Assessing the effects of three anthropogenic activities on the mosquito, Anopheles gambiae s.l. species composition and pyrethroid resistance mechanisms in Abidjan city, Côte d'Ivoire.

Pyrethroid resistance and mechanisms for resistance for Anopheles gambiae sensus lato (s.l.) (Diptera: Culicidae) Giles, were assessed in three urban areas (vegetable farming, industrial and residential) of Abidjan. Susceptibility to pyrethroids (deltamethrin, permethrin and alphacypermethrin), with and without piperonyl butoxide (PBO) pre-exposure was evaluated. Anopheles gambiae complex members were identified using Short Interspersed Nuclear Elements PCR (SINE PCR), and resistance mechanisms (kdr-west, kdr-east and ace-1) and metabolic gene expression (CYP6P5, CYP6M2, CYP6P3, CYP6P4) were determined by real-time polymerase chain reaction (PCR). High resistance to deltamethrin, permethrin and alphacypermethrin was observed in Port-Bouet (vegetable farming) and Treichville (industrial site), whereas moderate resistance to deltamethrin and high resistance to alphacypermethrin and permethrin were found in Abobo (residential site). Pre-exposure to PBO with pyrethroid increased mortalities in all sites. In Treichville, pre-exposure to PBO restored susceptibility to deltamethrin, but not in Port-Bouet or Abobo. In Treichville, An. gambiae Giles sensu stricto (s.s.) was predominant (92.9%), whereas in Abobo and Port-Bouet, An. coluzzii Giles was predominant (73.6% and 66.4%, respectively). The highest kdr-west mutation frequency was in An. gambiae s.s. (42.8%) from Abobo, followed by An. gambiae s.s. (40%) from Port-Bouet and An. gambiae s.s. (35.6%) from Treichville. In An. coluzzii, the highest kdr-west mutation frequency was in Port-Bouet (48.2%), followed by Abobo (28.00%) and Treichville (21.4%). Mutation frequencies of kdr-east were lower in An. gambiae s.s. from Treichville (4.1%) and Port-Bouet (2.1%) and absent in An. gambiae from Abobo. In industrial and vegetable farming areas, CYP6P3 and CYP6M2 were overexpressed compared with Kisumu. The study suggests An. gambiae s.l. distribution and pyrethroid resistance are influenced by human activities. Treichville's industrial area favoured An. gambiae s.s., whereas Abobo's residential and Port-Bouet's vegetable farming areas were dominated by An. coluzzii. Resistance in Treichville and Port-Bouet was associated with kdr (west and east) genes and metabolic genes, whereas in residential areas, only kdr-west genes were observed. These data suggest that PBO + deltamethrin impregnated nets could aid malaria control, benefiting industrial areas of Côte d'Ivoire and other African cities.

An HLA-I signature favouring KIR-educated Natural Killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+ T-cell-mediated immune control in adults.

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children.

Unmanned aerial vehicles for surveillance and control of vectors of malaria and other vector-borne diseases.

The use of Unmanned Aerial Vehicles (UAVs) has expanded rapidly in ecological conservation and agriculture, with a growing literature describing their potential applications in global health efforts including vector control. Vector-borne diseases carry severe public health and economic impacts to over half of the global population yet conventional approaches to the surveillance and treatment of vector habitats is typically laborious and slow. The high mobility of UAVs allows them to reach remote areas that might otherwise be inaccessible to ground-based teams. Given the rapidly expanding examples of these tools in vector control programmes, there is a need to establish the current knowledge base of applications for UAVs in this context and assess the strengths and challenges compared to conventional methodologies. This review aims to summarize the currently available knowledge on the capabilities of UAVs in both malaria control and in vector control more broadly in cases where the technology could be readily adapted to malaria vectors. This review will cover the current use of UAVs in vector habitat surveillance and deployment of control payloads, in comparison with their existing conventional approaches. Finally, this review will highlight the logistical and regulatory challenges in scaling up the use of UAVs in malaria control programmes and highlight potential future developments.

Evaluation of an accelerometer-based monitor for detecting bed net use and human entry/exit using a machine learning algorithm.

BACKGROUND: Distribution of long-lasting insecticidal bed nets (LLINs) is one of the main control strategies for malaria. Improving malaria prevention programmes requires understanding usage patterns in households receiving LLINs, but there are limits to what standard cross-sectional surveys of self-reported LLIN use can provide. This study was designed to assess the performance of an accelerometer-based approach for measuring a range of LLIN use behaviours as a proof of concept for more granular LLIN-use monitoring over longer time periods. METHODS: This study was carried out under controlled conditions from May to July 2018 in Liverpool, UK. A single accelerometer was affixed to the side panel of an LLIN and participants carried out five LLIN use behaviours: (1) unfurling a net; (2) entering an unfurled net; (3) lying still as if sleeping; (4) exiting from under a net; and, (5) folding up a net. The randomForest package in R, a supervised non-linear classification algorithm, was used to train models on 20-s epochs of tagged accelerometer data. Models were compared in a validation dataset using overall accuracy, sensitivity and specificity, receiver operating curves and the area under the curve (AUC). RESULTS: The five-category model had overall accuracy of 82.9% in the validation dataset, a sensitivity of 0.681 for entering a net, 0.632 for exiting, 0.733 for net down, and 0.800 for net up. A simplified four-category model, combining entering/exiting a net into one category had accuracy of 94.8%, and increased sensitivity for net down (0.756) and net up (0.829). A further simplified three-category model, identifying sleeping, net up, and a combined net down/enter/exit category had accuracy of 96.2% (483/502), with an AUC of 0.997 for net down and 0.987 for net up. Models for detecting entering/exiting by adults were significantly more accurate than for children (87.8% vs 70.0%; p < 0.001) and had a higher AUC (p = 0.03). CONCLUSIONS: Understanding how LLINs are used is crucial for planning malaria prevention programmes. Accelerometer-based systems provide a promising new methodology for studying LLIN use. Further work exploring accelerometer placement, frequency of measurements and other machine learning approaches could make these methods even more accurate in the future.

Guessing PINs, One Partial PIN at a Time.

Entering digits of a personal identification number (PIN) is a common form of authentication. One variant of this scheme is to request the digits from a random subset of positions, which is sometimes called a partial PIN. In this paper we consider strategies for guessing the PIN when a partial PIN scheme is in use, which allows the quantification of the strength of this mechanism. We suggest several strategies for guessing the PIN under the assumption that the organisation assigns PINs randomly and requests random positions from the PIN at each login. We present analytic and simulation results from the different strategies and explore their performance when guessing different sizes of PIN and requested subset. We find that the most effective strategies have a reasonable chance of recovering a PIN in tens to hundreds of guesses.

Tenebenal: a meta-diamide with potential for use as a novel mode of action insecticide for public health.

BACKGROUND: There is an urgent need for insecticides with novel modes of action against mosquito vectors. Broflanilide is a meta-diamide, discovered and named Tenebenal™ by Mitsui Chemicals Agro, Inc., which has been identified as a candidate insecticide for use in public health products. METHODS: To evaluate its potential for use in public health, Tenebenal™ was screened using an array of methodologies against Anopheles and Aedes strains. Initially it was assessed for intrinsic efficacy by topical application. Tarsal contact bioassays were then conducted to further investigate its efficacy, as well as its potency and speed of action. The potential of the compound for use in indoor residual spray (IRS) applications was investigated by testing the residual efficacy of a prototype IRS formulation on a range of typical house building substrates, and its potential for use in long-lasting insecticidal nets (LLIN) was tested using dipped net samples. Finally, bioassays using well-characterized insecticide-resistant mosquito strains and an in silico screen for mutations in the insecticide's target site were performed to assess the risk of cross-resistance to Tenebenal™. RESULTS: Tenebenal™ was effective as a tarsal contact insecticide against both Aedes and Anopheles mosquitoes, with no apparent cross-resistance caused by mechanisms that have evolved to insecticides currently used in vector control. Topical application showed potent intrinsic activity against a Kisumu reference strain and an insecticide-resistant strain of Anopheles gambiae. Applied to filter paper in a WHO tube bioassay, Tenebenal™ was effective in killing 100% of susceptible and resistant strains of An. gambiae and Aedes aegypti at a concentration of 0.01%. The discriminating concentration of 11.91 µg/bottle shows it to be very potent relative to chemistries previously identified as having potential for vector control. Mortality occurs within 24 h of exposure, 80% of this mortality occurring within the first 10 h, a speed of kill somewhat slower than seen with pyrethroids due to the mode of action. The potential of Tenebenal™ for development in LLIN and IRS products was demonstrated. At least 12 months residual efficacy of a prototype IRS formulation applied at concentrations up to 200 mg of AI/sq m was demonstrated on a range of representative wall substrates, and up to 18 months on more inert substrates. A dipped net with an application rate of around 2 g/sq m Tenebenal™ killed 100% of exposed mosquitoes within a 3-min exposure in a WHO cone test. CONCLUSIONS: Tenebenal™ is a potent insecticide against adult Aedes and Anopheles mosquitoes, including strains resistant to classes of insecticide currently used in vector control. The compound has shown great potential in laboratory assessment and warrants further investigation into development for the control of pyrethroid-resistant mosquitoes.

Convergence of Password Guessing to Optimal Success Rates.

Password guessing is one of the most common methods an attacker will use for compromising end users. We often hear that passwords belonging to website users have been leaked and revealed to the public. These leaks compromise the users involved but also feed the wealth of knowledge attackers have about users' passwords. The more informed attackers are about password creation, the better their password guessing becomes. In this paper, we demonstrate using proofs of convergence and real-world password data that the vulnerability of users increases as a result of password leaks. We show that a leak that reveals the passwords of just 1% of the users provides an attacker with enough information to potentially have a success rate of over 84% when trying to compromise other users of the same website. For researchers, it is often difficult to quantify the effectiveness of guessing strategies, particularly when guessing different datasets. We construct a model of password guessing that can be used to offer visual comparisons and formulate theorems corresponding to guessing success.

Chronic hepatitis delta virus infection leads to functional impairment and severe loss of MAIT cells.

BACKGROUND & AIMS: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. Although HDV-associated liver disease is considered immune-mediated, adaptive immune responses against HDV are weak. Thus, the role of several other cell-mediated mechanisms such as those driven by mucosa-associated invariant T (MAIT) cells, a group of innate-like T cells highly enriched in the human liver, has not been extensively studied in clinical HDV infection. METHODS: MAIT cells from a sizeable cohort of patients with chronic HDV were analyzed ex vivo and in vitro after stimulation. Results were compared with MAIT cells from hepatitis B virus (HBV) monoinfected patients and healthy controls. RESULTS: Circulating MAIT cells were dramatically decreased in the peripheral blood of HDV-infected patients. Signs of decline were also observed in the liver. In contrast, only a modest decrease of circulating MAIT cells was noted in HBV monoinfection. Unsupervised high-dimensional analysis of residual circulating MAIT cells in chronic HDV infection revealed the appearance of a compound phenotype of CD38hiPD-1hiCD28loCD127loPLZFloEomesloHelioslo cells indicative of activation. Corroborating these results, MAIT cells exhibited a functionally impaired responsiveness. In parallel to MAIT cell loss, HDV-infected patients exhibited signs of monocyte activation and increased levels of proinflammatory cytokines IL-12 and IL-18. In vitro, IL-12 and IL-18 induced an activated MAIT cell phenotype similar to the one observed ex vivo in HDV-infected patients. These cytokines also promoted MAIT cell death, suggesting that they may contribute to MAIT cell activation and subsequent loss during HDV infection. CONCLUSIONS: These results suggest that chronic HDV infection engages the MAIT cell compartment causing activation, functional impairment, and subsequent progressive loss of MAIT cells as the HDV-associated liver disease progresses. LAY SUMMARY: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. We found that in patients with HDV, a subset of innate-like T cells called mucosa-associated invariant T cells (or MAIT cells), which are normally abundant in peripheral blood and the liver, are activated, functionally impaired and severely depleted.

Proteome analysis of human CD56neg NK cells reveals a homogeneous phenotype surprisingly similar to CD56dim NK cells.

NK cells lacking CD56 (CD56neg ) were first identified in chronic HIV-1 infection. However, CD56neg NK cells also exist in healthy individuals, albeit in significantly lower numbers. Here, we provide an extensive proteomic characterisation of human CD56neg peripheral blood NK cells of healthy donors and compare them to their CD56dim and CD56bright counterparts. Unbiased large-scale surface receptor profiling clustered CD56neg cells as part of the main NK cell compartment and indicated an overall CD56dim -like phenotype. Total proteome analyses of CD56neg NK cells further confirmed their similarity with CD56dim NK cells, and revealed a complete cytolytic inventory with high levels of perforin and granzyme H and M. In the present study, twelve proteins discriminated CD56neg NK cells from CD56dim NK cells with nine up-regulated and three down-regulated proteins in the CD56neg NK cell population. Those proteins were functionally related to lytic granule composition and transport, interaction with the extracellular matrix, DNA transcription or repair, and proliferation. Corroborating these results, CD56neg NK cells showed modest cytotoxicity, degranulation, and IFN-É£ secretion as compared to CD56dim NK cells. In conclusion, CD56neg NK cells constitute functionally competent cells sharing many features of bona fide CD56dim NK cells in healthy individuals, but with some distinct characteristics.

Insecticide space spraying for preventing malaria transmission.

BACKGROUND: Space spraying is the dispersal of a liquid fog of insecticide into an outdoor area to kill adult insects. It has been regularly used in public health and pest control programmes, including use as an emergency response to malaria epidemics. This Cochrane Review aims to assist the decision-making of malaria vector control programmes by summarizing the evidence of the impact of space spraying on malaria transmission. OBJECTIVES: The review's primary objective was to evaluate the impact of space spraying on malaria transmission, or the incremental impact when applied in combination with other malaria control methods, in comparison to equivalent conditions with no space spraying intervention.To guide future evaluations of space spraying, a secondary objective was to identify and summarize the range of space spraying strategies that have been trialled, those which were promising and warrant further evaluation, and those which appear unlikely to warrant further evaluation (for example, if they were not feasible to implement, or were unacceptable to the population). SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; PubMed (MEDLINE); Embase (OVID), CAB Abstracts (Web of Science), LILACS (BIREME), the World Health Organization (WHO) International Clinical Trials Registry Platform, and ClinicalTrials.gov up to 18 April 2018. We contacted organizations for ongoing and unpublished trials, and checked the reference lists of all included studies for relevant studies. SELECTION CRITERIA: We included cluster-randomized controlled trials, interrupted time series (ITS) studies, randomized cross-over studies, and controlled before-and-after (CBA) studies comparing space spraying with no space spraying that met the inclusion criteria for the review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and risk of bias, and extracted the data. For ITS studies, we present findings graphically, and estimated the effect of space spraying on the step change and the slope change. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Two ITS studies, conducted between 1972 and 1984, met our inclusion criteria for the primary objective, and one study contributed to the quantitative analysis. This study was conducted in India, reported the incidence of malaria in four separate sites, and covered a total population of 18,460 people. In the pooled analysis across sites, there was no step effect for the incidence of uncomplicated malaria (step rate ratio 1.00, 95% confidence interval (CI) 0.51 to 1.92). There was an effect on the slope: the number of cases was reduced by 15% per month (slope rate ratio 0.85, 95% CI 0.79 to 0.91). Using these ratios, we estimated the effect of 12 months of space spraying on malaria incidence to be a reduction from 6 cases to 1 case per month per 1000 population (95% CI 0 to 2 cases, very low-certainty evidence). The second study reported the impact of space spraying on malaria incidence and adult mosquito density in a population of 15,106 in Haiti, but it did not provide data from previous years. Thus, we could not estimate an effect of space spraying that was independent from temporal trends.For the review's secondary objective, we identified a further two studies in addition to the two ITS studies; both used a CBA design and were conducted between 1973 and 2000. The four studies used a range of delivery methods including handheld, vehicle-mounted, and aircraft-mounted spraying equipment. A variety of insecticides, doses, and spraying times were also used, with methods typically determined based on environmental factors and vector profiles. AUTHORS' CONCLUSIONS: Evidence from one state in India conducted over 30 years ago suggests an effect of space spraying on the incidence of malaria, but the certainty of the evidence is very low. Reliable research in a variety of settings will help establish whether and when this intervention may be worthwhile.