vaccination impact, with a focus on vaccines for dengue. To realistically account for the many forms of heterogeneity in dengue virus (DENV) transmission, which could have implications for the dynamics of indirect protection, we used a stochastic, agent-based model for DENV transmission informed by more than a decade of empirical studies in the city of Iquitos, Peru. Following 20 years of routine vaccination of nine-year-old children at 80% coverage, projections of the proportion of disease episodes averted varied by a factor of 1.76 (95% CI: 1.54-2.06) across the range of uncertainty about breakthrough infections. This was equivalent to the range of vaccination impact projected across a range of uncertainty about vaccine efficacy of 0.268 (95% CI: 0.210-0.329). Until uncertainty about breakthrough infections can be addressed empirically, our results demonstrate the importance of accounting for it in models of vaccination impact.

Most organisms are built from a single genome. In striking contrast, arbuscular mycorrhizal fungi appear to maintain genomic variation within an individual fungal network. Arbuscular mycorrhizal fungi dwell in the soil, form mutualistic networks with plants, and bear multiple, potentially genetically diverse nuclei within a network. We explore, from a theoretical perspective, why such genetic diversity might be maintained within individuals. We consider selection acting within and between individual fungal networks. We show that genetic diversity could provide a benefit at the level of the individual, by improving growth in variable environments, and that this can stabilize genetic diversity even in the presence of nuclear conflict. Arbuscular mycorrhizal fungi complicate our understanding of organismality, but our findings offer a way of understanding such biological anomalies.

Experiments have shown that when one plant is attacked by a pathogen or herbivore, this can lead to other plants connected to the same mycorrhizal network up-regulating their defense mechanisms. It has been hypothesized that this represents signaling, with attacked plants producing a signal to warn other plants of impending harm. We examined the evolutionary plausibility of this and other hypotheses theoretically. We found that the evolution of plant signaling about an attack requires restrictive conditions, and so will rarely be evolutionarily stable. The problem is that signaling about an attack provides a benefit to competing neighbors, even if they are kin, and so reduces the relative fitness of signaling plants. Indeed, selection is often more likely to push plant behavior in the opposite direction--with plants signaling dishonestly about an attack that has not occurred, or suppressing a cue that they have been attacked. Instead, we show that there are two viable alternatives that could explain the empirical data: 1) the process of being attacked leads to a cue (information about the attack) which is too costly for the attacked plant to fully suppress; 2) mycorrhizal fungi monitor their host plants, detect when they are attacked, and then the fungi signal this information to warn other plants in their network. Our results suggest the empirical work that would be required to distinguish between these possibilities. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening complication caused by an uncontrolled immune response to infection that can lead to multi-organ dysfunction, including liver injury. Recent research has shown the critical role of gut microbiota in sepsis pathogenesis, with the gut–liver axis playing a crucial role in disease progression. Mechanisms such as the disruption of the gut barrier and liver injury pathways mediated by cytokines, chemokines, adhesion molecules, hydrogen sulfide (H2S). and substance P (SP) have been the focus of recent studies. Some potential biomarkers and gut microbiota-targeted therapies have shown promise as emerging tools for predicting and managing sepsis. This review describes the role of the gut–liver axis in sepsis and the potential of microbiota-targeted therapies and biomarker-driven interventions to improve sepsis outcomes. [ABSTRACT FROM AUTHOR]