Understanding the Potential Impact of Different Drug Properties on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission and Disease Burden: A Modelling Analysis.

BACKGROUND: The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. METHODS: Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. RESULTS: The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. CONCLUSIONS: Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Progress Toward Onchocerciasis Elimination in Brazil.

The single onchocerciasis-endemic focus in the remote Amazon rainforest is shared by Brazil and Venezuela and affects primarily the indigenous Yanomami people. Regional elimination of onchocerciasis is challenged by the magnitude and inaccessibility of this area. In Brazil, 272 onchocerciasis-endemic communities are operationally organized through 21 health centers ("polos bases"). Mass drug administration of ivermectin began in 1995, with 36 effective biannual rounds (≥85% coverage of the eligible population) through 2022. The national on chocerciasis program maintains community-level monitoring to prioritize treatment activities and epidemiological surveys. The Onchocerciasis Elimination Program for the Americas and the WHO onchocerciasis elimination guidelines have helped Brazil move toward its goal of stopping ivermectin treatment by 2025 and verifying transmission elimination by 2030. Additional challenges to the Brazilian onchocerciasis program include cross-border movements and insecurity due to illegal mining and inter-community conflicts. The new government in Brazil offers hope given its commitment to the equity of indigenous people and preservation of the Amazon environment.

Scorecard Approach to Eliminate Onchocerciasis in Venezuela.

In the Americas, onchocerciasis has been eliminated in 11 of 13 endemic foci by mass administration of ivermectin. The remaining at-risk population resides in a contiguous cross-border transmission zone located in the Amazon jungle in northwest Brazil and southern Venezuela, known as the Yanomami Focus Area. Here, we describe the development and implementation of a data-driven tool, called the Scorecard Approach (SCA), for the 393 communities that comprise the Venezuela South Focus. The SCA was first applied in 2018 and is reassessed on an annual basis. This operational strategy seeks to prioritize communities with low ivermectin coverage while taking into account the nature and variation of other epidemiological and logistical variables. Numeric scores are assigned for each factor and added together to yield a composite score for each community that is categorized as high, medium, or low priority. In this way, the SCA serves as a valuable and comprehensive strategy for planning, monitoring, and maximizing programmatic efficiency. In addition, it has allowed the country to face the main challenges of this endemic area: its remoteness, its large areas of territory to cover, the semi-nomadic nature of the Yanomami people, and their continuous cross-border movements. For 2022, the SCA categorized 54 (13.7%), 108 (27.5%), and 231 (58.8%) communities as high, medium, and low priority, respectively. The results presented here show that prioritizing communities at risk and with greatest needs increases the feasibility of interrupting the transmission of onchocerciasis by 2025 in the last endemic focus in the Americas.

Cooperation for malaria control and elimination in the Guiana Shield.

The Guiana Shield, a small region of South America, is currently one of the main hotspots of malaria transmission on the continent. This Amazonian area is characterised by remarkable socioeconomic, cultural, health, and political heterogeneity and a high degree of regional and cross-border population mobility, which has contributed to the increase of malaria in the region in the past few years. In this context, regional cooperation to control malaria represents both a challenge and an indispensable initiative. This Viewpoint advocates for the creation of a regional cooperative mechanism for the elimination of malaria in the Guiana Shield. This strategy would help address operational and political obstacles to successful technical cooperation in the region and could contribute to reversing the regional upsurge in malaria incidence through creating a functional international control and elimination partnership.

Reaching the malaria elimination goal in Brazil: a spatial analysis and time-series study.

BACKGROUND: Since 2015, the Global Technical Strategy (GTS) for Malaria 2016-2030 has been adopted by the World Health Organization (WHO) as a comprehensive framework to accelerate progress for malaria elimination in endemic countries. This strategy sets the target of reducing global malaria incidence and mortality rates by 90% in 2030. Here it is sought to evaluate Brazil's achievements towards reaching the WHO GTS milestone in 2030. Considering the total number of new malaria cases in 2015, the main research question is: will Brazil reach the malaria elimination goal in 2030? METHODS: Analytical strategies were undertaken using the SIVEP-malaria official databases of the Brazilian Malaria Control Programme for the Brazilian Amazon region from 2009 to 2020. Spatial and time-series analyses were applied for identifying municipalities that support the highest numbers of malaria cases over the years. Forecast analysis was used for predicting the estimated number of new cases in Brazil in 2025-2050. RESULTS: Brazil has significantly reduced the number of new malaria cases in 2020 in comparison with 2015 in the states of Acre (- 56%), Amapá (- 75%), and Amazonas (- 21%); however, they increased in the states of Pará (156%), Rondônia (74%), and Roraima (362%). Forecast of the predicted number of new malaria cases in 2030 is 74,764 (95% CI: 41,116-141,160) in the Brazilian Amazon. CONCLUSIONS: It is likely that Brazil will reduce the number of new malaria cases in the Brazilian Amazon in 2030 in relation to that in 2015. Herein forecast shows a reduction by 46% (74,754 in 2030 forecast/137,982 in 2015), but this reduction is yet far from the proposed reduction under the WHO GTS 2030 milestone (90%). Stable and unbeatable transmission in the Juruá River Valley, Manaus, and Lábrea still support endemic malaria in the Brazilian Amazon. Today's cross-border malaria is impacting the state of Roraima unprecedently. If this situation is maintained, the malaria elimination goal (zero cases) may not be reached before 2050. An enhanced political commitment is vital to ensure optimal public health intervention designs in the post-2030 milestones for malaria elimination.

Synergies between environmental degradation and climate variation on malaria re-emergence in southern Venezuela: a spatiotemporal modelling study.

BACKGROUND: Environmental degradation facilitates the emergence of vector-borne diseases, such as malaria, through changes in the ecological landscape that increase human-vector contacts and that expand vector habitats. However, the modifying effects of environmental degradation on climate-disease relationships have not been well explored. Here, we investigate the rapid re-emergence of malaria in a transmission hotspot in southern Venezuela and explore the synergistic effects of environmental degradation, specifically gold-mining activity, and climate variation. METHODS: In this spatiotemporal modelling study of the 46 parishes of the state of Bolívar, southeast Venezuela, we used data from the Venezuelan Ministry of Health including population data and monthly cases of Plasmodium falciparum malaria and Plasmodium vivax malaria between 1996 and 2016. We estimated mean precipitation and temperature using the ERA5-Land dataset and used monthly anomalies in sea-surface temperature as an indicator of El Niño events between 1996 and 2016. The location of suspected mining sites in Bolívar in 2009, 2017, and 2018 were sourced from the Amazon Geo-Referenced Socio-Environmental Information Network. We estimated measures of cumulative forest loss and urban development by km2 using annual land cover maps from the European Space Agency Climate Change Initiative between 1996 and 2016. We modelled monthly cases of P falciparum and P vivax malaria using a Bayesian hierarchical mixed model framework. We quantified the variation explained by mining activity before exploring the modifying effects of environmental degradation on climate-malaria relationships. FINDINGS: We observed a 27% reduction in the additional unexplained spatial variation in incidence of P falciparum malaria and a 23% reduction in P vivax malaria when mining was included in our models. The effect of temperature on malaria was greater in high mining areas than low mining areas, and the P falciparum malaria effect size at temperatures of 26·5°C (2·4 cases per 1000 people [95% CI 1·78-3·06]) was twice as high as the effect in low mining areas (1 case per 1000 people [0·68-1·49]). INTERPRETATION: We show that mining activity in southern Venezuela is associated with hotspots of malaria transmission. Increased temperatures exacerbated malaria transmission in mining areas, highlighting the need to consider how environmental degradation modulates climate effect on disease risk, which is especially important in areas subjected to rapidly rising temperatures and land-use change globally. Our findings have implications for the progress towards malaria elimination in the Latin American region. Our findings are also important for effectively targeting timely treatment programmes and vector-control activities in mining areas with high rates of malaria transmission. FUNDING: Biotechnology and Biological Sciences Research Council, Royal Society, US National Institutes of Health, and Global Challenges Research Fund. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Hotspots and correlates of soil-transmitted helminth infections in a Venezuelan rural community: Which are the "wormy" houses?

OBJECTIVES: To determine spatial clustering and risk factors for occurrence and intensity of infection for soil-transmitted helminthiasis (STH), namely Ascaris lumbricoides, Trichuris trichiura, Strongyloides stercoralis and hookworms in a Venezuelan rural community. METHODS: MIF-fixed faecal samples were individually collected for STH testing. The Getis-Ord statistic was used to determine significant STH clustering within 25/50/100 m radiuses around houses. Individual- and house-level factors associated with STH occurrence and intensity of infection were determined using generalized estimating equations. RESULTS: Significant clusters of "wormy" houses for one or multiple parasites were found at distances of 25-50 m around 13 houses. Risk factors differed between occurrence and intensity of infection. Overcrowding in the house increased occurrence of S. stercoralis, T. trichiura and hookworm infections, while poor housing conditions increased A. lumbricoides infection risk. Overcrowding, poor faecal disposal system, economic dependency and lack of basic services differentially influenced the STHs. The "wormy" houses were mainly those built with waste materials, under economic dependency and lacking indoor water supply. CONCLUSIONS: STH distribution in a community is clustered, with significant hotspots of STH occurrence and intensity of infection and different associated risk factors. Targeting the "wormy" houses is expected to affect STH morbidity more efficiently.

Back from the past: Molecular and morphological support for Simulium mutucuna Nunes de Mello & Vieira da Silva, 1974 (Diptera: Simuliidae) as a valid species.

Simulium mutucuna, a species described based on a single female from Roraima state, was previously synonymized with Simulium paynei and currently is considered a synonym of Simulium rubrithorax. In the present paper we present morphological and molecular evidence supporting the validity of S. mutucuna based on analysis of specimens from Brazil, Venezuela and Mexico. We redescribe the female and describe, for the first time, the male, pupa and larva of S. mutucuna and discuss the morphological differences between this species and the others that are already considered as its senior synonyms. Currently, the distribution of S. mutucuna is restricted to Roraima state. The distribution record for S. rubrithorax in Brazil's North region needs to be removed, since the previous records were based on occurrence of S. mutucuna. Finally, we present new evidence of cryptic diversity in the S. paynei complex based on molecular information.

Signatures of the Venezuelan Humanitarian Crisis in the First Wave of COVID-19: Fuel Shortages and Border Migration.

Testing and isolation have been crucial for controlling the COVID-19 pandemic. Venezuela has one of the weakest testing infrastructures in Latin America and the low number of reported cases in the country has been attributed to substantial underreporting. However, the Venezuelan epidemic seems to have lagged behind other countries in the region, with most cases occurring within the capital region and four border states. Here, we describe the spatial epidemiology of COVID-19 in Venezuela and its relation to the population mobility, migration patterns, non-pharmaceutical interventions and fuel availability that impact population movement. Using a metapopulation model of SARS-CoV-2 transmission dynamics, we explore how movement patterns could have driven the observed distribution of cases. Low within-country connectivity most likely delayed the onset of the epidemic in most states, except for those bordering Colombia and Brazil, where high immigration seeded outbreaks. NPIs slowed early epidemic growth and subsequent fuel shortages appeared to be responsible for limiting the spread of COVID-19 across the country.

Malaria in Southern Venezuela: The hottest hotspot in Latin America.

Malaria elimination in Latin America is becoming an elusive goal. Malaria cases reached a historical ~1 million in 2017 and 2018, with Venezuela contributing 53% and 51% of those cases, respectively. Historically, malaria incidence in southern Venezuela has accounted for most of the country's total number of cases. The efficient deployment of disease prevention measures and prediction of disease spread to new regions requires an in-depth understanding of spatial heterogeneity on malaria transmission dynamics. Herein, we characterized the spatial epidemiology of malaria in southern Venezuela from 2007 through 2017 and described the extent to which malaria distribution has changed country-wide over the recent years. We found that disease transmission was focal and more prevalent in the southeast region of southern Venezuela where two persistent hotspots of Plasmodium vivax (76%) and P. falciparum (18%) accounted for ~60% of the total number of cases. Such hotspots are linked to deforestation as a consequence of illegal gold mining activities. Incidence has increased nearly tenfold over the last decade, showing an explosive epidemic growth due to a significant lack of disease control programs. Our findings highlight the importance of spatially oriented interventions to contain the ongoing malaria epidemic in Venezuela. This work also provides baseline epidemiological data to assess cross-border malaria dynamics and advocates for innovative control efforts in the Latin American region.

Onchocerca-Simulium interactions and the population and evolutionary biology of Onchocerca volvulus.

Parasite-vector interactions shape the population dynamics of vector-borne infections and contribute to observed epidemiological patterns. Also, parasites and their vectors may co-evolve, giving rise to locally adapted combinations or complexes with the potential to stabilise the infection. Here, we focus on Onchocerca-Simulium interactions with particular reference to the transmission dynamics of human onchocerciasis. A wide range of simuliid species may act as vectors of Onchocerca volvulus, each exerting their own influence over the local epidemiology and the feasibility of controlling/eliminating the infection. Firstly, current understanding of the processes involved in parasite acquisition by, and development within, different Simulium species in West Africa and Latin America will be reviewed. A description of how Onchocerca and Simulium exert reciprocal effects on each other's survival at various stages of the parasite's life cycle within the blackfly, and may have adapted to minimise deleterious effects on fitness and maximise transmission will be given. Second, we describe the interactions in terms of resultant (positive and negative) density-dependent processes that regulate parasite abundance, and discuss their incorporation into mathematical models that provide useful qualitative insight regarding transmission breakpoints. Finally, we examine the interactions' influence upon the evolution of anthelmintic resistance, and conclude that local adaptation of Onchocerca-Simulium complexes will influence the feasibility of eliminating the parasite reservoir in different foci.

Vector competence of Simulium oyapockense s.l. and S. incrustatum for Onchocerca volvulus: Implications for ivermectin-based control in the Amazonian focus of human onchocerciasis, a multi-vector-host system.

Although it is now well established that in the Amazonian onchocerciasis focus, straddling between Venezuela and Brazil, the main vectors in the highland (hyperendemic) and lowland (hypoendemic) areas, are respectively Simulium guianense sensu lato Wise and S. oyapockense s.l. Floch and Abonnenc, investigation of the vectorial role of a third anthropophagic species, Simulium incrustatum Lutz has remained inconclusive. Here we compare the vector competence of S. incrustatum with that of S. oyapockense s.l. by conducting, in the Venezuelan part of the focus, a series of feeding experiments designed to analyze their relative: (a) microfilarial intakes when fed upon the same skin load; (b) proportions of microfilariae (mf) surviving damage inflicted by the cibarial armature (present in both species); and (c) infective (L3) larval outputs. Although the ability of S. oyapockense s.l. to ingest mf, for a given microfilaridermia, was markedly higher than that of S. incrustatum, the (density-dependent) proportions of those ingested mf that were damaged by the armature were also consistently higher, with the resulting output of L3 larvae being significantly lower in S. oyapockense s.l. than in S. incrustatum. These results indicate that S. incrustatum plays a more important role in onchocerciasis transmission in the Amazonian focus than previously realized. We discuss the implications of our findings for the control and elimination of onchocerciasis with mass administration of ivermectin in this focus, where the three main anthropophagic species often co-occur.

Modelling malaria incidence by an autoregressive distributed lag model with spatial component.

The influence of climatic variables on the dynamics of human malaria has been widely highlighted. Also, it is known that this mosquito-borne infection varies in space and time. However, when the data is spatially incomplete most popular spatio-temporal methods of analysis cannot be applied directly. In this paper, we develop a two step methodology to model the spatio-temporal dependence of malaria incidence on local rainfall, temperature, and humidity as well as the regional sea surface temperatures (SST) in the northern coast of Venezuela. First, we fit an autoregressive distributed lag model (ARDL) to the weekly data, and then, we adjust a linear separable spacial vectorial autoregressive model (VAR) to the residuals of the ARDL. Finally, the model parameters are tuned using a Markov Chain Monte Carlo (MCMC) procedure derived from the Metropolis-Hastings algorithm. Our results show that the best model to account for the variations of malaria incidence from 2001 to 2008 in 10 endemic Municipalities in North-Eastern Venezuela is a logit model that included the accumulated local precipitation in combination with the local maximum temperature of the preceding month as positive regressors. Additionally, we show that although malaria dynamics is highly heterogeneous in space, a detailed analysis of the estimated spatial parameters in our model yield important insights regarding the joint behavior of the disease incidence across the different counties in our study.

River-specific macrogenomic diversity in Simulium guianense s. l. (Diptera: Simuliidae), a complex of tropical American vectors associated with human onchocerciasis.

Simulium guianense Wise is a Latin American vector complex of black flies associated with transmission of the causal agent of human onchocerciasis (river blindness). An analysis of the chromosomal banding patterns of 607 larvae of S. guianense s. l. revealed a high level of variation involving 83 macrogenomic rearrangements across 25 populations in Brazil, French Guiana, and Venezuela. The 25 populations were assigned to 13 cytoforms (A1, A2, B1-B4, C, D, E1-E4, and F), some of which are probably valid species. Based on geographical proximity, a member of the B group of cytoforms probably represents the name-bearing type specimen of S. guianense and the primary vector in the last-remaining onchocerciasis foci in the Western Hemisphere. Cytoform B3 in Amapá State is implicated as an anthropophilic simuliid in an area currently and historically free of onchocerciasis. Distributions of cytoforms are associated with geography, elevation, and drainage basin, and are largely congruent with ecoregions. Despite extraordinarily large larval populations of S. guianense s. l. in big rivers and consequent production of female flies for dispersal, the cytoforms maintain their chromosomal distinction within individual rivers, suggesting a high degree of fidelity to the specialized breeding habitats-rocky shoals-of the natal rivers.

Spatial Analysis of Dengue Seroprevalence and Modeling of Transmission Risk Factors in a Dengue Hyperendemic City of Venezuela.

BACKGROUND: Dengue virus (DENV) transmission is spatially heterogeneous. Hence, to stratify dengue prevalence in space may be an efficacious strategy to target surveillance and control efforts in a cost-effective manner particularly in Venezuela where dengue is hyperendemic and public health resources are scarce. Here, we determine hot spots of dengue seroprevalence and the risk factors associated with these clusters using local spatial statistics and a regression modeling approach. METHODOLOGY/PRINCIPAL FINDINGS: From August 2010 to January 2011, a community-based cross-sectional study of 2012 individuals in 840 households was performed in high incidence neighborhoods of a dengue hyperendemic city in Venezuela. Local spatial statistics conducted at household- and block-level identified clusters of recent dengue seroprevalence (39 hot spot households and 9 hot spot blocks) in all neighborhoods. However, no clusters were found for past dengue seroprevalence. Clustering of infection was detected at a very small scale (20-110m) suggesting a high disease focal aggregation. Factors associated with living in a hot spot household were occupation (being a domestic worker/housewife (P = 0.002), lower socio-economic status (living in a shack (P<0.001), sharing a household with <7 people (P = 0.004), promoting potential vector breeding sites (storing water in containers (P = 0.024), having litter outdoors (P = 0.002) and mosquito preventive measures (such as using repellent, P = 0.011). Similarly, low socio-economic status (living in crowded conditions, P<0.001), having an occupation of domestic worker/housewife (P = 0.012) and not using certain preventive measures against mosquitoes (P<0.05) were directly associated with living in a hot spot block. CONCLUSIONS/SIGNIFICANCE: Our findings contribute to a better comprehension of the spatial dynamics of dengue by assessing the relationship between disease clusters and their risk factors. These results can inform health authorities in the design of surveillance and control activities. Focalizing dengue control measures during epidemic and inter-epidemic periods to disease high risk zones at household and neighborhood-level may significantly reduce virus transmission in comparison to random interventions.

Evidence of suppression of onchocerciasis transmission in the Venezuelan Amazonian focus.

BACKGROUND: The World Health Organization (WHO) has set goals for onchocerciasis elimination in Latin America by 2015. Most of the six previously endemic countries are attaining this goal by implementing twice a year (and in some foci, quarterly) mass ivermectin (Mectizan®) distribution. Elimination of transmission has been verified in Colombia, Ecuador and Mexico. Challenges remain in the Amazonian focus straddling Venezuela and Brazil, where the disease affects the hard-to-reach Yanomami indigenous population. We provide evidence of suppression of Onchocerca volvulus transmission by Simulium guianense s.l. in 16 previously hyperendemic Yanomami communities in southern Venezuela after 15 years of 6-monthly and 5 years of 3-monthly mass ivermectin treatment. METHODS: Baseline and monitoring and evaluation parasitological, ophthalmological, entomological and serological surveys were conducted in selected sentinel and extra-sentinel communities of the focus throughout the implementation of the programme. RESULTS: From 2010 to 2012-2015, clinico-parasitological surveys indicate a substantial decrease in skin microfilarial prevalence and intensity of infection; accompanied by no evidence (or very low prevalence and intensity) of ocular microfilariae in the examined population. Of a total of 51,341 S. guianense flies tested by PCR none had L3 infection (heads only). Prevalence of infective flies and seasonal transmission potentials in 2012-2013 were, respectively, under 1% and 20 L3/person/transmission season. Serology in children aged 1-10 years demonstrated that although 26 out of 396 (7%) individuals still had Ov-16 antibodies, only 4/218 (2%) seropositives were aged 1-5 years. CONCLUSIONS: We report evidence of recent transmission and morbidity suppression in some communities of the focus representing 75% of the Yanomami population and 70% of all known communities. We conclude that onchocerciasis transmission could be feasibly interrupted in the Venezuelan Amazonian focus.

Ephemeroptera from the Venezuelan Guayanas's Uplands: Families Leptophlebiidae, Euthyplociidae and Oligoneuriidae.

As a continuation of a series of papers to improve the knowledge of the Ephemeroptera fauna of the Venezuelan Guayana's Uplands, an update of the families Leptophlebiidae, Euthyplociidae and Oligoneuriidae in the region is presented. As a result, Paramaka incognita sp. nov. is described, the female of Askola emmerichi is described for the first time, and the genera Askola, Hydrosmilodon and Leentvaaria, the subgenus Miroculis (Atroari) and the species Miroculis (M.) marauiae are recorded for the first time for Venezuela.

The periodicity of Plasmodium vivax and Plasmodium falciparum in Venezuela.

We investigated the periodicity of Plasmodium vivax and P. falciparum incidence in time-series of malaria data (1990-2010) from three endemic regions in Venezuela. In particular, we determined whether disease epidemics were related to local climate variability and regional climate anomalies such as the El Niño Southern Oscillation (ENSO). Malaria periodicity was found to exhibit unique features in each studied region. Significant multi-annual cycles of 2- to about 6-year periods were identified. The inter-annual variability of malaria cases was coherent with that of SSTs (ENSO), mainly at temporal scales within the 3-6 year periods. Additionally, malaria cases were intensified approximately 1 year after an El Niño event, a pattern that highlights the role of climate inter-annual variability in the epidemic patterns. Rainfall mediated the effect of ENSO on malaria locally. Particularly, rains from the last phase of the season had a critical role in the temporal dynamics of Plasmodium. The malaria-climate relationship was complex and transient, varying in strength with the region and species. By identifying temporal cycles of malaria we have made a first step in predicting high-risk years in Venezuela. Our findings emphasize the importance of analyzing high-resolution spatial-temporal data to better understand malaria transmission dynamics.