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We developed a novel and portable fluorescent sensor that integrates a lateral flow assay with a quantum dot (Qdots) label and a mobile phone reader for detection of specific antibodies in human serum. We evaluated the utility of this assay to test for antibodies to the Taenia solium rT24H antigen. It was a retrospective study by examining 112 positive human sera from patients with neurocysticercosis (NCC) including samples from patients with single viable cyst (n = 18), two or more viable cysts (n = 71), and subarachnoid (racemose) cysts (n = 23). These samples were collected from previous study subjects in Lima, Peru that conducted under an approved study protocol in Peru. The sera were made anonymous under a protocol approved by the CDC Institutional Review Board. Definitive diagnosis of the specimen was established by computed-tomography and/or magnetic resonance imaging. To test the specificity of the assay, we evaluated a panel of serum samples obtained from patients with other infections (n = 24), and serum samples from persons in the United States and Egypt who had not traveled outside their country, and therefore are presumed negative for cysticercosis (n = 128). The assay specificity in the negative panel was 99% (95–100%) while assay sensitivity was 89% (79–95%) in NCC patients with two or more viable cysts. Our assay has performance characteristics similar to those of traditional platforms for the detection of NCC and shows promise as a mobile phone reader-based point-of-care test for antibody detection. [ABSTRACT FROM AUTHOR]

Introduction: Epidemic forecasting and prediction tools have the potential to provide actionable information in the midst of emerging epidemics. While numerous predictive studies were published during the 2016–2017 Zika Virus (ZIKV) pandemic, it remains unknown how timely, reproducible, and actionable the information produced by these studies was. Methods: To improve the functional use of mathematical modeling in support of future infectious disease outbreaks, we conducted a systematic review of all ZIKV prediction studies published during the recent ZIKV pandemic using the PRISMA guidelines. Using MEDLINE, EMBASE, and grey literature review, we identified studies that forecasted, predicted, or simulated ecological or epidemiological phenomena related to the Zika pandemic that were published as of March 01, 2017. Eligible studies underwent evaluation of objectives, data sources, methods, timeliness, reproducibility, accessibility, and clarity by independent reviewers. Results: 2034 studies were identified, of which n = 73 met the eligibility criteria. Spatial spread, R0 (basic reproductive number), and epidemic dynamics were most commonly predicted, with few studies predicting Guillain-Barré Syndrome burden (4%), sexual transmission risk (4%), and intervention impact (4%). Most studies specifically examined populations in the Americas (52%), with few African-specific studies (4%). Case count (67%), vector (41%), and demographic data (37%) were the most common data sources. Real-time internet data and pathogen genomic information were used in 7% and 0% of studies, respectively, and social science and behavioral data were typically absent in modeling efforts. Deterministic models were favored over stochastic approaches. Forty percent of studies made model data entirely available, 29% provided all relevant model code, 43% presented uncertainty in all predictions, and 54% provided sufficient methodological detail to allow complete reproducibility. Fifty-one percent of predictions were published after the epidemic peak in the Americas. While the use of preprints improved the accessibility of ZIKV predictions by a median of 119 days sooner than journal publication dates, they were used in only 30% of studies. Conclusions: Many ZIKV predictions were published during the 2016–2017 pandemic. The accessibility, reproducibility, timeliness, and incorporation of uncertainty in these published predictions varied and indicates there is substantial room for improvement. To enhance the utility of analytical tools for outbreak response it is essential to improve the sharing of model data, code, and preprints for future outbreaks, epidemics, and pandemics. [ABSTRACT FROM AUTHOR]

This study aimed to assess the impact of the Zika epidemic on the registration of birth defects in Brazil. We used an interrupted time series analysis design to identify changes in the trends in the registration of congenital anomalies. We obtained monthly data from Brazilian Live Birth Information System and used two outcome definitions: 1) rate of congenital malformation of the brain and eye (likely to be affected by Zika and its complications) 2) rate of congenital malformation not related to the brain or eye unlikely to be causally affected by Zika. The period between maternal infection with Zika and diagnosis of congenital abnormality attributable to the infection is around six months. We therefore used September 2015 as the interruption point in the time series, six months following March 2015 when cases of Zika started to increase. For the purposes of this analysis, we considered the period from January 2010 to September 2015 to be “pre-Zika event,” and the period from just after September 2015 to December 2017 to be “post-Zika event.” We found that immediately after the interruption point, there was a great increase in the notification rate of congenital anomalies of 14.9/10,000 live births in the brain and eye group and of 5.2/10,000 live births in the group not related with brain or eye malformations. This increase in reporting was in all regions of the country (except in the South) and especially in the Northeast. In the period “post-Zika event”, unlike the brain and eye group which showed a monthly decrease, the group without brain or eye malformations showed a slow but significant increase (relative to the pre-Zika trend) of 0.2/10,000 live births. These findings suggest an overall improvement in the registration of birth malformations, including malformations that were not attributed to Zika, during and after the Zika epidemic. [ABSTRACT FROM AUTHOR]

Long term surveillance of vectors and arboviruses is an integral aspect of disease prevention and control systems in countries affected by increasing risk. Yet, little effort has been made to adjust space-time risk estimation by integrating disease case counts with vector surveillance data, which may result in inaccurate risk projection when several vector species are present, and when little is known about their likely role in local transmission. Here, we integrate 13 years of dengue case surveillance and associated Aedes occurrence data across 462 localities in 63 districts to estimate the risk of infection in the Republic of Panama. Our exploratory space-time modelling approach detected the presence of five clusters, which varied by duration, relative risk, and spatial extent after incorporating vector species as covariates. The Ae. aegypti model contained the highest number of districts with more dengue cases than would be expected given baseline population levels, followed by the model accounting for both Ae. aegypti and Ae. albopictus. This implies that arbovirus case surveillance coupled with entomological surveillance can affect cluster detection and risk estimation, potentially improving efforts to understand outbreak dynamics at national scales. [ABSTRACT FROM AUTHOR]

Background: Helminthiases are a group of disabling neglected tropical diseases that affect billions of people worldwide. Current control methods use preventative chemotherapy but reinfection is common and an inter-sectoral approach is required if elimination is to be achieved. Household and community scale water treatment can be used to provide a safe alternative water supply for contact activities, reducing exposure to WASH (water, sanitation, and hygiene) -related helminths. With the introduction of ultraviolet light emitting diodes (UV-C LEDs), ultraviolet (UV) disinfection could be a realistic option for water treatment in low-income regions in the near future, to provide safe alternative water supplies for drinking and contact activities such as handwashing, bathing, and laundry, but currently there is no guidance for the use of UV or solar disinfection against helminths. Methodology: A qualitative systematic review of existing literature was carried out to establish which WASH-related helminths are more susceptible to UV disinfection and identify gaps in research to inform future studies. The search included all species that can infect humans and can be transmitted through water or wastewater. Five online databases were searched and results were categorized based on the UV source: sunlight and solar simulators, UV-A and UV-B (long wavelength) sources, and UV-C (germicidal) sources. Conclusions: There has been very little research into the UV sensitivity of helminths; only 47 studies were included in this review and the majority were carried out before the standard protocol for UV disinfection experiments was published. Only 18 species were studied; however all species could be inactivated by UV light. Fluences required to achieve a 1-log inactivation ranged from 5 mJ/cm2 to over 800 mJ/cm2. Larval forms were generally more sensitive to UV light than species which remain as an egg in the environment. This review confirms that further research is required to produce detailed recommendations for household or community scale UV-C LED or solar disinfection (SODIS) of water for preventing helminthiases. [ABSTRACT FROM AUTHOR]

Dengue is one of the most serious mosquito-borne infectious diseases in the world. Aedes albopictus is the most invasive mosquito and one of the primary vectors of dengue. Vector control using insecticides is the only viable strategy to prevent dengue virus transmission. In Guangzhou, after the 2014 pandemic, massive insecticides have been implemented. Massive insecticide use may lead to the development of resistance, but few reports are available on the status of insecticide resistance in Guangzhou after 2014. In this study, Ae. albopictus were collected from four districts with varied dengue virus transmission intensity in Guangzhou from 2015 to 2017. Adult Ae. albopictus insecticide susceptibility to deltamethrin (0.03%), permethrin(0.25%), DDT(4%), malathion (0.8%) and bendiocarb (0.1%) was determined by the standard WHO tube test, and larval resistance bioassays were conducted using temephos, Bacillus thuringiensis israelensis (Bti), pyriproxyfen (PPF) and hexaflumuron. Mutations at the voltage-gated sodium channel (VGSC) gene and acetylcholinesterase (AChE) gene were analyzed. The effect of cytochrome P450s on the resistance of Ae. albopictus to deltamethrin was tested using the synergistic agent piperonyl butoxide (PBO). The results showed that Ae. albopictus populations have rapidly developed very high resistances to multiple commonly used insecticides at all study areas except malathion, Bti and hexaflumuron. We found 1534 codon mutations in the VGSC gene that were significantly correlated with the resistance to pyrethroids and DDT, and 11 synonymous mutations were also found in the gene. The resistance to deltamethrin can be significantly reduced by PBO but may generated cross-resistance to PPF. Fast emerging resistance in Ae. albopictus may affect mosquito management and threaten the prevention and control of dengue, similar to the resistance in Anopheles mosquitoes has prevented the elimination of malaria and call for timely and guided insecticide management. [ABSTRACT FROM AUTHOR]

Background: Identification of blood sources of hematophagous arthropods is crucial for understanding the transmission cycles of vector-borne diseases. Many different approaches towards host determination were proposed, including precipitin test, ELISA, DNA- and mass spectrometry-based methods; yet all face certain complications and limitations, mostly related to blood degradation. This study presents a novel method for blood meal identification, peptide mass mapping (PMM) analysis of host-specific hemoglobin peptides using MALDI-TOF mass spectrometry. Methodology/Principal findings: To identify blood meal source, proteins from abdomens of engorged sand fly females were extracted, cleaved by trypsin and peptide fragments of host hemoglobin were sequenced using MALDI-TOF MS. The method provided correct host identification of 100% experimentally fed sand flies until 36h post blood meal (PBM) and for 80% samples even 48h PBM. In females fed on two hosts, both blood meal sources were correctly assigned for 60% of specimens until 36h PBM. In a validation study on field-collected females, the method yielded unambiguous host determination for 96% of specimens. The suitability of PMM-based MALDI-TOF MS was proven experimentally also on lab-reared Culex mosquitoes. Conclusions/Significance: PMM-based MALDI-TOF MS analysis targeting host specific hemoglobin peptides represents a sensitive and cost-effective method with a fast and simple preparation protocol. As demonstrated here on phlebotomine sand flies and mosquitoes, it allows reliable and rapid blood source determination even 48h PBM with minimal material input and provides more robust and specific results than other currently used methods. This approach was also successfully tested on field-caught engorged females and proved to be a promising useful tool for large-scale screening of host preferences studies. Unlike other methods including MALDI-TOF protein profiling, it allows correct identification of mixed blood meals as was demonstrated on both experimentally fed and field-collected sand flies. [ABSTRACT FROM AUTHOR]

A subpopulation of the arctic fox lineage of rabies virus has circulated extensively in red fox populations of Ontario, Canada, between the 1960s and 1990s. An intensive wildlife rabies control program, in which field operations were initiated in 1989, resulted in elimination of the disease in eastern Ontario. However in southwestern Ontario, as numbers of rabid foxes declined the proportion of skunks confirmed to be infected with this rabies virus variant increased and concerted control efforts targeting this species were employed to eliminate the disease. Since 2012 no cases due to this viral variant were reported in southwestern Ontario until 2015 when a single case of rabies due to the arctic fox variant was reported in a bovine. Several additional cases have been documented subsequently. Since routine antigenic typing cannot discriminate between the variants which previously circulated in Ontario and those from northern Canada it was unknown whether these recent cases were the result of a new introduction of this variant or a continuation of the previous enzootic. To explore the origins of this new outbreak whole genome sequences of a collection of 128 rabies viruses recovered from Ontario between the 1990s to the present were compared with those representative of variants circulating in the Canadian north. Phylogenetic analysis shows that the variant responsible for current cases in southwestern Ontario has evolved from those variants known to circulate in Ontario previously and is not due to a new introduction from northern regions. Thus despite ongoing passive surveillance the persistence of wildlife rabies went undetected in the study area for almost three years. The apparent adaptation of this rabies virus variant to the skunk host provided the opportunity to explore coding changes in the viral genome which might be associated with this host shift. Several such changes were identified including a subset for which the operation of positive selection was supported. The location of a small number of these amino acid substitutions in or close to protein motifs of functional importance suggests that some of them may have played a role in this host shift. [ABSTRACT FROM AUTHOR]

Background: Although trachoma causes more cases of preventable blindness than any other infectious disease, a combination of strategies is reducing its global prevalence. As a district moves toward eliminating trachoma as a public health problem, national programs conduct trachoma impact surveys (TIS) to assess whether to stop preventative interventions and trachoma surveillance surveys (TSS) to determine whether the prevalence of active trachoma has rebounded after interventions have halted. In some contexts, programs also conduct trachomatous trichiasis (TT)-only surveys. A few costing studies of trachoma prevalence surveys exist, but none examine TIS, TSS, or TT-only surveys. Methodology/Principal findings: We assessed the incremental financial cost to the national program of TIS, TSS, and TT-only surveys, which are standardized cluster-sampled prevalence surveys. We conducted a retrospective review of expenditures and grant disbursements for TIS and TSS in 322 evaluation units in 11 countries between 2011 and 2018. We also assessed the costs of three pilot and five standard TT-only surveys in four countries between 2017 and 2018. The median cost of TIS and TSS was $8,298 per evaluation unit [interquartile range (IQR): $6,532–$10,111, 2017 USD]. Based on a linear regression with bootstrapped confidence intervals, after controlling for country, costs per survey did not change significantly over time but did decline by $83 per survey implemented in a single round (95% CI: -$108 –-$63). Of total costs, 80% went to survey fieldwork; of that, 58% went towards per diems and 38% towards travel. TT-only surveys cost a median of $9,707 (IQR: $8,537–$11,635); within a given country, they cost slightly more (106% [IQR: 94%–136%]) than TIS and TSS. Conclusions/Significance: The World Health Organization requires trachoma prevalence estimates for validating the elimination of trachoma as a public health problem. This study will help programs improve their planning as they assemble resources for that effort. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is a re-emerging arbovirus known to cause chronic myalgia and arthralgia with high morbidity. CHIKV is now considered endemic in many countries across Asia and Africa. In this study, the susceptibility of various human, mammalian and mosquito cell lines to CHIKV infection was evaluated. CHIKV infection was found to be cell-type dependent and virus strain-specific. Furthermore, SJCRH30 (human rhabdomyosarcoma cell line) was showed to be highly permissive to CHIKV infection, with maximum production of infectious virions observed at 12 h.p.i. Pre-infection treatment of SJCRH30 with various inhibitors of endocytosis, including monodansylcadaverine (receptor-mediated endocytic inhibitor), dynasore (clathrin-mediated endocytic inhibitor), as well as filipin (caveolin-mediated endocytosis inhibitor), resulted in minimal inhibition of CHIKV infection. In contrast, dose-dependent inhibition of CHIKV infection was observed with the treatment of macropinocytosis inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA). Furthermore, siRNA-mediated knockdown of sortin nexin 9 (SNX9) a protein involved in macropinosome formation, also resulted in a significant dose-dependent reduction in viral titre. By performing a virus entry assay, CHIKV particles were also observed to colocalize with FITC-dextran, a macropinosome marker. This study shows for the first time, that the infectious entry of CHIKV into human muscle cells is mediated by macropinocytosis. Together, the data from this study may pave the way for the development of specific inhibitors that target the entry process of CHIKV into cells. [ABSTRACT FROM AUTHOR]

Background: Amoebiasis, caused by Entamoeba histolytica infection, is a global public health problem. However, available drugs to treat amoebiasis are currently limited, and no effective vaccine exists. Therefore, development of new preventive measures against amoebiasis is urgently needed. Methodology/Principal findings: Here, to develop new drugs against amoebiasis, we focused on E. histolytica adenosine 5′-phosphosulfate kinase (EhAPSK), an essential enzyme in Entamoeba sulfolipid metabolism. Fatty alcohol disulfates and cholesteryl sulfate, sulfolipids synthesized in Entamoeba, play important roles in trophozoite proliferation and cyst formation. These processes are closely associated with clinical manifestation and severe pathogenesis of amoebiasis and with disease transmission, respectively. We validated a combination approach of in silico molecular docking analysis and an in vitro enzyme activity assay for large scale screening. Docking simulation ranked the binding free energy between a homology modeling structure of EhAPSK and 400 compounds. The 400 compounds were also screened by a 96-well plate-based in vitro APSK activity assay. Among fifteen compounds identified as EhAPSK inhibitors by the in vitro system, six were ranked by the in silico analysis as having high affinity toward EhAPSK. Furthermore, 2-(3-fluorophenoxy)-N-[4-(2-pyridyl)thiazol-2-yl]-acetamide, 3-phenyl-N-[4-(2-pyridyl)thiazol-2-yl]-imidazole-4-carboxamide, and auranofin, which were identified as EhAPSK inhibitors by both in silico and in vitro analyses, halted not only Entamoeba trophozoite proliferation but also cyst formation. These three compounds also dose-dependently impaired the synthesis of sulfolipids in E. histolytica. Conclusions/Significance: Hence, the combined approach of in silico and in vitro-based EhAPSK analyses identified compounds that can be evaluated for their effects on Entamoeba. This can provide leads for the development of new anti-amoebic and amoebiasis transmission-blocking drugs. This strategy can also be applied to identify specific APSK inhibitors, which will benefit research into sulfur metabolism and the ubiquitous pathway terminally synthesizing essential sulfur-containing biomolecules. [ABSTRACT FROM AUTHOR]

Background: Changes in climate and environmental conditions could be the driving factors for the transmission of hantavirus. Thus, a thorough collection and analysis of data related to the epidemic status of hemorrhagic fever with renal syndrome (HFRS) and the association between HFRS incidence and meteorological factors, such as air temperature, is necessary for the disease control and prevention. Methods: Journal articles and theses in both English and Chinese from Jan 2014 to Feb 2019 were identified from PubMed, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Data and VIP Info. All identified studies were subject to the six criteria established to ensure the consistency with research objectives, (i) they provided the data of the incidence of HFRS in mainland China; (ii) they provided the type of air temperature indexes; (iii) they indicated the underlying geographical scale information, temporal data aggregation unit, and the data sources; (iv) they provided the statistical analysis method that had been used; (v) from peer-reviewed journals or dissertation; (vi) the time range for the inclusion of data exceeded two consecutive calendar years. Results: A total of 27 publications were included in the systematic review, among them, the correlation between HFRS activity and air temperature was explored in 12 provinces and autonomous regions and also at national level. The study period ranged from 3 years to 54 years with a median of 10 years, 62.3% of the studies were based on the monthly HFRS incidence data, 21 studies considered the lagged effect of air temperature factors on the HFRS activity and the longest lag period considered in the included studies was 34 weeks. The correlation between HFRS activity and air temperature varied widely, and the effect of temperature on the HFRS epidemic was seasonal. Conclusions: The present systematic review described the heterogeneity of geographical scale, data aggregation unit and study period chosen in the ecological studies that seeking the correlation between air temperature indexes and the incidence of HFRS in mainland China during the period from January 2014 to February 2019. The appropriate adoption of geographical scale, data aggregation unit, the length of lag period and the length of incidence collection period should be considered when exploring the relationship between HFRS incidence and meteorological factors such as air temperature. Further investigation is warranted to detect the thresholds of meteorological factors for the HFRS early warning purposes, to measure the duration of lagged effects and determine the timing of maximum effects for reducing the effects of meteorological factors on HFRS via continuous interventions and to identify the vulnerable populations for target protection. [ABSTRACT FROM AUTHOR]

Buruli Ulcer (BU) is a cutaneous disease caused by Mycobacterium ulcerans. The pathogenesis of this disease is closely related to the secretion of the toxin mycolactone that induces extensive destruction of the skin and soft tissues. Currently, there are no effective measures to prevent the disease and, despite availability of antibiotherapy and surgical treatments, these therapeutic options are often associated with severe side effects. Therefore, it is important to develop alternative strategies for the treatment of BU. Endolysins (lysins) are phage encoded enzymes that degrade peptidoglycan of bacterial cell walls. Over the past years, lysins have been emerging as alternative antimicrobial agents against bacterial infections. However, mycobacteria have an unusual outer membrane composed of mycolylarabinogalactan-peptidoglycan. To overcome this complex barrier, some mycobacteriophages encode a lipolytic enzyme, Lysin B (LysB). In this study, we demonstrate for the first time that recombinant LysB displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with LysB prevented further bacterial proliferation, associated with IFN-γ and TNF production in the draining lymph node. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease. [ABSTRACT FROM AUTHOR]

Objective: Where human African trypanosomiasis (HAT) patients are seen, failure to microscopically diagnose infections by Trypanosoma brucei gambiense in blood smears and/or cerebrospinal fluid (CSF) in the critical early stages of the disease is the single most important factor in treatment failure, a result of delayed treatment onset or its absence. We hypothesized that the enhanced sensitivity of detergent-enhanced loop-mediated isothermal amplification (LAMP) will allow for point of care (POC) detection of African trypanosomes in the CSF of HAT patients where the probability for detecting a single parasite or parasite DNA molecule in 1 μL of CSF sample is negligible by current methods. Methodology: We used LAMP targeting the multicopy pan-T. brucei repetitive insertion mobile element (RIME LAMP) and the Trypanosoma brucei gambiense 5.8S rRNA-internal transcribed spacer 2 gene (TBG1 LAMP). We tested 1 μL out of 20 μL sham or Triton X-100 treated CSFs from 73 stage-1 and 77 stage-2 HAT patients from the Central African Republic and 100 CSF negative controls. Results: Under sham conditions, parasite DNA was detected by RIME and TBG1 LAMP in 1.4% of the stage-1 and stage-2 gambiense HAT CSF samples tested. After sample incubation with detergent, the number of LAMP parasite positive stage-2 CSF’s increased to 26%, a value which included the 2 of the 4 CSF samples where trypanosomes were identified microscopically. Unexpected was the 41% increase in parasite positive stage-1 CSF’s detected by LAMP. Cohen’s kappa coefficients for RIME versus TBG1 LAMP of 0.92 (95%CI: 0.82–1.00) for stage-1 and 0.90 (95%CI: 0.80–1.00) for stage-2 reflected a high level of agreement between the data sets indicating that the results were not due to amplicon contamination, data confirmed in χ2 tests (p<0.001) and Fisher’s exact probability test (p = 4.7e-13). Conclusion: This study detected genomic trypanosome DNA in the CSF independent of the HAT stage and may be consistent with early CNS entry and other scenarios that identify critical knowledge gaps for future studies. Detergent-enhanced LAMP could be applicable for non-invasive African trypanosome detection in human skin and saliva or as an epidemiologic tool for the determination of human (or animal) African trypanosome prevalence in areas where chronically low parasitemias are present. [ABSTRACT FROM AUTHOR]

Background: Accurate and accessible diagnosis is key for the control of visceral leishmaniasis (VL). Yet, current diagnostic tests for VL have severe limitations: they are invasive or not suitable as point of care (POC) test or their performance is suboptimal in East Africa. We analysed the antigens in the VL serodiagnostics development pipeline to identify shortcomings and to propose strategies in the development of an alternative POC test for VL in East Africa. Objectives: The objective of this study was to identify and to analyse all antigens for VL serodiagnosis that have been published before 2018 in order to identify candidates and gaps in the pipeline for a new POC test in East Africa. Methods: A systematic literature search was performed on PubMed for original research articles on Leishmania-specific antigens for antibody detection of VL in humans. From each article, the following information was extracted: the antigen name, test format and characteristics, its reported sensitivity and specificity and study cohort specifications. Results: One hundred and seven articles containing information about 96 tests based on 89 different antigens were included in this study. Eighty six of these tests, comprising 80 antigens, were evaluated in phase I and II studies only. Only 20 antigens, all of which are native, contain a carbohydrate and/or lipid moiety. Twenty-four antigens, of which 7 are non-native, are composed of antigen mixtures. Nineteen tests, comprising 18 antigens, have been evaluated on East African specimens, of which only 2 (rK28 based immunochromatographic test and intact promastigote based indirect fluorescent antibody technique) consistently showed sensitivities above 94 and specificities above 97% in a phase III study and one in a phase II study (dot blot with SLA). Only rK28 is a non-native mixture of antigens which we consider suitable for further evaluation and implementation. Conclusions: The development pipeline for an alternative serodiagnostic test for VL is almost empty. Most antigens are not sufficiently evaluated. Non-protein antigens and antigen mixtures are being neglected. We propose to expand the evaluation of existing antigen candidates and to investigate the diagnostic potential of defined non-native carbohydrate and lipid antigens for VL serodiagnosis in East Africa. [ABSTRACT FROM AUTHOR]

The metacercariae of the Clonorchis sinensis liver fluke excyst in the duodenum of mammalian hosts, and the newly excysted juveniles (CsNEJs) migrate along the bile duct via bile chemotaxis. Cholic acid is a major component of bile that induces this migration. We investigated the neuronal control of chemotactic behavior of CsNEJs toward cholic acid. The migration of CsNEJs was strongly inhibited at sub-micromolar concentration by dopamine D1 (LE-300 and SKF-83566), D2 (spiramide, nemonapride, and sulpiride), and D3 (GR-103691 and NGB-2904) receptor antagonists, as well as a dopamine reuptake inhibitor (BTCP). Neuropeptides, FMRFamide, peptide YY, and neuropeptide Y were also potent inhibitors of chemotaxis. Meanwhile, serotonergic, glutamatergic, and cholinergic inhibitors did not affect chemotaxis, with the exception of fluoxetine and CNQX. Confocal immunofluorescence analysis indicated that dopaminergic and cholinergic neurons were colocalized in the somatic muscle tissues of adult C. sinensis. Our findings suggest that dopaminergic neurons and neuropeptides play a major role in the chemotactic migration of CsNEJs to bile, and their inhibitors or modulators could be utilized to prevent their migration from the bile duct. [ABSTRACT FROM AUTHOR]

Background: As of February 25, 2019, 875 cases of Ebola virus disease (EVD) were reported in North Kivu and Ituri Provinces, Democratic Republic of Congo. Since the beginning of October 2018, the outbreak has largely shifted into regions in which active armed conflict has occurred, and in which EVD cases and their contacts have been difficult for health workers to reach. We used available data on the current outbreak, with case-count time series from prior outbreaks, to project the short-term and long-term course of the outbreak. Methods: For short- and long-term projections, we modeled Ebola virus transmission using a stochastic branching process that assumes gradually quenching transmission rates estimated from past EVD outbreaks, with outbreak trajectories conditioned on agreement with the course of the current outbreak, and with multiple levels of vaccination coverage. We used two regression models to estimate similar projection periods. Short- and long-term projections were estimated using negative binomial autoregression and Theil-Sen regression, respectively. We also used Gott’s rule to estimate a baseline minimum-information projection. We then constructed an ensemble of forecasts to be compared and recorded for future evaluation against final outcomes. From August 20, 2018 to February 25, 2019, short-term model projections were validated against known case counts. Results: During validation of short-term projections, from one week to four weeks, we found models consistently scored higher on shorter-term forecasts. Based on case counts as of February 25, the stochastic model projected a median case count of 933 cases by February 18 (95% prediction interval: 872–1054) and 955 cases by March 4 (95% prediction interval: 874–1105), while the auto-regression model projects median case counts of 889 (95% prediction interval: 876–933) and 898 (95% prediction interval: 877–983) cases for those dates, respectively. Projected median final counts range from 953 to 1,749. Although the outbreak is already larger than all past Ebola outbreaks other than the 2013–2016 outbreak of over 26,000 cases, our models do not project that it is likely to grow to that scale. The stochastic model estimates that vaccination coverage in this outbreak is lower than reported in its trial setting in Sierra Leone. Conclusions: Our projections are concentrated in a range up to about 300 cases beyond those already reported. While a catastrophic outbreak is not projected, it is not ruled out, and prevention and vigilance are warranted. Prospective validation of our models in real time allowed us to generate more accurate short-term forecasts, and this process may prove useful for future real-time short-term forecasting. We estimate that transmission rates are higher than would be seen under target levels of 62% coverage due to contact tracing and vaccination, and this model estimate may offer a surrogate indicator for the outbreak response challenges. [ABSTRACT FROM AUTHOR]

Targeted environmental and ecosystem management remain crucial in control of dengue. However, providing detailed environmental information on a large scale to effectively target dengue control efforts remains a challenge. An important piece of such information is the extent of the presence of potential dengue vector breeding sites, which consist primarily of open containers such as ceramic jars, buckets, old tires, and flowerpots. In this paper we present the design and implementation of a pipeline to detect outdoor open containers which constitute potential dengue vector breeding sites from geotagged images and to create highly detailed container density maps at unprecedented scale. We implement the approach using Google Street View images which have the advantage of broad coverage and of often being two to three years old which allows correlation analyses of container counts against historical data from manual surveys. Containers comprising eight of the most common breeding sites are detected in the images using convolutional neural network transfer learning. Over a test set of images the object recognition algorithm has an accuracy of 0.91 in terms of F-score. Container density counts are generated and displayed on a decision support dashboard. Analyses of the approach are carried out over three provinces in Thailand. The container counts obtained agree well with container counts from available manual surveys. Multi-variate linear regression relating densities of the eight container types to larval survey data shows good prediction of larval index values with an R-squared of 0.674. To delineate conditions under which the container density counts are indicative of larval counts, a number of factors affecting correlation with larval survey data are analyzed. We conclude that creation of container density maps from geotagged images is a promising approach to providing detailed risk maps at large scale. [ABSTRACT FROM AUTHOR]

Viroporins like influenza A virus M2, hepatitis C virus p7, HIV-1 Vpu and picornavirus 2B associate with host membranes, and create hydrophilic corridors, which are critical for viral entry, replication and egress. The 6K proteins from alphaviruses are conjectured to be viroporins, essential during egress of progeny viruses from host membranes, although the analogue in Chikungunya Virus (CHIKV) remains relatively uncharacterized. Using a combination of electrophysiology, confocal and electron microscopy, and molecular dynamics simulations we show for the first time that CHIKV 6K is an ion channel forming protein that primarily associates with endoplasmic reticulum (ER) membranes. The ion channel activity of 6K can be inhibited by amantadine, an antiviral developed against the M2 protein of Influenza A virus; and CHIKV infection of cultured cells can be effectively inhibited in presence of this drug. Our study provides crucial mechanistic insights into the functionality of 6K during CHIKV-host interaction and suggests that 6K is a potential therapeutic drug target, with amantadine and its derivatives being strong candidates for further development. [ABSTRACT FROM AUTHOR]

Enzymes of the M32 family are Zn-dependent metallocarboxypeptidases (MCPs) widely distributed among prokaryotic organisms and just a few eukaryotes including Trypanosoma brucei and Trypanosoma cruzi, the causative agents of sleeping sickness and Chagas disease, respectively. These enzymes are absent in humans and several functions have been proposed for trypanosomatid M32 MCPs. However, no synthetic inhibitors have been reported so far for these enzymes. Here, we present the identification of a set of inhibitors for TcMCP-1 and TbMCP-1 (two trypanosomatid M32 enzymes sharing 71% protein sequence identity) from the GlaxoSmithKline HAT and CHAGAS chemical boxes; two collections grouping 404 compounds with high antiparasitic potency, drug-likeness, structural diversity and scientific novelty. For this purpose, we adapted continuous fluorescent enzymatic assays to a medium-throughput format and carried out the screening of both collections, followed by the construction of dose-response curves for the most promising hits. As a result, 30 micromolar-range inhibitors were discovered for one or both enzymes. The best hit, TCMDC-143620, showed sub-micromolar affinity for TcMCP-1, inhibited TbMCP-1 in the low micromolar range and was inactive against angiotensin I-converting enzyme (ACE), a potential mammalian off-target structurally related to M32 MCPs. This is the first inhibitor reported for this family of MCPs and considering its potency and specificity, TCMDC-143620 seems to be a promissory starting point to develop more specific and potent chemical tools targeting M32 MCPs from trypanosomatid parasites. [ABSTRACT FROM AUTHOR]

Contact patterns strongly influence the dynamics of disease transmission in both human and non-human animal populations. Domestic dogs Canis familiaris are a social species and are a reservoir for several zoonotic infections, yet few studies have empirically determined contact patterns within dog populations. Using high-resolution proximity logging technology, we characterised the contact networks of free-ranging domestic dogs from two settlements (n = 108 dogs, covering >80% of the population in each settlement) in rural Chad. We used these data to simulate the transmission of an infection comparable to rabies and investigated the effects of including observed contact heterogeneities on epidemic outcomes. We found that dog contact networks displayed considerable heterogeneity, particularly in the duration of contacts and that the network had communities that were highly correlated with household membership. Simulations using observed contact networks had smaller epidemic sizes than those that assumed random mixing, demonstrating the unsuitability of homogenous mixing models in predicting epidemic outcomes. When contact heterogeneities were included in simulations, the network position of the individual initially infected had an important effect on epidemic outcomes. The risk of an epidemic occurring was best predicted by the initially infected individual’s ranked degree, while epidemic size was best predicted by the individual’s ranked eigenvector centrality. For dogs in one settlement, we found that ranked eigenvector centrality was correlated with range size. Our results demonstrate that observed heterogeneities in contacts are important for the prediction of epidemiological outcomes in free-ranging domestic dogs. We show that individuals presenting a higher risk for disease transmission can be identified by their network position and provide evidence that observable traits hold potential for informing targeted disease management strategies. [ABSTRACT FROM AUTHOR]

Background: Glanders caused by Burkholderia mallei is a re-emerging zoonotic disease affecting solipeds and humans. Furthermore, B. mallei is genetically related to B. pseudomallei, which is the causative agent of melioidosis. Both facultative intracellular bacteria are classified as tier 1 select biothreat agents. Our previous study with a B. mallei ΔtonB Δhcp1 (CLH001) live-attenuated vaccine demonstrated that it is attenuated, safe and protective against B. mallei wild-type strain in the susceptible BALB/c mouse model. Methodology/Principal finding: In our current work, we evaluated the protective efficacy of CLH001 against glanders and melioidosis in the more disease-resistant C57BL/6 mouse strain. The humoral as well as cellular immune responses were also examined. We found that CLH001-immunized mice showed 100% survival against intranasal and aerosol challenge with B. mallei ATCC 23344. Moreover, this vaccine also afforded significant cross-protection against B. pseudomallei K96243, with low level bacterial burden detected in organs. Immunization with a prime and boost regimen of CLH001 induced significantly greater levels of total and subclasses of IgG, and generated antigen-specific splenocyte production of IFN-γ and IL-17A. Interestingly, protection induced by CLH001 is primarily dependent on humoral immunity, while CD4+ and CD8+ T cells played a less critical protective role. Conclusions/Significance: Our data indicate that CLH001 serves as an effective live attenuated vaccine to prevent glanders and melioidosis. The quantity and quality of antibody responses as well as improving cell-mediated immune responses following vaccination need to be further investigated prior to advancement to preclinical studies. [ABSTRACT FROM AUTHOR]

Background: Vector control remains the primary method to prevent dengue infections. Environmental interventions represent sustainable and safe methods as there are limited risks of environmental contamination and toxicity. The objective of this study is to perform a systematic review and meta-analysis of the effectiveness of the following environmental methods for dengue vector control. Methodology/Principal findings: Following the PRISMA guidelines, a systematic literature search was conducted using the databases PubMed, EMBASE, LILACS, the Cochrane Library and Google Scholar. Quality assessment was done using the CONSORT 2010 checklist. For the meta-analysis the difference-in-differences (DID) and the difference-of-endlines (DOE) were calculated according to the Schmidt-Hunter method for the Breteau index (BI) and the pupae per person index (PPI). Nineteen studies were eligible for the systematic review, sixteen contributed data to the meta-analysis. The following methods were evaluated: (a) container covers with and without insecticides, (b) waste management and clean-up campaigns, and (c) elimination of breeding sites by rendering potential mosquito breeding sites unusable or by eliminating them. Study quality was highest for container covers with insecticides, followed by waste management without direct garbage collection and elimination of breeding places. Both, systematic review and meta-analysis, showed a weak effect of the interventions on larval populations, with no obvious differences between the results of each individual method. For the meta-analysis, both, container covers without insecticides (BI: DID -7.9, DOE -5) and waste management with direct garbage collection (BI: DID -8.83, DOE -6.2) achieved the strongest reductions for the BI, whereas for the PPI results were almost opposite, with container covers with insecticides (PPI: DID -0.83, DOE 0.09) and elimination of breeding places (PPI: DID -0.95, DOE -0.83) showing the strongest effects. Conclusions: Each of the investigated environmental methods showed some effectiveness in reducing larval and pupal densities of Aedes sp. mosquitoes. However, there is a need for more comparable high-quality studies at an adequate standard to strengthen this evidence. [ABSTRACT FROM AUTHOR]

Invasive fungal infections (IFI) is a worldwide serious health problem and Amphotericin B (AmB) has been considered the drug of choice for IFI treatment. Despite its efficacy, clinical use of AmB has been associated with renal toxicity. Some lines of evidence have shown that an extemporaneous lipid emulsion preparation of AmB (AmB/LE) was able to attenuate nephrotoxicity, presenting similar benefits at a lower cost. Studies have been demonstrating that hypovitaminosis D may hasten the progression of kidney disease and reflect on a worse prognosis in cases of drug-induced nephrotoxicity. In view of the high worldwide incidence of hypovitaminosis D, the aim of this study was to investigate whether vitamin D deficiency may induce AmB/LE-related nephrotoxicity. Wistar rats were divided into four groups: control, received a standard diet for 34 days; AmB/LE, received a standard diet for 34 days and AmB/LE (5 mg/kg/day) intraperitoneally in the last 4 days; VDD, received a vitamin D-free diet for 34 days; and VDD+AmB/LE, received a vitamin D-free diet for 34 days and AmB/LE as described. At the end of the protocol, animals were euthanized and blood, urine and renal tissue samples were collected in order to evaluate AmB/LE effects on renal function and morphology. Association of AmB/LE and vitamin D deficiency led to diminished glomerular filtration rate and increased tubular injury, evidenced by reduced renal protein expression of NaPi-IIa and TRPM6 leading to hyperphosphaturia / hypermagnesuria. VDD+AmB/LE rats also presented alterations in the PTH-Klotho-FGF-23 signaling axis, urinary concentrating defect and hypertension, probably due to an inappropriate activation of the renin-angiotensin-aldosterone system. Hence, it is important to monitor vitamin D levels in AmB/LE treated patients, since vitamin D deficiency induces AmB/LE nephrotoxicity. [ABSTRACT FROM AUTHOR]

Background: A blend of compounds (pentanoic acid, guaiacol, δ-octalactone and geranylacetone) identified in waterbuck (Kobus defassa) body odour referred to as waterbuck repellent compounds (WRC) and a synthetic repellent 4-methylguaiacol have previously been shown to repel tsetse flies from the morsitans group. However, these repellents have not been evaluated on palpalis group tsetse flies. In this study, we evaluated the effect of these repellents on catches of Glossina fuscipes fuscipes (major vector of human sleeping sickness) in biconical traps and on sticky small targets which are visually attractive to palpalis group flies. The attractive devices were baited with different doses and blends of the repellent compounds. We also assessed the effect of removal of individual constituents in the synthetic blend of WRC on catches of G. f. fuscipes. Methodology/Principal findings: The study was conducted in western Kenya on four islands of Lake Victoria namely Big Chamaunga, Small Chamaunga, Manga and Rusinga. The tsetse fly catches from the treatments were modeled using a negative binomial regression to determine their effect on catches. In the presence of WRC and 4-methylguaiacol (released at ≈2 mg/h and ≈1.4 mg/h respectively), catches of G. f. fuscipes were significantly reduced by 33% (P<0.001) and 22% (P<0.001) respectively in biconical traps relative to control. On sticky small targets the reduction in fly catches were approximately 30% (P<0.001) for both 4-methylguiacol and WRC. In subtractive assays, only removal of geranylacetone from WRC significantly increased catches (by 1.8 times; P <0.001) compared to the complete blend of WRC. Conclusions/Significance: We conclude that WRC and 4-methylguaiacol reduce catches of G. f. fuscipes at stationary visually attractive traps and suggest that they may serve as broad spectrum repellents for Glossina species. We recommend further studies to investigate the effects of these compounds on reduction of G. f. fuscipes attracted to human hosts as this may lead to development of new strategies of reducing the prevalence and incidence of sleeping sickness. [ABSTRACT FROM AUTHOR]

Background: Salt fortified with the drug, diethylcarbamazine (DEC), and introduced into a competitive market has the potential to overcome the obstacles associated with tablet-based Lymphatic Filariasis (LF) elimination programs. Questions remain, however, regarding the economic viability, production capacity, and effectiveness of this strategy as a sustainable means to bring about LF elimination in resource poor settings. Methodology and principal findings: We evaluated the performance and effectiveness of a novel social enterprise-based approach developed and tested in Léogâne, Haiti, as a strategy to sustainably and cost-efficiently distribute DEC-medicated salt into a competitive market at quantities sufficient to bring about the elimination of LF. We undertook a cost-revenue analysis to evaluate the production capability and financial feasibility of the developed DEC salt social enterprise, and a modeling study centered on applying a dynamic mathematical model localized to reflect local LF transmission dynamics to evaluate the cost-effectiveness of using this intervention versus standard annual Mass Drug Administration (MDA) for eliminating LF in Léogâne. We show that the salt enterprise because of its mixed product business strategy may have already reached the production capacity for delivering sufficient quantities of edible DEC-medicated salt to bring about LF transmission in the Léogâne study setting. Due to increasing revenues obtained from the sale of DEC salt over time, expansion of its delivery in the population, and greater cumulative impact on the survival of worms leading to shorter timelines to extinction, this strategy could also represent a significantly more cost-effective option than annual DEC tablet-based MDA for accomplishing LF elimination. Significance: A social enterprise approach can offer an innovative market-based strategy by which edible salt fortified with DEC could be distributed to communities both on a financially sustainable basis and at sufficient quantity to eliminate LF. Deployment of similarly fashioned intervention strategies would improve current efforts to successfully accomplish the goal of LF elimination, particularly in difficult-to-control settings. [ABSTRACT FROM AUTHOR]

Background: In summer 2014, an autochthonous outbreak of dengue occurred in Tokyo, Japan, in which Yoyogi Park acted as the focal area of transmission. Recognizing the outbreak, concerted efforts were made to control viral spread, which included mosquito control, public announcement of the outbreak, and a total ban on entering the park. We sought to assess the effectiveness of these control measures. Methodology/Principal findings: We used a mathematical model to describe the transmission dynamics. Using dates of exposure and illness onset, we categorized cases into three groups according to the availability of these datasets. The infection process was parametrically modeled by generation, and convolution of the infection process and the incubation period was fitted to the data. By estimating the effective reproduction number, we determined that the effect of dengue risk communication together with mosquito control from 28 August 2014 was insufficiently large to lower the reproduction number to below 1. However, once Yoyogi Park was closed on 4 September, the value of the effective reproduction number began to fall below 1, and the associated relative reduction in the effective reproduction number was estimated to be 20%–60%. The mean incubation period was an estimated 5.8 days. Conclusions/Significance: Regardless of the assumed number of generations of cases, the combined effect of mosquito control, risk communication, and park closure appeared to be successful in interrupting the chain of dengue transmission in Tokyo. [ABSTRACT FROM AUTHOR]

Background: Strongyloides stercoralis is a neglected soil-transmitted helminth that occurs worldwide, though it is particularly endemic in tropical and subtropical areas. It can cause long-lasting and potentially fatal infections due to its ability to replicate within its host. S. stercoralis causes gastrointestinal and dermatological morbidity. The objective of this study was to assess the S. stercoralis infection risk and, using geostatistical models, to predict its geographical distribution in Cambodia. Methodology / Principal findings: A nation-wide, community-based parasitological survey was conducted among the Cambodian population, aged 6 years and older. S. stercoralis was diagnosed using a serological diagnostic test that detects IgG antibodies in urine. Data on demography, hygiene and knowledge about helminth infection were collected. S. stercoralis prevalence among 7,246 participants with a complete data record was 30.5%, ranging from 10.9% to 48.2% across provinces. The parasite was ubiquitous in Cambodia; only five south-eastern provinces had prevalence rates below 20%. Infection risk increased with age for both men and women, although girls under the age of 13 and women aged 50 years and over had lower odds of infection than their male counterparts. Open defecation was associated with higher odds of infection, while having some knowledge of the health problems caused by worms was a protective factor. Infection risk was positively associated with nighttime maximum temperature, minimum rainfall, and distance to water; it was negatively associated with land occupied by rice fields. Conclusions / Significance: S. stercoralis infection is rampant in Cambodia. Control programs delivering ivermectin are needed to manage the parasite. However, the high cost of this drug in Cambodia currently precludes the implementation of control initiatives. Donations, subsidies or affordable generics are needed so that S. stercoralis, which infects almost a third of the Cambodian population, can be addressed through an adequate control program. [ABSTRACT FROM AUTHOR]

Background: Individual helminth infections are ubiquitous in the tropics; geographical overlaps in endemicity and epidemiological reports suggest areas endemic for multiple helminthiases are also burdened with high prevalences of intestinal protozoan infections, malaria, tuberculosis (TB), and human immunodeficiency virus (HIV). Despite this, pathogens tend to be studied in isolation, and there remains a need for a better understanding of the community ecology and health consequences of helminth polyparasitism to inform the design of effective parasite control programs. Methodology: We performed meta-analyses to (i) evaluate the commonality of polyparasitism for helminth-helminth, helminth-intestinal protozoa, helminth-malaria, helminth-TB, and helminth-HIV co-infections, (ii) assess the potential for interspecies interactions among helminth-helminth and helminth-intestinal protozoan infections, and (iii) determine the presence and magnitude of association between specific parasite pairs. Additionally, we conducted a review of reported health consequences of multiply-infected individuals compared to singly- or not multiply-infected individuals. Principal findings: We found that helminth-helminth and helminth-intestinal protozoan multiple infections were significantly more common than single infections, while individuals with malaria, TB, and HIV were more likely to be singly-infected with these infections than co-infected with at least one helminth. Most observed species density distributions significantly differed from the expected distributions, suggesting the potential presence of interspecies interactions. All significant associations between parasite pairs were positive in direction, irrespective of the combination of pathogens. Polyparasitized individuals largely exhibited lower hemoglobin levels and higher anemia prevalence, while the differences in growth-related variables were mostly statistically insignificant. Conclusions: Our findings confirm that helminth polyparasitism and co-infection with major diseases is common in the tropics. A multitude of factors acting at various hierarchical levels, such as interspecies interactions at the within-host infra-parasite community level and environmental variables at the higher host community level, could explain the observed positive associations between pathogens; there remains a need to develop new frameworks which can consider these multilevel factors to better understand the processes structuring parasite communities to accomplish their control. [ABSTRACT FROM AUTHOR]

Antivenoms from hyperimmune animal plasma are the only specific pharmaceuticals against snakebites. The improvement of downstream processing strategies is of great interest, not only in terms of purity profile, but also from yield-to-cost perspective and rational use of plasma of animal origin. We report on development of an efficient refinement strategy for F(ab')2-based antivenom preparation. Process design was driven by the imperative to keep the active principle constantly in solution as a precautionary measure to preserve stability of its conformation (precipitation of active principle or its adsorption to chromatographic stationary phase has been completely avoided). IgG was extracted from hyperimmune horse plasma by 2% (V/V) caprylic acid, depleted from traces of precipitating agent and digested by pepsin. Balance between incomplete IgG fraction breakdown, F(ab')2 over-digestion and loss of the active principle's protective efficacy was achieved by adjusting pepsin to substrate ratio at the value of 4:300 (w/w), setting pH to 3.2 and incubation period to 1.5 h. Final polishing was accomplished by a combination of diafiltration and flow-through chromatography. Developed manufacturing strategy gave 100% pure and aggregate-free F(ab')2 preparation, as shown by size-exclusion HPLC and confirmed by MS/MS. The overall yield of 75% or higher compares favorably to others so far reported. This optimised procedure looks also promising for large-scale production of therapeutic antivenoms, since high yield of the active drug and fulfillment of the regulatory demand considering purity was achieved. The recovery of the active substance was precisely determined in each purification step enabling accurate estimation of the process cost-effectiveness. [ABSTRACT FROM AUTHOR]

As emerging and re-emerging infectious arboviruses like dengue, chikungunya, and Zika threaten new populations worldwide, officials scramble to assess local severity and transmissibility, with little to no epidemiological history to draw upon. Indirect estimates of risk from vector habitat suitability maps are prone to great uncertainty, while direct estimates from epidemiological data are only possible after cases accumulate and, given environmental constraints on arbovirus transmission, cannot be widely generalized beyond the focal region. Combining these complementary methods, we use disease importation and transmission data to improve the accuracy and precision of a priori ecological risk estimates. We demonstrate this approach by estimating the spatiotemporal risks of Zika virus transmission throughout Texas, a high-risk region in the southern United States. Our estimates are, on average, 80% lower than published ecological estimates—with only six of 254 Texas counties deemed capable of sustaining a Zika epidemic—and they are consistent with the number of autochthonous cases detected in 2017. Importantly our method provides a framework for model comparison, as our mechanistic understanding of arbovirus transmission continues to improve. Real-time updating of prior risk estimates as importations and outbreaks arise can thereby provide critical, early insight into local transmission risks as emerging arboviruses expand their global reach. [ABSTRACT FROM AUTHOR]

The preparedness of health systems to detect, treat, and prevent onward transmission of Ebola virus disease (EVD) is central to mitigating future outbreaks. Early detection of outbreaks is critical to timely response, but estimating detection rates is difficult because unreported spillover events and outbreaks do not generate data. Using three independent datasets available on the distributions of secondary infections during EVD outbreaks across West Africa, in a single district (Western Area) of Sierra Leone, and in the city of Conakry, Guinea, we simulated realistic outbreak size distributions and compared them to reported outbreak sizes. These three empirical distributions lead to estimates for the proportion of detected spillover events and small outbreaks of 26% (range 8–40%, based on the full outbreak data), 48% (range 39–62%, based on the Sierra Leone data), and 17% (range 11–24%, based on the Guinea data). We conclude that at least half of all spillover events have failed to be reported since EVD was first recognized. We also estimate the probability of detecting outbreaks of different sizes, which is likely less than 10% for single-case spillover events. Comparing models of the observation process also suggests the probability of detecting an outbreak is not simply the cumulative probability of independently detecting any one individual. Rather, we find that any individual’s probability of detection is highly dependent upon the size of the cluster of cases. These findings highlight the importance of primary health care and local case management to detect and contain undetected early stage outbreaks at source. [ABSTRACT FROM AUTHOR]

Insecticide resistance (IR) can undermine efforts to control vectors of public health importance. Aedes aegypti is the main vector of resurging diseases in the Americas such as yellow fever and dengue, and recently emerging chikungunya and Zika fever, which have caused unprecedented epidemics in the region. Vector control remains the primary intervention to prevent outbreaks of Aedes-transmitted diseases. In many high-risk regions, like southern Ecuador, we have limited information on IR. In this study, Ae. aegypti IR was measured across four cities in southern Ecuador using phenotypic assays and genetic screening for alleles associated with pyrethroid IR. Bottle bioassays showed significant inter-seasonal variation in resistance to deltamethrin, a pyrethroid commonly used by the Ministry of Health, and alpha-cypermethrin, as well as between-city differences in deltamethrin resistance. There was also a significant difference in phenotypic response to the organophosphate, Malathion, between two cities during the second sampling season. Frequencies of the resistant V1016I genotype ranged from 0.13 to 0.68. Frequencies of the resistant F1534C genotype ranged from 0.63 to 1.0, with sampled populations in Machala and Huaquillas at fixation for the resistant genotype in all sampled seasons. In Machala and Portovelo, there were statistically significant inter-seasonal variation in genotype frequencies for V1016I. Resistance levels were highest in Machala, a city with hyperendemic dengue transmission and historically intense insecticide use. Despite evidence that resistance alleles conferred phenotypic resistance to pyrethroids, there was not a precise correspondence between these indicators. For the F1534C gene, 17.6% of homozygous mutant mosquitoes and 70.8% of heterozygotes were susceptible, while for the V1016I gene, 45.6% homozygous mutants and 55.6% of heterozygotes were susceptible. This study shows spatiotemporal variability in IR in Ae. aegypti populations in southern coastal Ecuador, and provides an initial examination of IR in this region, helping to guide vector control efforts for Ae. aegypti. [ABSTRACT FROM AUTHOR]

Background: African trypanosomosis, primarily transmitted by tsetse flies, remains a serious public health and economic challenge in sub-Saharan Africa. Interventions employing natural repellents from non-preferred hosts of tsetse flies represent a promising management approach. Although zebras have been identified as non-preferred hosts of tsetse flies, the basis for this repellency is poorly understood. We hypothesized that zebra skin odors contribute to their avoidance by tsetse flies. Methodology/Principal findings: We evaluated the effect of crude zebra skin odors on catches of wild savannah tsetse flies (Glossina pallidipes Austen, 1903) using unbaited Ngu traps compared to the traps baited with two known tsetse fly management chemicals; a repellent blend derived from waterbuck odor, WRC (comprising geranylacetone, guaiacol, pentanoic acid and δ-octalactone), and an attractant comprising cow urine and acetone, in a series of Latin square-designed experiments. Coupled gas chromatography-electroantennographic detection (GC/EAD) and GC-mass spectrometry (GC/MS) analyses of zebra skin odors identified seven electrophysiologically-active components; 6-methyl-5-hepten-2-one, acetophenone, geranylacetone, heptanal, octanal, nonanal and decanal, which were tested in blends and singly for repellency to tsetse flies when combined with Ngu traps baited with cow urine and acetone in field trials. The crude zebra skin odors and a seven-component blend of the EAD-active components, formulated in their natural ratio of occurrence in zebra skin odor, significantly reduced catches of G. pallidipesby 66.7% and 48.9% respectively, and compared favorably with the repellency of WRC (58.1%– 59.2%). Repellency of the seven-component blend was attributed to the presence of the three ketones 6-methyl-5-hepten-2-one, acetophenone and geranylacetone, which when in a blend caused a 62.7% reduction in trap catch of G. pallidipes. Conclusions/Significance: Our findings reveal fundamental insights into tsetse fly ecology and the allomonal effect of zebra skin odor, and potential integration of the three-component ketone blend into the management toolkit for tsetse and African trypanosomosis control. [ABSTRACT FROM AUTHOR]

Background: Schistosomiasis japonica is a zoonotic parasitic disease. After nearly 70 years of control efforts in China, Schistosomiasis transmission has been reduced to a much lower level. The absence or near absence of infections in humans or livestock, based on traditional fecal and serological tests, has made the targets and priorities of future control efforts difficult to determine. However, detection of schistosome cercariae in waters using sentinel mice could be an alternative way of identifying remaining foci of infection, or even serve as a tool for evaluation of control efficacy. This method has been employed in China over last forty years. We therefore performed a meta-analysis of the relevant research to investigate if infections in sentinel mice mirror the ongoing trend of schistosomiasis transmission in China. Methods: We conducted a meta-analysis of studies reporting infection rates of S. japonicum in sentinel mice in China before Sep 1, 2018 in accordance with the PRISMA guidelines. We retrieved all relative studies based on five databases (CNKI, WanFang, VIP, PubMed and Web of Science) and the reference lists of resulting articles. For each individual study, the infection rate in sentinel mice is presented together with its 95% confidence interval (CI). Point estimates of the overall infection rates and their 95% CIs were calculated. Subgroup analyses were performed according to study periods, seasons or regions. Results: We identified 90 articles, including 290 studies covering eight endemic provinces. The overall rate in sentinel mice was 12.31% (95% CI: 10.14–14.65%) from 1980 to 2018. The value of 3.66% (95% CI: 2.62–4.85%) estimated in 2004 to 2018 was significantly lower than in 1980 to 2003 (22.96%, 95% CI: 19.25–26.89%). The estimate was significantly higher in the middle and lower reaches than in the upper reaches of the Yangtze River. The highest estimates were obtained in Hunan (30.11%, 95% CI: 25.64–34.77%) followed by Anhui (26.34%, 95% CI: 12.88–42.44%) and then Jiangxi (13.73%, 95% CI: 6.71–22.56%). Unlike the other provinces in the middle and lower reaches, no significant reduction was seen in Hubei after 2003. Even in Hubei two studies carried out after 2014 reported infections in sentinel mice, although no infected snails were reported across the province. Infections were most found in April (17.40%, 95% CI: 1.13–45.49%), July (24.98%, 95% CI: 15.64–35.62%) and October (17.08%, 95% CI 5.94–32.05%). High degrees of heterogeneity were observed. Conclusion: This meta-analysis provides a comprehensive analysis of schistosome infection in sentinel mice across China. The estimates largely mirror the ongoing trends of transmission in terms of periods and regions. Infections were most likely to occur in April, July and October. In areas where no infected snails were reported infections in sentinel mice were still observed. Due to the presence of snails and infected wildlife, detection of schistosomes in waters using such a highly sensitive method as the deployment of sentinel mice, remains of importance in schistosomiasis monitoring. We would suggest the current criteria for transmission interruption or elimination of schistosomiasis in China be adjusted by integrating the results of sentinel mice based surveys. [ABSTRACT FROM AUTHOR]

Background: Invasive non-typhoidal Salmonella (iNTS) serovars S. Typhimurium and S. Enteritidis are major etiologic agents of invasive bacterial disease among infants and young children in sub-Saharan Africa, including in Mali. Early studies of iNTS serovars in several countries indicated that S. Typhimurium was more prevalent than S. Enteritidis, including in Mali before 2008. We investigated genomic and associated phenotypic changes associated with an increase in the relative proportion of iNTS caused by S. Enteritidis versus S. Typhimurium in Bamako, Mali, during the period 2002–2012. Methodology/Principal findings: Comparative genomics studies identified homologs of tetracycline resistance and arsenic utilization genes that were associated with the temporal shift of serovars causing iNTS shift, along with several hypothetical proteins. These findings, validated through PCR screening and phenotypic assays, provide initial steps towards characterizing the genomic changes consequent to unknown evolutionary pressures associated with the shift in serovar prevalence. Conclusions/Significance: This work identified a shift to S. Enteritidis from the more classic S. Typhimurium, associated with iNTS in Bamako, Mali, during the period 2002–2012. This type of shift in underlying iNTS pathogens are of great importance to pediatric public health in endemic regions of sub-Saharan Africa. Additionally, this work demonstrates the utility of combining epidemiologic data, whole genome sequencing, and functional characterization in the laboratory to identify and characterize genomic changes in the isolates that may be involved with the observed shift in circulating iNTS agents. [ABSTRACT FROM AUTHOR]

The ability to appropriately mimic human disease is critical for using animal models as a tool for understanding virus pathogenesis. In the case of Nipah virus (NiV), infection of humans appears to occur either through inhalation, contact with or consumption of infected material. In two of these circumstances, respiratory or sinusoidal exposure represents a likely route of infection. In this study, intermediate-size aerosol particles (~7 μm) of NiV-Malaysia were used to mimic potential routes of exposure by focusing viral deposition in the upper respiratory tract. Our previous report showed this route of exposure extended the disease course and a single animal survived the infection. Here, analysis of the peripheral immune response found minimal evidence of systemic inflammation and depletion of B cells during acute disease. However, the animal that survived infection developed an early IgM response with rapid development of neutralizing antibodies that likely afforded protection. The increase in NiV-specific antibodies correlated with an expansion of the B cell population in the survivor. Cell-mediated immunity was not clearly apparent in animals that succumbed during the acute phase of disease. However, CD4+ and CD8+ effector memory cells increased in the survivor with correlating increases in cytokines and chemokines associated with cell-mediated immunity. Interestingly, kinetic changes of the CD4+ and CD8bright T cell populations over the course of acute disease were opposite from animals that succumbed to infection. In addition, increases in NK cells and basophils during convalescence of the surviving animal were also evident, with viral antigen found in NK cells. These data suggest that a systemic inflammatory response and “cytokine storm” are not major contributors to NiV-Malaysia pathogenesis in the AGM model using this exposure route. Further, these data demonstrate that regulation of cell-mediated immunity, in addition to rapid production of NiV specific antibodies, may be critical for surviving NiV infection. [ABSTRACT FROM AUTHOR]

Background: Multiple mutations in the voltage-gated sodium channel have been associated with knockdown resistance (kdr) to DDT and pyrethroid insecticides in a major human disease vector Aedes aegypti. One mutation, V1016G, confers sodium channel resistance to pyrethroids, but a different substitution in the same position V1016I alone had no effect. In pyrethroid-resistant Ae. aegypti populations, V1016I is often linked to another mutation, F1534C, which confers sodium channel resistance only to Type I pyrethroids including permethrin (PMT), but not to Type II pyrethroids including deltamethrin (DMT). Mosquitoes carrying both V1016G and F1534C exhibited a greater level of pyrethroid resistance than those carrying F1534C alone. More recently, a new mutation T1520I co-existing with F1534C was detected in India. However, whether V1016I or T1520I enhances pyrethroid resistance of sodium channels carrying F1534C remains unknown. Methodology/Principal findings: V1016I, V1016G, T1520I and F1534C substitutions were introduced alone and in various combinations into AaNav1-1, a sodium channel from Aedes aegypti. The mutant channels were then expressed in Xenopus oocytes and examined for channel properties and sensitivity to pyrethroids using the two-electrode voltage clamping technique. The results showed that V1016I or T1520I alone did not alter the AaNav1-1 sensitivity to PMT or DMT. However, the double mutant T1520I+F1534C was more resistant to PMT than F1534C, but remained sensitive to DMT. In contrast, the double mutant V1016I+F1534C was resistant to DMT and more resistant to PMT than F1534C. Furthermore, V1016I/G and F1534C channels, but not T1520I, were resistant to dichlorodiphenyltrichloroethane (DDT). Cryo-EM structures of sodium channels suggest that T1520I allosterically deforms geometry of the pyrethroid receptor site PyR1 in AaNav1-1. The small deformation does not affect binding of DDT, PMT or DMT, but in combination with F1534C it increases the channel resistance to PMT and DDT. Conclusions/Significance: Our data corroborated the previously proposed sequential selection of kdr mutations in Ae. aegypti. We proposed that mutation F1534C first emerged in response to DDT/pyrethroids providing a platform for subsequent selection of mutations V1016I and T1520I that confer greater and broader spectrum of pyrethroid resistance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that is caused by a novel bunyavirus SFTSV. Currently our knowledge of the host-related factors that influence the pathogenesis of disease is inadequate to allow prediction of fatal outcome. Here we conducted a prospective study of the largest database on the SFTS patients, to identify the presence of comorbidities in SFTS, and estimate their effect on the fatal outcome. Among 2096 patients eligible for inclusion, we identified nine kinds of comorbidities, from which hyperlipidemia (12.2%; 95% CI: 10.8%–13.6%), hypertension (11.0%; 95% CI: 9.6%–12.3%), chronic viral hepatitis (CVH) (9.3%; 95% CI: 8.1%–10.5%), and diabetes mellitus (DM) (6.8%; 95% CI: 5.7%–7.9%) were prevalent. Higher risk of death was found in patients with DM (adjusted OR = 2.304; 95% CI: 1.520–3.492; P<0.001), CVH (adjusted OR = 1.551; 95% CI: 1.053–2.285; P = 0.026) and chronic obstructive pulmonary diseases (COPD) (adjusted OR = 2.170; 95% CI: 1.215–3.872; P = 0.009) after adjusting for age, sex, delay from disease onset to admission and treatment regimens. When analyzing the comorbidities separately, we found that the high serum glucose could augment diseases severity. Compared to the group with max glucose < 7.0 mmol/L, patients with glucose between 7.0–11.1 mmol/L and glucose ≥11.1 mmol/L conferred higher death risk, with the adjusted OR to be 1.467 (95% CI: 1.081–1.989; P = 0.014) and 3.443 (95% CI: 2.427–4.884; P<0.001). Insulin therapy could effectively reduce the risk of severe outcome in DM patients with the adjusted OR 0.146 (95% CI: 0.058–0.365; P<0.001). For CVH patients, severe damage of liver and prolongation of blood coagulation time, as well as high prevalence of bleeding phenotype were observed. These data supported the provocative hypothesis that treating SFTS related complications can attain potentially beneficial effects on SFTS. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is a principle tool for the control and prevention of piroplasmosis. The search for a new chemotherapy against Babesia and Theileria parasites has become increasingly urgent due to the toxic side effects of and developed resistance to the current drugs. Chalcones have attracted much attention due to their diverse biological activities. With the aim to discover new drugs and drug targets, in vitro and in vivo antibabesial activity of trans-chalcone (TC) and chalcone 4 hydrate (CH) alone and combined with diminazene aceturate (DA), clofazimine (CF) and atovaquone (AQ) were investigated. Methodology/Principal findings: The fluorescence-based assay was used for evaluating the inhibitory effect of TC and CH on four Babesia species, including B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi, the combination with DA, CF, and AQ on in vitro cultures, and on the multiplication of a B. microti–infected mouse model. The cytotoxicity of compounds was tested on Madin–Darby bovine kidney (MDBK), mouse embryonic fibroblast (NIH/3T3), and human foreskin fibroblast (HFF) cell lines. The half maximal inhibitory concentration (IC50) values of TC and CH against B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi were 69.6 ± 2.3, 33.3 ± 1.2, 64.8 ± 2.5, 18.9 ± 1.7, and 14.3 ± 1.6 μM and 138.4 ± 4.4, 60.9 ± 1.1, 82.3 ± 2.3, 27.9 ± 1.2, and 19.2 ± 1.5 μM, respectively. In toxicity assays, TC and CH affected the viability of MDBK, NIH/3T3, and HFF cell lines the with half maximum effective concentration (EC50) values of 293.9 ± 2.9, 434.4 ± 2.7, and 498 ± 3.1 μM and 252.7 ± 1.7, 406.3 ± 9.7, and 466 ± 5.7 μM, respectively. In the mouse experiment, TC reduced the peak parasitemia of B. microti by 71.8% when administered intraperitoneally at 25 mg/kg. Combination therapies of TC–DA and TC–CF were more potent against B. microti infection in mice than their monotherapies. Conclusions/Significance: In conclusion, both TC and CH inhibited the growth of Babesia and Theileria in vitro, and TC inhibited the growth of B. microti in vivo. Therefore, TC and CH could be candidates for the treatment of piroplasmosis after further studies. [ABSTRACT FROM AUTHOR]

Background: Recent outbreaks of dengue and other Aedes aegypti-borne arboviruses highlight the importance of a rapid response for effective vector control. Data on insecticide resistance and underlying mechanisms are essential for outbreak preparedness, but are sparse in much of Africa. We investigated the levels and heterogeneity of insecticide resistance and mechanisms of Ae. aegypti from contrasting settings within and around Ouagadougou, Burkina Faso. Methodology/Principal findings: Bioassays were performed on larvae and adults to diagnose prevalence of resistance, and to assess levels where resistance was detected. Investigation of resistance mechanisms was performed using synergist bioassays, knockdown resistance (kdr) target site mutation genotyping and quantitative PCR expression analysis of candidate P450 genes. Larval dose-response assays indicated susceptibility to the organophosphates tested. Adult females were also susceptible to organophosphates, but resistance to carbamates was suspected in urban and semi-urban localities. Females from all localities showed resistance to pyrethroids but resistance prevalence and level were higher in urban and especially in semi-urban areas, compared to the rural population. Environment was also associated with susceptibility: adults reared from larvae collected in tires from the semi-urban site were significantly less resistant to pyrethroids than those collected from large outdoor drinking water containers (‘drums’). Susceptibility to both pyrethroids tested was largely restored by pre-exposure to Piperonyl Butoxide (PBO), suggesting a strong metabolic basis to resistance. The 1534C kdr mutation was nearly fixed in semi-urban and urban areas but was far less common in the rural area, where the 1016I kdr mutation frequency was also significantly lower. P450 gene analysis detected limited over-expression of single candidates but significantly elevated average expression in the semi-urban site compared to both a susceptible laboratory colony, and females from the other collection sites. Conclusions/Significance: Our results reveal pyrethroid resistance and paired kdr mutations in both urban and semi-urban sites at levels that are unprecedented for mainland Africa. The combination of target site and metabolic mechanisms is common in Ae. aegypti populations from other continents but is a worrying finding for African populations. However, organophosphate insecticides are still active against both larvae and adults of Ae. aegypti, providing useful insecticidal options for control and resistance management. [ABSTRACT FROM AUTHOR]

Background: Salmonella enterica subsp. enterica contains more than 2,600 serovars of which four are of major medical relevance for humans. While the typhoidal serovars (Typhi and Paratyphi A) are human-restricted and cause enteric fever, non-typhoidal Salmonella serovars (Typhimurium and Enteritidis) have a broad host range and predominantly cause gastroenteritis. Methodology/Principle findings: We compared the core proteomes of Salmonella Typhi, Paratyphi A, Typhimurium and Enteritidis using contemporary proteomics. For each serovar, five clinical isolates (covering different geographical origins) and one reference strain were grown in vitro to the exponential phase. Levels of orthologous proteins quantified in all four serovars and within the typhoidal and non-typhoidal groups were compared and subjected to gene ontology term enrichment and inferred regulatory interactions. Differential expression of the core proteomes of the typhoidal serovars appears mainly related to cell surface components and, for the non-typhoidal serovars, to pathogenicity. Conclusions/Significance: Our comparative proteome analysis indicated differences in the expression of surface proteins between Salmonella Typhi and Paratyphi A, and in pathogenesis-related proteins between Salmonella Typhimurium and Enteritidis. Our findings may guide future development of novel diagnostics and vaccines, as well as understanding of disease progression. [ABSTRACT FROM AUTHOR]

Background: Acanthamoeba castellanii, which causes keratitis and blindness in under-resourced countries, is an emerging pathogen worldwide, because of its association with contact lens use. The wall makes cysts resistant to sterilizing reagents in lens solutions and to antibiotics applied to the eye. Methodology/Principal findings: Transmission electron microscopy and structured illumination microscopy (SIM) showed purified cyst walls of A. castellanii retained an outer ectocyst layer, an inner endocyst layer, and conical ostioles that connect them. Mass spectrometry showed candidate cyst wall proteins were dominated by three families of lectins (named here Jonah, Luke, and Leo), which bound well to cellulose and less well to chitin. An abundant Jonah lectin, which has one choice-of-anchor A (CAA) domain, was made early during encystation and localized to the ectocyst layer of cyst walls. An abundant Luke lectin, which has two carbohydrate-binding modules (CBM49), outlined small, flat ostioles in a single-layered primordial wall and localized to the endocyst layer and ostioles of mature walls. An abundant Leo lectin, which has two unique domains with eight Cys residues each (8-Cys), localized to the endocyst layer and ostioles. The Jonah lectin and glycopolymers, to which it binds, were accessible in the ectocyst layer. In contrast, Luke and Leo lectins and the glycopolymers, to which they bind, were mostly inaccessible in the endocyst layer and ostioles. Conclusions/Significance: The most abundant A. castellanii cyst wall proteins are three sets of lectins, which have carbohydrate-binding modules that are conserved (CBM49s of Luke), newly characterized (CAA of Jonah), or unique to Acanthamoebae (8-Cys of Leo). Cyst wall formation is a tightly choreographed event, in which lectins and glycopolymers combine to form a mature wall with a protected endocyst layer. Because of its accessibility in the ectocyst layer, an abundant Jonah lectin is an excellent diagnostic target. [ABSTRACT FROM AUTHOR]

Background: Typhoid fevers are infections caused by the bacteria Salmonella enterica serovar Typhi (Salmonella Typhi) and Paratyphi A, B and C (Salmonella Paratyphi). Approximately 17.8 million incident cases of typhoid fever occur annually, and incidence is highest in children. The accuracy of current diagnostic tests of typhoid fever is poorly understood. We aimed to determine the comparative accuracy of available tests for the pediatric population. Methods: We first conducted a systematic literature review to identify studies that compared diagnostic tests for typhoid fever in children (aged ≤15 years) to blood culture results. We applied a Bayesian latent-class extension to a network meta-analysis model. We modelled known diagnostic properties of bone marrow culture and the relationship between bone marrow and blood culture as informative priors in a Bayesian framework. We tested sensitivities for the proportion of negative blood samples that were false as well as bone marrow sensitivity and specificity. Results: We found 510 comparisons from 196 studies and 57 specific to the pediatric population. IgM-based tests outperformed their IgG-based counterparts for ELISA and Typhidot tests. The lateral flow IgG test performed comparatively well with 92% sensitivity (72% to 98% across scenario analyses) and 94% specificity. The most sensitive test of those investigated for the South Asian pediatric population was the Reverse Passive Hemagglutination Assay with 96% sensitivity (98% - 100% across scenario analyses). Adding a Widal slide test to other typhoid diagnostics did not substantially improve diagnostic performance beyond the single test alone, however, a lateral flow-based IgG rapid test combined with the typhoid/paratyphoid (TPT) assay yielded improvements in sensitivity without substantial declines in specificity and was the best performing combination test in this setting. Conclusion: In the pediatric population, lateral-flow IgG, TPT and Reverse Passive Hemagglutination tests had high diagnostic accuracy compared to other diagnostics. Combinations of tests may provide a feasible option to increase diagnostic sensitivity. South Asia has the most informed set of data on typhoid diagnostic testing accuracy, and the evidence base in other important regions needs to be expanded. [ABSTRACT FROM AUTHOR]

Triatomine vectors transmit Trypanosoma cruzi, the etiological agent of Chagas disease in humans. Transmission to humans typically occurs when contaminated triatomine feces come in contact with the bite site or mucosal membranes. In the Southern Cone of South America, where the highest burden of disease exists, Triatoma infestans is the principal vector for T. cruzi. Recent studies of other vector-borne illnesses have shown that arthropod microbiota influences the ability of infectious agents to colonize the insect vector and transmit to the human host. This has garnered attention as a potential control strategy against T. cruzi, as vector control is the main tool of Chagas disease prevention. Here we characterized the microbiota in T. infestans feces of both wild-caught and laboratory-reared insects and examined the relationship between microbial composition and T. cruzi infection using highly sensitive high-throughput sequencing technology to sequence the V3-V4 region of the 16S ribosomal RNA gene on the MiSeq Illumina platform. We collected 59 wild (9 with T. cruzi infection) and 10 lab-reared T. infestans (4 with T. cruzi infection) from the endemic area of Arequipa, Perú. Wild T. infestans had greater hindgut bacterial diversity than laboratory-reared bugs. Microbiota of lab insects comprised a subset of those identified in their wild counterparts, with 96 of the total 124 genera also observed in laboratory-reared insects. Among wild insects, variation in bacterial composition was observed, but time and location of collection and development stage did not explain this variation. T. cruzi infection in lab insects did not affect α- or β-diversity; however, we did find that the β-diversity of wild insects differed if they were infected with T. cruzi and identified 10 specific taxa that had significantly different relative abundances in infected vs. uninfected wild T. infestans (Bosea, Mesorhizobium, Dietzia, and Cupriavidus were underrepresented in infected bugs; Sporosarcina, an unclassified genus of Porphyromonadaceae, Nestenrenkonia, Alkalibacterium, Peptoniphilus, Marinilactibacillus were overrepresented in infected bugs). Our findings suggest that T. cruzi infection is associated with the microbiota of T. infestans and that inferring the microbiota of wild T. infestans may not be possible through sampling of T. infestans reared in the insectary. [ABSTRACT FROM AUTHOR]

Objectives: We contribute a new methodological approach to the ongoing efforts towards evaluating public health surveillance. Specifically, we apply a descriptive framework, grounded in prospect theory (PT), for the evaluation of decisions on disease surveillance deployment. We focus on two attributes of any surveillance system: timeliness, and false positive rate (FPR). Methods: In a sample of 69 health professionals from a number of health related networks polled online, we elicited PT preferences, specifically respondents’ attitudes towards gains, losses and probabilities (i.e., if they overweight or underweight extreme probabilities) by means of a series of lotteries for either timeliness or FPR. Moreover, we estimated willingness to pay (WTP) for improvements in the two surveillance attributes. For contextualization, we apply our framework to rabies surveillance. Results: Our data reveal considerable probability weighting, both for gains and losses. In other words, respondents underestimate their chances of getting a good outcome in uncertain situations, and they overestimate their chances of bad outcomes. Moreover, there is convex utility for losses and loss aversion, that is, losses loom larger than gains of the same absolute magnitude to the respondents. We find no differences between the estimated parameters for timeliness and FPR. The median WTP is $7,250 per day gained in detection time and $30 per 1/10,000 reduction in FPR. Conclusion: Our results indicate that the biases described by PT are present among public health professionals, which highlights the need to incorporate a PT framework when eliciting their preferences for surveillance systems. [ABSTRACT FROM AUTHOR]

Canine rabies is endemic in urban India. A questionnaire was administered to 204 residents of the urbanised municipality of Panchkula in north India to assess the influence of gender, age, family size, social status and dog ownership, over the knowledge, attitudes and practices (KAP) towards rabies control and free-roaming dogs (FRD) in their locality. Bivariate analyses revealed significant knowledge gaps regarding crucial information on the control and transmission of rabies. Multivariable logistic regression models found that the respondents with a high/middle socio-economic status were likely to be more knowledgeable than those from low socio-economic levels (OR 3.03, 95%CI 1.5–6.0, p = 0.001). Households with children ≤14 years of age were likely to be lacking in knowledge about rabies compared to households with older or no children (OR 0.5, 95%CI 0.3–0.9, p = 0.04). The attitudes and practices of the respondents towards rabies control was positive in households with a high/middle socio-economic status (OR 3.4, 95%CI 1.7–7.2, p = 0.0008) but poor in older (≥ 35 years) participants (OR 0.4, 95%CI 0.2–0.7, p = 0.001). It is concluded that rabies awareness campaigns should be developed and conducted to target sectors of the urban community such as those belonging to lower socio-economic sections and schools to improve the residents’ knowledge and practices towards rabies. Educating dog owners about sterilising their pets is also recommended to alter the attitudes of the residents towards FRD population control. [ABSTRACT FROM AUTHOR]

The intracellular protozoan parasite Leishmania donovani causes human visceral leishmaniasis. Intracellular L. donovani that proliferate inside macrophage phagolysosomes compete with the host for arginine, creating a situation that endangers parasite survival. Parasites have a sensor that upon arginine deficiency activates an Arginine Deprivation Response (ADR). L. donovani transport arginine via a high-affinity transporter (LdAAP3) that is rapidly up-regulated by ADR in intracellular amastigotes. To date, the sensor and its ligand have not been identified. Here, we show that the conserved amidino group at the distal cap of the arginine side chain is the ligand that activates ADR, in both promastigotes and intracellular amastigotes, and that arginine sensing and transport binding sites are distinct in L. donovani. Finally, upon addition of arginine and analogues to deprived cells, the amidino ligand activates rapid degradation of LdAAP3. This study provides the first identification of an intra-molecular ligand of a sensor that acts during infection. [ABSTRACT FROM AUTHOR]