Selective activation of TCR-γδ+ cells in endemic Burkitt's lymphoma

<p>Abstract</p> <p>Background</p> <p>The overlap in geographical distribution of <it>Plasmodium falciparum </it>malaria and endemic Burkitt's lymphoma (eBL) – an aggressive Epstein-Barr virus (EBV)-associated B-cell tumour occurring almost exclusively in the tropics – strongly suggests a link between the two diseases. It is suspected that the polyclonal B-cell activation in <it>P. falciparum </it>malaria may precipitate a breakdown in homeostatic T-cell control of EBV-immortalized B-cell proliferation. Previous studies have suggested that a particular T-cell subset, characterized by expression of V<it>δ</it>1⁺<it>γδ </it>T-cell receptors, is important for maintaining B-cell homeostasis, both in <it>P. falciparum</it>- exposed populations and in individuals subject to polyclonal B-cell activation of other aetiology. The objective of the present study was, therefore, to characterize lymphocyte phenotypes and to investigate possible differences in T-cell subset composition and activation status in <it>P. falciparum</it>-exposed Ghanaian children with and without eBL.</p> <p>Methods</p> <p>Venous blood samples in heparin from 21 eBL patients (mean age: 7.0 years; range: 3–11 years), referred to the Burkitt's Tumour Centre at Korle-Bu Teaching Hospital, Accra and 15 healthy, age and sex matched children, were stained with fluorescein isothiocyanate (FITC)-, phycoerythrin (PE)-, R-phycoerythrin (RPE)- and RPE-Cy5-conjugated antibodies (CD3, CD4, CD8, CD25, CD69, CD95, HLA-DR, TCR-<it>γδ</it>, V<it>δ</it>1, V<it>δ</it>3, V<it>γ</it>9 and B-cells) and acquired on a flow cytometer.</p> <p>Results</p> <p>A reduction in the proportion of CD3⁺cells in eBL patients, due mainly to perturbations among TCR-<it>γδ</it>⁺cells was observed. In contrast, the proportions of CD4⁺or CD8⁺cells were relatively unaffected, as were the mean numbers of peripheral blood mononuclear cells.</p> <p>Conclusion</p> <p>Selective changes in numbers and activation status of TCR-<it>γδ</it>⁺cells occurs in Ghanaian children with eBL, a pattern which is similar to <it>P. falciparum</it>-induced changes. The data supports the hypothesis of a regulatory role for V<it>δ</it>1⁺TcR-<it>γδ </it>T-cells in maintaining B-cell homeostasis and provides insights into the pathogenesis of eBL.</p

Empirical and theoretical investigation into the potential impacts of insecticide resistance on the effectiveness of insecticide-treated bed nets.

In spite of widespread insecticide resistance in vector mosquitoes throughout Africa, there is limited evidence that long-lasting insecticidal bed nets (LLINs) are failing to protect against malaria. Here, we showed that LLIN contact in the course of host-seeking resulted in higher mortality of resistant Anopheles spp. mosquitoes than predicted from standard laboratory exposures with the same net. We also found that sublethal contact with an LLIN caused a reduction in blood feeding and subsequent host-seeking success in multiple lines of resistant mosquitoes from the laboratory and the field. Using a transmission model, we showed that when these LLIN-related lethal and sublethal effects were accrued over mosquito lifetimes, they greatly reduced the impact of resistance on malaria transmission potential under conditions of high net coverage. If coverage falls, the epidemiological impact is far more pronounced. Similarly, if the intensity of resistance intensifies, the loss of malaria control increases nonlinearly. Our findings help explain why insecticide resistance has not yet led to wide-scale failure of LLINs, but reinforce the call for alternative control tools and informed resistance management strategies

Screening and field performance of powder-formulated insecticides on eave tube inserts against pyrethroid resistant Anopheles gambiae s.l.:an investigation into 'actives' prior to a randomized controlled trial in Côte d'Ivoire

BACKGROUND: The widespread emergence of insecticide resistance in African malaria vectors remains one of the main challenges facing control programmes. Electrostatic coating that uses polarity to bind insecticide particles is a new way of delivering insecticides to mosquitoes. Although previous tests demonstrated the resistance breaking potential of this application method, studies screening and investigating the residual efficacy of a broader range of insecticides are necessary. METHODS: Eleven insecticide powder formulations belonging to six insecticide classes (pyrethroid, carbamate, organophosphate, neonicotinoid, entomopathogenic fungus and boric acid) were initially screened for residual activity over 4 weeks against pyrethroid resistant Anopheles gambiae sensu lato (s.l.) from the M'bé valley, central Côte d'Ivoire. Tests were performed using the eave tube assay that simulates the behavioural interaction between mosquitoes and insecticide-treated inserts. With the best performing insecticide, persistence was monitored over 12 months and the actual contact time lethal to mosquitoes was explored, using a range of transient exposure time (5 s, 30 s, 1 min up to 2 min) in the tube assays in laboratory. The mortality data were calibrated against overnight release-recapture data from enclosure around experimental huts incorporating treated inserts at the M'bé site. The natural recruitment rate of mosquitoes to the tube without insecticide treatment was assessed using fluorescent dust particles. RESULTS: Although most insecticides assayed during the initial screening induced significant mortality (45-100%) of pyrethroid resistant An. gambiae during the first 2 weeks, only 10% beta-cyfluthrin retained high residual efficacy, killing 100% of An. gambiae during the first month and > 80% over 8 subsequent months. Transient exposure for 5 s of mosquitoes to 10% beta-cyfluthrin produced 56% mortality, with an increase to 98% when contact time was extended to 2 min (P = 0.001). In the experimental hut enclosures, mortality of An. gambiae with 10% beta-cyfluthrin treated inserts was 55% compared to similar rate (44%) of mosquitoes that contacted the inserts treated with fluorescent dusts. This suggests that all host-seeking female mosquitoes that contacted beta-cyfluthrin treated inserts during host-seeking were killed. CONCLUSION: The eave tube technology is a novel malaria control approach which combines house proofing and targeted control of anopheline mosquitoes using insecticide treated inserts. Beta-cyfluthrin showed great promise for providing prolonged control of pyrethroid resistant An. gambiae and has potential to be deployed year-round in areas where malaria parasites are transmitted by highly pyrethroid resistant An. gambiae across sub-Saharan Africa

The role of human and mosquito behaviour in the efficacy of a house-based intervention : Lethal House Lure for Malaria Mosquitoes

Housing improvement such as blocking eaves and screening windows can help in reducing exposure to indoor biting mosquitoes. The impacts of physical barriers could potentially be boosted by the addition of a mechanism that kills mosquitoes as they attempt to enter the house. One example is to combine household screening with EaveTubes, which are insecticide-treated tubes inserted into closed eaves that attract and kill host-searching mosquitoes. The epidemiological impact of screening + EaveTubes is being evaluated in a large cluster randomized trial in Cote d'Ivoire. The study presented here is designed as a complement to this trial to help better understand the functional roles of screening and EaveTubes. We began by evaluating householder behaviour and household condition in the study villages. This work revealed that doors (and to some extent windows) were left open for large parts of the evening and morning, and that even houses modified to make them more 'mosquito proof' often had possible entry points for mosquitoes. We next built two realistic experimental houses in a village to enable us to explore how these aspects of behaviour and household quality affected the impact of screening and EaveTubes. We found that screening could have a substantial impact on indoor mosquito densities, even with realistic household condition and behaviour. By contrast, EaveTubes had no significant impact on indoor mosquito density, either as a stand-alone intervention or in combination with screening. However, there was evidence that mosquitoes recruited to the EaveTubes, and the resulting mortality could create a community benefit. These complementary modes of action of screening and EaveTubes support the rationale of combining the technologies to create a 'Lethal House Lure'. This article is part of the theme issue 'Novel control strategies for mosquito-borne diseases'

Impact and cost-effectiveness of a lethal house lure against malaria transmission in central Côte d'Ivoire : a two-arm, cluster-randomised controlled trial

Background: New vector control tools are required to sustain the fight against malaria. Lethal house lures, which target mosquitoes as they attempt to enter houses to blood feed, are one approach. Here we evaluated lethal house lures consisting of In2Care (Wageningen, Netherlands) Eave Tubes, which provide point-source insecticide treatments against host-seeking mosquitoes, in combination with house screening, which aims to reduce mosquito entry. Methods: We did a two-arm, cluster-randomised controlled trial with 40 village-level clusters in central Côte d'Ivoire between Sept 26, 2016, and April 10, 2019. All households received new insecticide-treated nets at universal coverage (one bednet per two people). Suitable households within the clusters assigned to the treatment group were offered screening plus Eave Tubes, with Eave Tubes treated using a 10% wettable powder formulation of the pyrethroid β-cyfluthrin. Because of the nature of the intervention, treatment could not be masked for households and field teams, but all analyses were blinded. The primary endpoint was clinical malaria incidence recorded by active case detection over 2 years in cohorts of children aged 6 months to 10 years. This trial is registered with ISRCTN, ISRCTN18145556. Findings: 3022 houses received screening plus Eave Tubes, with an average coverage of 70% across the intervention clusters. 1300 eligible children were recruited for active case detection in the control group and 1260 in the intervention group. During the 2-year follow-up period, malaria case incidence was 2·29 per child-year (95% CI 1·97–2·61) in the control group and 1·43 per child-year (1·21–1·65) in the intervention group (hazard ratio 0·62, 95% CI 0·51–0·76; p<0·0001). Cost-effectiveness simulations suggested that screening plus Eave Tubes has a 74·0% chance of representing a cost-effective intervention, compared with existing healthcare activities in Côte d'Ivoire, and is similarly cost-effective to other core vector control interventions across sub-Saharan Africa. No serious adverse events associated with the intervention were reported during follow-up. Interpretation: Screening plus Eave Tubes can provide protection against malaria in addition to the effects of insecticide-treated nets, offering potential for a new, cost-effective strategy to supplement existing vector control tools. Additional trials are needed to confirm these initial results and further optimise Eave Tubes and the lethal house lure concept to facilitate adoption. Funding: The Bill & Melinda Gates Foundation

Global malaria predictors at a localized scale

Malaria is a life-threatening disease caused by Plasmodium parasites transmitted by Anopheles mosquitoes. In 2022, more than 249 million cases of malaria were reported worldwide, with an estimated 608,000 deaths. While malaria incidence has decreased globally in recent decades, some public health gains have plateaued, and many endemic hotspots still face high transmission rates. Understanding local drivers of malaria transmission is crucial but challenging due to the complex interactions between climate, entomological and human variables, and land use. This study focuses on highly climatically suitable and endemic areas in Côte d’Ivoire to assess the explanatory power of coarse climatic predictors of malaria transmission at a fine scale. Using data from 40 villages participating in a randomized controlled trial of a household malaria intervention, the study examines the effects of climate variation over time on malaria transmission. Through panel regressions and statistical modeling, the study investigates which variable (temperature, precipitation, or entomological inoculation rate) and its form (linear or unimodal) best explains seasonal malaria transmission and the factors predicting spatial variation in transmission. The results highlight the importance of temperature and rainfall, with quadratic temperature and all precipitation models performing well, but the causal influence of each driver remains unclear due to their strong correlation. Further, an independent, mechanistic temperature-dependent R0 model based on laboratory data, which predicts that malaria transmission peaks at 25°C and declines at lower and higher temperatures, aligns well with observed malaria incidence rates, emphasizing the significance and predictability of temperature suitability across scales. By contrast, entomological variables, such as entomological inoculation rate, were not strong predictors of human incidence in this context. Finally, the study explores the predictors of spatial variation in malaria, considering land use, intervention, and entomological variables. The findings contribute to a better understanding of malaria transmission dynamics at local scales, aiding in the development of effective control strategies in endemic regions

Registration of cancer in girls remains lower than expected in countries with low/middle incomes and low female education rates.

BACKGROUND: A decade ago it was reported that childhood cancer incidence was higher in boys than girls in many countries, particularly those with low gross domestic product (GDP) and high infant mortality rate. Research suggests that socio-economic and cultural factors are likely to be responsible. This study aimed to investigate the association between cancer registration rate sex ratios and economic, social and healthcare-related factors using recent data (1998-2002). METHODS: For 62 countries, childhood (0-15 years) cancer registration rate sex ratios were calculated from Cancer Incidence in Five Continents Vol IX, and economic, social and healthcare indicator data were collated. RESULTS: Increased age standardised cancer registration rate sex ratio (M:F) was significantly associated with decreasing life expectancy (P=0.05), physician density (P=0.05), per capita health expenditure (P=0.05), GDP (P=0.01), education sex ratios (primary school enrolment sex ratio (P<0.01); secondary school enrolment sex ratio (P<0.01); adult literacy sex ratio (P<0.01)) and increasing proportion living on less than Int$1 per day (P=0.03). CONCLUSION: The previously described cancer registration sex disparity remains, particularly, in countries with poor health system indicators and low female education rates. We suggest that girls with cancer continue to go undiagnosed and that incidence data, particularly in low- and middle-income countries, should continue to be interpreted with caution

Single domain antibodies: promising experimental and therapeutic tools in infection and immunity

Antibodies are important tools for experimental research and medical applications. Most antibodies are composed of two heavy and two light chains. Both chains contribute to the antigen-binding site which is usually flat or concave. In addition to these conventional antibodies, llamas, other camelids, and sharks also produce antibodies composed only of heavy chains. The antigen-binding site of these unusual heavy chain antibodies (hcAbs) is formed only by a single domain, designated VHH in camelid hcAbs and VNAR in shark hcAbs. VHH and VNAR are easily produced as recombinant proteins, designated single domain antibodies (sdAbs) or nanobodies. The CDR3 region of these sdAbs possesses the extraordinary capacity to form long fingerlike extensions that can extend into cavities on antigens, e.g., the active site crevice of enzymes. Other advantageous features of nanobodies include their small size, high solubility, thermal stability, refolding capacity, and good tissue penetration in vivo. Here we review the results of several recent proof-of-principle studies that open the exciting perspective of using sdAbs for modulating immune functions and for targeting toxins and microbes

Evaluating the impact of screening plus eave tubes on malaria transmission compared to current best practice in central Côte d'Ivoire : A two armed cluster randomized controlled trial

Background: Access to long-lasting insecticidal nets (LLINs) has increased and malaria has decreased globally, but malaria transmission remains high in parts of sub-Saharan Africa and insecticide resistance threatens current progress. Eave tubes are a new tool for the targeted delivery of insecticides against mosquitoes attempting to enter houses. The primary objective of this trial is to test whether screening plus eave tubes (SET) provides protection against malaria, on top of universal coverage with LLINs in an area of intense pyrethroid resistance. The trial will also assess acceptability and cost-effectiveness of the intervention. Methods/design: A two-armed, cluster randomized controlled trial will be conducted to evaluate the effect of SET on clinical malaria incidence in children living in central Côte d'Ivoire. Forty villages will be selected based on population size and the proportion of houses suitable for modification with SET. Using restricted randomization, half the villages will be assigned to the treatment arm (SET + LLINs) and the remainder will be assigned to the control arm (LLINs only). In both arms, LLINs will be distributed and in the treatment arm, householders will be offered SET. Fifty children aged six months to eight years old will be enrolled from randomly selected households in each of the 40 villages. Cohorts will be cleared of malaria parasites at the start of the study and one year after recruitment, and will be monitored for clinical malaria case incidence by active case detection over two years. Mosquito densities will be assessed using CDC light traps and human landing catches and a subset of Anopheles mosquitoes will be examined for parity status and tested for sporozoite infection. Acceptability of SET will be monitored using surveys and focus groups. Cost-effectiveness analysis will measure the incremental cost per case averted and per disability-adjusted life year (DALY) averted of adding SET to LLINs. Economic and financial costs will be estimated from societal and provider perspective using standard economic evaluation methods. Discussion: This study will be the first evaluation of the epidemiological impact of SET. Trial findings will show whether SET is a viable, cost-effective technology for malaria control in Côte d'Ivoire and possibly elsewhere. Trial registration: ISRCTN18145556, registered on 01 February 2017 - retrospectively registered