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Population genetic analysis of Chadian Guinea worms reveals that human and non-human hosts share common parasite populations

4 October 2018 - 9:00pm

by Elizabeth A. Thiele, Mark L. Eberhard, James A. Cotton, Caroline Durrant, Jeffrey Berg, Kelsey Hamm, Ernesto Ruiz-Tiben

Following almost 10 years of no reported cases, Guinea worm disease (GWD or dracunculiasis) reemerged in Chad in 2010 with peculiar epidemiological patterns and unprecedented prevalence of infection among non-human hosts, particularly domestic dogs. Since 2014, animal infections with Guinea worms have also been observed in the other three countries with endemic transmission (Ethiopia, Mali, and South Sudan), causing concern and generating interest in the parasites’ true taxonomic identity and population genetics. We present the first extensive population genetic data for Guinea worm, investigating mitochondrial and microsatellite variation in adult female worms from both human and non-human hosts in the four endemic countries to elucidate the origins of Chad’s current outbreak and possible host-specific differences between parasites. Genetic diversity of Chadian Guinea worms was considerably higher than that of the other three countries, even after controlling for sample size through rarefaction, and demographic analyses are consistent with a large, stable parasite population. Genealogical analyses eliminate the other three countries as possible sources of parasite reintroduction into Chad, and sequence divergence and distribution of genetic variation provide no evidence that parasites in human and non-human hosts are separate species or maintain isolated transmission cycles. Both among and within countries, geographic origin appears to have more influence on parasite population structure than host species. Guinea worm infection in non-human hosts has been occasionally reported throughout the history of the disease, particularly when elimination programs appear to be reaching their end goals. However, no previous reports have evaluated molecular support of the parasite species identity. Our data confirm that Guinea worms collected from non-human hosts in the remaining endemic countries of Africa are Dracunculus medinensis and that the same population of worms infects both humans and dogs in Chad. Our genetic data and the epidemiological evidence suggest that transmission in the Chadian context is currently being maintained by canine hosts.

Engineered nanoparticles bind elapid snake venom toxins and inhibit venom-induced dermonecrosis

4 October 2018 - 9:00pm

by Jeffrey O’Brien, Shih-Hui Lee, José María Gutiérrez, Kenneth J. Shea

Envenomings by snakebites constitute a serious and challenging global health issue. The mainstay in the therapy of snakebite envenomings is the parenteral administration of animal-derived antivenoms. Significantly, antivenoms are only partially effective in the control of local tissue damage. A novel approach to mitigate the progression of local tissue damage that could complement the antivenom therapy of envenomings is proposed. We describe an abiotic hydrogel nanoparticle engineered to bind to and modulate the activity of a diverse array of PLA2 and 3FTX isoforms found in Elapidae snake venoms. These two families of protein toxins share features that are associated with their common (membrane) targets, allowing for nanoparticle sequestration by a mechanism that differs from immunological (epitope) selection. The nanoparticles are non-toxic in mice and inhibit dose-dependently the dermonecrotic activity of Naja nigricollis venom.

A rare case of visceral leishmaniasis in an immunocompetent traveler returning to the United States from Europe

4 October 2018 - 9:00pm

by Lamia Haque, Merceditas Villanueva, Armand Russo, Youzhong Yuan, Eun-Ju Lee, Jeffrey Topal, Nikolai Podoltsev

A young, healthy traveler returning to the United States presented with fever, night sweats, splenomegaly, and pancytopenia. Bone marrow biopsy revealed leishmaniasis (Leishmania infantum), likely acquired in southern France. Although many cases of endemic visceral leishmaniasis (VL) have been reported in Europe, this is a rare case of imported VL in a healthy traveler returning from Europe to the US. Despite successful initial treatment with liposomal amphotericin B (LamB), relapse occurred. Treatments for VL in immunocompetent individuals are highly effective, but relapse can occur. There is more extensive experience in endemic areas with treating relapse that may be lacking in North America. This case alerts physicians in the US that immunocompetent adults can acquire VL during brief visits to endemic areas in Europe. It is important that travelers be counseled on preventive measures. Patients should be monitored after treatment for relapse.

Dengue illness index—A tool to characterize the subjective dengue illness experience

4 October 2018 - 9:00pm

by Stephen J. Thomas, Liane Agulto, Kim Hendrickx, Martin Erpicum, Kay M. Tomashek, M. Cristina Cassetti, Catherine Laughlin, Alexander Precioso, Alexander C. Schmidt, Federico Narvaez, João Bosco Siqueira, Hasitha Tissera, Robert Edelman

Dengue virus infections are a major cause of febrile illness that significantly affects individual and societal productivity and drives up health care costs principally in the developing world. Two dengue vaccine candidates are in advanced clinical efficacy trials in Latin America and Asia, and another has been licensed in more than fifteen countries but its uptake has been limited. Despite these advances, standardized metrics for comparability of protective efficacy between dengue vaccines remain poorly defined. The Dengue Illness Index (DII) is a tool that we developed thru refinement of previous similar iterations in an attempt to improve and standardize the measurement of vaccine and drug efficacy in reducing moderate dengue illness. The tool is designed to capture an individual’s overall disease experience based on how the totality of their symptoms impacts their general wellness and daily functionality. We applied the DII to a diary card, the Dengue Illness Card (DIC), which was examined and further developed by a working group. The card was then refined with feedback garnered from a Delphi methodology-based query that addressed the adequacy and applicability of the tool in clinical dengue research. There was overall agreement that the tool would generate useful data and provide an alternative perspective to the assessment of drug or vaccine candidates, which in the case of vaccines, are assessed by their reduction in any virologically confirmed dengue of any severity with a focus on the more severe. The DIC needs to be evaluated in the field in the context of vaccine or drug trials, prospective cohort studies, or during experimental human infection studies. Here, we present the final DIC resulting from the Delphi process and offer its further development or use to the dengue research community.

Development of standard clinical endpoints for use in dengue interventional trials

4 October 2018 - 9:00pm

by Kay M. Tomashek, Bridget Wills, Lucy Chai See Lum, Laurent Thomas, Anna Durbin, Yee-Sin Leo, Norma de Bosch, Elsa Rojas, Kim Hendrickx, Martin Erpicum, Liane Agulto, Thomas Jaenisch, Hasitha Tissera, Piyarat Suntarattiwong, Beth Ann Collers, Derek Wallace, Alexander C. Schmidt, Alexander Precioso, Federico Narvaez, Stephen J. Thomas, Robert Edelman, João Bosco Siqueira, M. Cristina Cassetti, Walla Dempsey, Duane J. Gubler

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials.

Typhoid fever outbreak in the Democratic Republic of Congo: Case control and ecological study

3 October 2018 - 9:00pm

by Julii Brainard, Rob D’hondt, Engy Ali, Rafael Van den Bergh, Anja De Weggheleire, Yves Baudot, Frederic Patigny, Vincent Lambert, Rony Zachariah, Peter Maes, Donat Kuma-Kuma Kenge, Paul R. Hunter

During 2011 a large outbreak of typhoid fever affected an estimated 1430 people in Kikwit, Democratic Republic of Congo. The outbreak started in military camps in the city but then spread to the general population. This paper reports the results of an ecological analysis and a case-control study undertaken to examine water and other possible transmission pathways. Attack rates were determined for health areas and risk ratios were estimated with respect to spatial exposures. Approximately 15 months after the outbreak, demographic, environmental and exposure data were collected for 320 cases and 640 controls residing in the worst affected areas, using a structured interview questionnaire. Unadjusted and adjusted odds ratios were estimated. Complete data were available for 956 respondents. Residents of areas with water supplied via gravity on the mains network were at much greater risk of disease acquisition (risk ratio = 6.20, 95%CI 3.39–11.35) than residents of areas not supplied by this mains network. In the case control study, typhoid was found to be associated with ever using tap water from the municipal supply (OR = 4.29, 95% CI 2.20–8.38). Visible urine or faeces in the latrine was also associated with increased risk of typhoid and having chosen a water source because it is protected was negatively associated. Knowledge that washing hands can prevent typhoid fever, and stated habit of handwashing habits before cooking or after toileting was associated with increased risk of disease. However, observed associations between handwashing or plate-sharing with disease risk could very likely be due to recall bias. This outbreak of typhoid fever was strongly associated with drinking water from the municipal drinking water supply, based on the descriptive and analytic epidemiology and the finding of high levels of faecal contamination of drinking water. Future outbreaks of potentially waterborne disease need an integrated response that includes epidemiology and environmental microbiology during early stages of the outbreak.

Beating the odds: Sustained Chagas disease vector control in remote indigenous communities of the Argentine Chaco over a seven-year period

2 October 2018 - 9:00pm

by M. Sol Gaspe, Yael M. Provecho, María P. Fernández, Claudia V. Vassena, Pablo L. Santo Orihuela, Ricardo E. Gürtler

Background

Rapid reinfestation of insecticide-treated dwellings hamper the sustained elimination of Triatoma infestans, the main vector of Chagas disease in the Gran Chaco region. We conducted a seven-year longitudinal study including community-wide spraying with pyrethroid insecticides combined with periodic vector surveillance to investigate the house reinfestation process in connection with baseline pyrethroid resistance, housing quality and household mobility in a rural section of Pampa del Indio mainly inhabited by deprived indigenous people (Qom).

Methodology/Principal findings

Despite evidence of moderate pyrethroid resistance in local T. infestans populations, house infestation dropped from 31.9% at baseline to 0.7% at 10 months post-spraying (MPS), with no triatomine found at 59 and 78 MPS. Household-based surveillance corroborated the rare occurrence of T. infestans and the house invasion of other four triatomine species. The annual rates of loss of initially occupied houses and of household mobility were high (4.6–8.0%). Housing improvements did not translate into a significant reduction of mud-walled houses and refuges for triatomines because most households kept the former dwelling or built new ones with mud walls.

Conclusions/Significance

Our results refute the assumption that vector control actions performed in marginalized communities of the Gran Chaco are doomed to fail. The larger-than-expected impacts of the intervention program were likely associated with the combined effects of high-coverage, professional insecticide spraying followed by systematic vector surveillance-and-response, broad geographic coverage creating a buffer zone, frequent housing replacement and residential mobility. The dynamical interactions among housing quality, mobility and insecticide-based control largely affect the chances of vector elimination.

Leprosy in children under 15 years of age in Brazil: A systematic review of the literature

2 October 2018 - 9:00pm

by Michelle Christini Araújo Vieira, Joilda Silva Nery, Enny S. Paixão, Kaio Vinicius Freitas de Andrade, Gerson Oliveira Penna, Maria Glória Teixeira

Background

Leprosy is a chronic infectious disease neglected, caused by Mycobacterium leprae, considered a public health problem because may cause permanent physical disabilities and deformities, leading to severe limitations. This review presents an overview of the results of epidemiological studies on leprosy occurrence in childhood in Brazil, aiming to alert health planners and managers to the actual need to institute special control strategies.

Methodology/Principal findings

Data collection consisted of an electronic search for publications in eight databases: Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Scientific Electronic Library Online (SciELO), PuBMed, Biblioteca Virtual em Saúde (BVS), SciVerse Scopus (Scopus), CAPES theses database, CAPES journals database and Web of Science of papers published up to 2016. After apply selection criteria, twenty-two papers of studies conducted in four different regions of Brazil and published between 2001 and 2016 were included in the review. The leprosy detection rate ranged from 10.9 to 78.4 per 100,000 inhabitants. Despite affecting both sexes, leprosy was more common in boys and in 10-14-year-olds. Although the authors reported a high cure proportion (82–90%), between 1.7% and 5.5% of the individuals developed a disability resulting from the disease.

Conclusions/Significance

The findings of this review shows that leprosy situation in Brazilian children under 15 years is extremely adverse in that the leprosy detection rate remains high in the majority of studies. The proportion of cases involving disability is also high and reflects the difficulties and the poor effectiveness of actions aimed at controlling the disease. The authors suggest the development of studies in spatial clusters of leprosy, where beyond the routine actions established, are included news strategies of active search and campaigns and actions of educations inside the clusters of this disease. The new agenda needs to involve the precepts of ethical, humane and supportive care, in order to achieve a new level of leprosy control in Brazil.

Defining stopping criteria for ending randomized clinical trials that investigate the interruption of transmission of soil-transmitted helminths employing mass drug administration

1 October 2018 - 9:00pm

by Marleen Werkman, Jaspreet Toor, Carolin Vegvari, James E. Wright, James E. Truscott, Kristjana H. Ásbjörnsdóttir, Arianna Rubin Means, Judd L. Walson, Roy M. Anderson

The current World Health Organization strategy to address soil-transmitted helminth (STH) infections in children is based on morbidity control through routine deworming of school and pre-school aged children. However, given that transmission continues to occur as a result of persistent reservoirs of infection in untreated individuals (including adults) and in the environment, in many settings such a strategy will need to be continued for very extended periods of time, or until social, economic and environmental conditions result in interruption of transmission. As a result, there is currently much discussion surrounding the possibility of accelerating the interruption of transmission using alternative strategies of mass drug administration (MDA). However, the feasibility of achieving transmission interruption using MDA remains uncertain due to challenges in sustaining high MDA coverage levels across entire communities. The DeWorm3 trial, designed to test the feasibility of interrupting STH transmission, is currently ongoing. In DeWorm3, three years of high treatment coverage—indicated by mathematical models as necessary for breaking transmission—will be followed by two years of surveillance. Given the fast reinfection (bounce-back) rates of STH, a two year no treatment period is regarded as adequate to assess whether bounce-back or transmission interruption have occurred in a given location. In this study, we investigate if criteria to determine whether transmission interruption is unlikely can be defined at earlier timepoints. A stochastic, individual-based simulation model is employed to simulate core aspects of the DeWorm3 community-based cluster-randomized trial. This trial compares a control arm (annual treatment of children alone with MDA) with an intervention arm (community-wide biannual treatment with MDA). Simulations were run for each scenario for both Ascaris lumbricoides and hookworm (Necator americanus). A range of threshold prevalences measured at six months after the last round of MDA and the impact of MDA coverage levels were evaluated to see if the likelihood of bounce-back or elimination could reliably be assessed at that point, rather than after two years of subsequent surveillance. The analyses suggest that all clusters should be assessed for transmission interruption after two years of surveillance, unless transmission interruption can be effectively ruled out through evidence of low treatment coverage. Models suggest a tight range of homogenous prevalence estimates following high coverage MDA across clusters which do not allow for discrimination between bounce back or transmission interruption within 24 months following cessation of MDA.

Indoor residual spraying for kala-azar vector control in Bangladesh: A continuing challenge

1 October 2018 - 9:00pm

by Rajib Chowdhury, Vashkar Chowdhury, Shyla Faria, Saiful Islam, Narayan Prosad Maheswary, Shireen Akhter, Md. Sahidul Islam, Aditya Prasad Dash, Axel Kroeger, Qamar Banu

Background

Visceral leishmaniasis (VL) in the Indian subcontinent is a fatal disease if left untreated. Between 1994 to 2013, the Ministry of Health of Bangladesh reported 1,09,266 cases of VL and 329 VL related deaths in 37 endemic districts. Indoor residual spraying (IRS) using dichlorodiphenyltrichloroethane (DDT) was used by the national programme in the 1960s to control malaria. Despite findings of research trials demonstrating that the synthetic pyrethroid deltamethrin 5 WP was very effective at reducing vector densities, no national VL vector control operations took place in Bangladesh between 1999 to early 2012. In 2012, IRS using deltamethrin 5 WP was re-introduced by the national programme, which consisted of pre-monsoon spraying in eight highly endemic sub-districts (upazilas). The present study aims to evaluate the effectiveness of IRS on VL vectors, as well as the process and performance of the spraying activities by national programme staff.

Methods

Five highly endemic upazilas of Mymensingh district were purposively selected (Fulbaria, Trishal, Mukthagacha, Gaforgaon and Bhaluka) to conduct the present study using the WHO/TDR monitoring and evaluation tool kit. IRS operations, conducted by 136 squads/teams, and 544 spraymen, were observed using check lists and questionnaires included in the WHO/TDR monitoring and evaluation tool kit. A household (HH) acceptability survey of IRS was conducted in all study areas using a structured questionnaire in 600 HHs. To measure the efficacy of IRS, pre-IRS (two weeks prior) and post-IRS (at one and five months after), vector density was measured using CDC light traps for two consecutive nights. Bioassays, using the WHO cone-method, were carried out in 80 HHs (40 sprayed and 40 unsprayed) to measure the effectiveness of the insecticide on sprayed surfaces.

Results

Of the 544 spraymen interviewed pre-IRS, 60%, 3% and 37% had received training for one, two and three days respectively. During spraying activities, 64% of the spraying squads had a supervisor in 4 upazilas but only one upazila (Mukthagacha) achieved 100% supervision of squads. Overall, 72.8% of the spraying squads in the study upazilas had informed HHs members to prepare their houses prior to spraying. The required personal protective equipment was not provided by the national programme during our observations and the spraying techniques used by all sprayers were sub-standard compared to the standard procedure mentioned in the M&E toolkit. In the HH interviews, 94.8% of the 600 respondents said that all their living rooms and cattle sheds had been sprayed. Regarding the effectiveness measurements (i.e. reduction of vector densities), a total of 4132 sand flies were trapped in three intervals, of which 3310 (80.1%) were P. argentipes; 46.5% (1540) males and 53.5% (1770) females. At one month post-IRS, P. argentipes densities were reduced by 22.5% but the 5 months post-IRS reduction was only 6.4% for both male and female. The bioassay tests showed a mean corrected mortality of P. argentipes sand flies at one month post-IRS of 87.3% which dropped to 74.5% at 4 months post-IRS in three upazilas, which is below the WHO threshold level (80%).

Conclusion

The national programme should conduct monitoring and evaluation activities to ensure high quality of IRS operations as a pre-condition for achieving a fast and sustained reduction in vector densities. This will continue to be important during the maintenance phase of VL elimination on the Indian subcontinent. Further research is needed to determine other suitable vector control option(s) when the case numbers are very low.

Stress susceptibility in <i>Trypanosoma brucei</i> lacking the RNA-binding protein ZC3H30

1 October 2018 - 9:00pm

by Chaitali Chakraborty, Christine Clayton

Trypanosomes rely on post-transcriptional mechanisms and mRNA-binding proteins for control of gene expression. Trypanosoma brucei ZC3H30 is an mRNA-binding protein that is expressed in both the bloodstream form (which grows in mammals) and the procyclic form (which grows in the tsetse fly midgut). Attachment of ZC3H30 to an mRNA causes degradation of that mRNA. Cells lacking ZC3H30 showed no growth defect under normal culture conditions; but they were more susceptible than wild-type cells to heat shock, starvation, and treatment with DTT, arsenite or ethanol. Transcriptomes of procyclic-form trypanosomes lacking ZC3H30 were indistinguishable from those of cells in which ZC3H30 had been re-expressed, but un-stressed bloodstream forms lacking ZC3H30 had about 2-fold more HSP70 mRNA. Results from pull-downs suggested that ZC3H30 mRNA binding may not be very specific. ZC3H30 was found in stress-induced granules and co-purified with another stress granule protein, Tb927.8.3820; but RNAi targeting Tb927.8.3820 did not affect either ZC3H30 granule association or stress resistance. The conservation of the ZC3H30 gene in both monogenetic and digenetic kinetoplastids, combined with the increased stress susceptibility of cells lacking it, suggests that ZC3H30 confers a selective advantage in the wild, where the parasites are subject to temperature fluctuations and immune attack in both the insect and mammalian hosts.

Knowledge, attitudes and practices about human African trypanosomiasis and their implications in designing intervention strategies for Yei county, South Sudan

1 October 2018 - 9:00pm

by Salome A. Bukachi, Angeline A. Mumbo, Ayak C. D. Alak, Wilson Sebit, John Rumunu, Sylvain Biéler, Joseph M. Ndung'u

Background

A clear understanding of the knowledge, attitudes and practices (KAP) of a particular community is necessary in order to improve control of human African trypanosomiasis (HAT).New screening and diagnostic tools and strategies were introduced into South Sudan, as part of integrated delivery of primary healthcare. Knowledge and awareness on HAT, its new/improved screening and diagnostic tools, the places and processes of getting a confirmatory diagnosis and treatment are crucial to the success of this strategy.

Methodology

A KAP survey was carried out in Yei County, South Sudan, to identify gaps in community KAP and determine the preferred channels and sources of information on the disease. The cross-sectional KAP survey utilized questionnaires, complemented with key informant interviews and a focus group discussion to elicit communal as well as individual KAP on HAT.

Findings

Most (90%) of the respondents had general knowledge on HAT. Lower levels of education, gender and geographic locations without a history of HAT interventions were associated with incorrect knowledge and/or negative perceptions about the treatability of HAT. Symptoms appearing in the late stage were best known. A majority (97.2%) would seek treatment for HAT only in a health centre. However, qualitative data indicates that existing myths circulating in the popular imagination could influence people’s practices. Seventy-one percent of the respondents said they would offer social support to patients with HAT but qualitative data highlights that stigma still exists. Misconceptions and stigma can negatively influence the health seeking behaviour of HAT cases. In relation to communication, the top preferred and effective source of communication was radio (24%).

Conclusion

Gaps in relation to KAP on HAT still exist in the community. Perceptions on HAT, specifically myths and stigma, were key gaps that need to be bridged through effective education and communication strategies for HAT control alongside other interventions.

Bile acids drive chemotaxis of <i>Clonorchis sinensis</i> juveniles to the bile duct

1 October 2018 - 9:00pm

by Shunyu Li, Won Gi Yoo, Jin-Ho Song, Tae Im Kim, Sung-Jong Hong

Clonorchiasis is a neglected tropical disease caused by Chinese liver fluke, Clonorchis sinensis infection. C. sinensis is a biological carcinogen causing cholangiocarcinoma in humans. In the mammalian host, C. sinensis newly excysted juveniles (CsNEJs) migrate from the duodenum into the bile duct. Bile drives the chemotactic behavior of CsNEJs. Little is known about which components of bile induce the chemotaxis. We designed a chemotaxis assay panel and measured the chemotactic behavior of CsNEJs in response to bile or bile acids. The CsNEJs migrated toward 0.1–1% bile but away from 5–10% bile. The CsNEJs showed strong chemoattraction to cholic acid ≥25 mM, but chemorepulsion to lithocholic acid ≥0.25 mM. To the CsNEJs, mixture of cholic acid and lithocholic acid was chemoattractive at a ratio greater than 25:1 but chemorepulsive at one smaller than that. Regarding migration in the mammalian hosts, high concentration of lithocholic acid in the gallbladder bile may repel CsNEJs from entering it. However, bile in the hepatic bile duct has a chemoattractive strength of cholic acid but a trace amount of lithocholic acid. Collectively, our results explain why the CsNEJs migrate principally to the hepatic bile ducts, bypassing the gallbladder.

STLV-1 co-infection is correlated with an increased SFV proviral load in the peripheral blood of SFV/STLV-1 naturally infected non-human primates

1 October 2018 - 9:00pm

by Sandrine Alais, Amandine Pasquier, Brice Jegado, Chloé Journo, Réjane Rua, Antoine Gessain, Joelle Tobaly-Tapiero, Romain Lacoste, Jocelyn Turpin, Renaud Mahieux

Simian T-Leukemia Virus type 1 and Simian Foamy Virus infect non-human primates. While STLV-1, as HTLV-1, causes Adult T-cell Leukemia/lymphoma, SFV infection is asymptomatic. Both retroviruses can be transmitted from NHPs to humans through bites that allow contact between infected saliva and recipient blood. Because both viruses infect CD4+ T-cells, they might interfere with each other replication, and this might impact viral transmission. Impact of STLV-1 co-infection on SFV replication was analyzed in 18 SFV-positive/STLV-1-negative and 18 naturally SFV/STLV-1 co-infected Papio anubis. Even if 9 animals were found STLV-1-positive in saliva, STLV-1 PVL was much higher in the blood. SFV proviruses were detected in the saliva of all animals. Interestingly, SFV proviral load was much higher in the blood of STLV-1/SFV co-infected animals, compared to STLV-1-negative animals. Given that soluble Tax protein can enter uninfected cells, we tested its effect on foamy virus promoter and we show that Tax protein can transactivate the foamy LTR. This demonstrates that true STLV-1 co-infection or Tax only has an impact on SFV replication and may influence the ability of the virus to be zoonotically transmitted as well as its ability to promote hematological abnormalities.

Use of structural equation models to predict dengue illness phenotype

1 October 2018 - 9:00pm

by Sangshin Park, Anon Srikiatkhachorn, Siripen Kalayanarooj, Louis Macareo, Sharone Green, Jennifer F. Friedman, Alan L. Rothman

Background

Early recognition of dengue, particularly patients at risk for plasma leakage, is important to clinical management. The objective of this study was to build predictive models for dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) using structural equation modelling (SEM), a statistical method that evaluates mechanistic pathways.

Methods/Findings

We performed SEM using data from 257 Thai children enrolled within 72 h of febrile illness onset, 156 with dengue and 101 with non-dengue febrile illnesses. Models for dengue, DHF, and DSS were developed based on data obtained three and one day(s) prior to fever resolution (fever days -3 and -1, respectively). Models were validated using data from 897 subjects who were not used for model development. Predictors for dengue and DSS included age, tourniquet test, aspartate aminotransferase, and white blood cell, % lymphocytes, and platelet counts. Predictors for DHF included age, aspartate aminotransferase, hematocrit, tourniquet test, and white blood cell and platelet counts. The models showed good predictive performances in the validation set, with area under the receiver operating characteristic curves (AUC) at fever day -3 of 0.84, 0.67, and 0.70 for prediction of dengue, DHF, and DSS, respectively. Predictive performance was comparable using data based on the timing relative to enrollment or illness onset, and improved closer to the critical phase (AUC 0.73 to 0.94, 0.61 to 0.93, and 0.70 to 0.96 for dengue, DHF, and DSS, respectively).

Conclusions

Predictive models developed using SEM have potential use in guiding clinical management of suspected dengue prior to the critical phase of illness.

Quantification of dengue virus specific T cell responses and correlation with viral load and clinical disease severity in acute dengue infection

1 October 2018 - 9:00pm

by Dulharie T. Wijeratne, Samitha Fernando, Laksiri Gomes, Chandima Jeewandara, Anushka Ginneliya, Supun Samarasekara, Ananda Wijewickrama, Clare S. Hardman, Graham S. Ogg, Gathsaurie Neelika Malavige

Background

In order to understand the role of dengue virus (DENV) specific T cell responses that associate with protection, we studied their frequency and phenotype in relation to clinical disease severity and resolution of viraemia in a large cohort of patients with varying severity of acute dengue infection.

Methodology/Principal findings

Using ex vivo IFNγ ELISpot assays we determined the frequency of dengue viral peptide (DENV)-NS3, NS1 and NS5 responsive T cells in 74 adult patients with acute dengue infection and examined the association of responsive T cell frequency with the extent of viraemia and clinical disease severity. We found that total DENV-specific and DENV-NS3-specific T cell responses, were higher in patients with dengue fever (DF), when compared to those with dengue haemorrhagic fever (DHF). In addition, those with DF had significantly higher (p = 0.02) DENV-specific T cell responses on day 4 of infection compared to those who subsequently developed DHF. DENV peptide specific T cell responses inversely correlated with the degree of viraemia, which was most significant for DENV-NS3 specific T cell responses (Spearman’s r = -0.47, p = 0.0003). The frequency of T cell responses to NS1, NS5 and pooled DENV peptides, correlated with the degree of thrombocytopenia but had no association with levels of liver transaminases. In contrast, total DENV-IgG inversely correlated with the degree of thrombocytopenia and levels of liver transaminases.

Conclusions/Significance

Early appearance of DENV-specific T cell IFNγ responses before the onset of plasma leakage, appears to associate with milder clinical disease and resolution of viraemia, suggesting a protective role in acute dengue infection.

Isosorbide and nifedipine for Chagas' megaesophagus: A systematic review and meta-analysis

28 September 2018 - 9:00pm

by Celina Borges Migliavaca, Cinara Stein, Verônica Colpani, Sandro René Pinto de Sousa Miguel, Luciane Nascimento Cruz, Roberto Oliveira Dantas, Maicon Falavigna

Background

Chagas disease is a neglected tropical disease. About 6 to 8 million people are chronically infected and 10% to 15% develop irreversible gastrointestinal disorders, including megaesophagus. Treatment focuses on improving symptoms, and isosorbide and nifedipine may be used for this purpose.

Methodology

We conducted a systematic review to evaluate the effectiveness of pharmacological treatment for Chagas’ megaesophagus. We searched MEDLINE, Embase and LILACS databases up to January 2018. We included both observational studies and RCTs evaluating the effects of isosorbide or nifedipine in adult patients with Chagas’ megaesophagus. Two reviewers screened titles and abstracts, selected eligible studies and extracted data. We assessed the risk of bias using NIH ‘Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group’ and RoB 2.0 tool. Overall quality of evidence was assessed using GRADE.

Principal findings

We included eight studies (four crossover RCTs, four before-after studies). Three studies evaluated the effect of isosorbide on lower esophageal sphincter pressure (LESP), showing a significant reduction (mean difference −10.52mmHg, 95%CI −13.57 to−7.47, very low quality of evidence). Three studies reported the effect of isosorbide on esophageal emptying, showing a decrease in esophageal retention rates (mean difference −22.16%, 95%CI −29.94 to −14.38, low quality of evidence). In one study, patients on isosorbide reported improvement in the frequency and severity of dysphagia (moderate quality of evidence). Studies evaluating nifedipine observed a decrease in LESP but no effect on esophageal emptying (very low and low quality of evidence, respectively). Isosorbide had a higher incidence of headache as a side effect than nifedipine.

Conclusions

Although limited, available evidence shows that both isosorbide and nifedipine are effective in reducing esophageal symptoms. Isosorbide appears to be more effective, and its use is supported by a larger number of studies; nifedipine, however, appears to have a better tolerability profile.

Trial registration

PROSPERO CRD42017055143.ClinicalTrials.gov CRD42017055143.

Chagas disease mortality in Brazil: A Bayesian analysis of age-period-cohort effects and forecasts for two decades

28 September 2018 - 9:00pm

by Taynãna Simões, Laiane Borges, Auzenda Assis, Maria Vitórias Silva, Juliano dos Santos, Karina Meira

Background

Chagas disease (CD) is a neglected chronic parasitic infection and a public health problem that is preventable, and has serious complications. In this study, the effects of age, period and birth cohort (APC Effects) on the evolution of the mortality of that disease in Brazil, from 1980–2014, according to sex and geographic region of the country, were analyzed. Mortality forecasts from the years 2015 to 2034 were estimated.

Methods

This is an ecological cross-sectional study in which death records and population data were extracted from the DATASUS (Department of Information Technology of the National Health System) website, in age groups from 20–24 years of age to 80 years and over, from 1980 to 2014. The rates were standardized according to age and sex distributions using the direct method. The APC models were estimated using the Bayesian approach, and the INLA (Integrated Nested Laplace Approximations) method was used for parameter inference. Super dispersion of the data was considered, and we included unstructured random terms in the models.

Results

During the analyzed period, there were 178,823 deaths in Brazil (3.85 annual deaths per 100,000 inhabitants). It was found that temporal effects on CD mortality varied by sex and region. In general, there was an increase in mortality rates up to 30 years of age, and the mortality rates were higher between 50 and 64 years of age. On average, men died five years younger than women. Mortality rates were highest in the Central West and Southeast regions. The Central West, Southeast and Southern regions had a reduction over time in the rate of CD deaths between 2000 and 2014. The mortality rate in the Northeast was not statistically different in any period analyzed, while the North had tendency to increase; however, a significant risk increase was only observed between 1995 and 1999. The rate of mortality was high in older birth cohorts. The overall prediction for the next two decades showed a progressive decline in CD mortality, which will be highest among the young. The expected average reduction was 76.1% compared to the last observed period (2010–2014) and the last predicted (2030–2034) period. The average reduction ranged from 86% in the 20–24 age group to 50% in the 80 and over age group.

Conclusions

In the present study, a higher death rate was observed for ages above 30 years, especially 50 to 64 years, and in the older birth cohorts. We believe these results can be related to period effects of vector control actions and preventive and care measures by the health system of Brazil, in addition to demographic changes in the period. The differences among the regions reflect socioeconomic inequities and access to the healthcare systems in the Brazilian population.

Using the health belief model to identify communication opportunities to prevent Chagas disease in Southern Ecuador

27 September 2018 - 9:00pm

by Nelson M. Patterson, Benjamin R. Bates, Amy E. Chadwick, Claudia Nieto-Sanchez, Mario J. Grijalva

Background

Chagas disease (CD) is a life-threatening illness caused by the protozoan parasite Trypanosoma cruzi, which is transmitted by triatomine bugs. Triatomine bugs inhabit poorly constructed homes that create multiple hiding spots for the bugs. Modifying the actual structure of a home, along with the homeowners’ practices, can reduce triatomine infestation. This research was designed to collect culturally-relevant information to develop a health campaign to decrease risk of CD transmission by promoting home maintenance and better hygiene in rural communities of southern Ecuador.

Methods and main findings

The Health Belief Model (HBM) guided focus group discussions and the interpretation of the results. Four focus groups ranging from 4 to 10 participants were conducted between May and June 2014 in three communities of Loja province in Southern Ecuador. A thematic analysis was used to identify within the data related to perceptions of susceptibility, severity, benefits, barriers and self-efficacy related to CD and its prevention. The results provide clear guidance for the development of Chagas-prevention messages.

Conclusion

Data obtained emphasize the importance of standardizing messages presented to the communities for CD prevention. Messages should provide more information on the protective nature of the behaviors promoted for CD prevention; overcoming barriers such as cost and convenience, and build on facilitating factors, including community members’ interest on quality of life, protection of their families, and relationship with the land.

Secreted aspartyl proteinase (PbSap) contributes to the virulence of <i>Paracoccidioides brasiliensis</i> infection

27 September 2018 - 9:00pm

by Daniele Gonçalves Castilho, Alison Felipe Alencar Chaves, Marina Valente Navarro, Palloma Mendes Conceição, Karen Spadari Ferreira, Luiz Severino da Silva, Patricia Xander, Wagner Luiz Batista

Paracoccidioidomycosis (PCM) is the most prevalent deep mycosis in Latin America and is caused by fungi from the Paracoccidioides genus. Virulence factors are important fungal characteristics that support the development of disease. Aspartyl proteases (Saps) are virulence factors in many human fungal pathogens that play an important role in the host invasion process. We report here that immunization with recombinant Sap from Paracoccidioides brasiliensis (rPbSap) imparted a protective effect in an experimental PCM model. The rPbSap-immunized mice had decreased fungal loads, and their lung parenchyma were notably preserved. An aspartyl protease inhibitor (pepstatin A) significantly decreased pulmonary injury and reduced fungal loads in the lung. Additionally, we observed that pepstatin A enhanced the fungicidal and phagocytic profile of macrophages against P. brasiliensis. Furthermore, PbSAP expression was highly altered by environmental conditions, including thermal stress, dimorphism switching and low pH. Hence, our data suggest that PbSap is an important virulence regulator in P. brasiliensis.

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