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 &gt; 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.</p

Integrating Models of Diffusion and Behavior to Predict Innovation Adoption, Maintenance, and Social Diffusion

This study documents an investigation into the adoption and diffusion of eave tubes, a novel mosquito vector control, during a large-scale scientific field trial in West Africa. The diffusion of innovations (DOI) and the integrated model of behavior (IMB) were integrated (i.e., innovation attributes with attitudes and social pressures with norms) to predict participants’ (N = 329) diffusion intentions. The findings showed that positive attitudes about the innovation’s attributes were a consistent positive predictor of diffusion intentions: adopting it, maintaining it, and talking with others about it. As expected by the DOI and the IMB, the social pressure created by a descriptive norm positively predicted intentions to adopt and maintain the innovation. Drawing upon sharing research, we argued that the descriptive norm may dampen future talk about the innovation, because it may no longer be seen as a novel, useful topic to discuss. As predicted, the results showed that as the descriptive norm increased, the intention to talk about the innovation decreased. These results provide broad support for integrating the DOI and the IMB to predict diffusion and for efforts to draw on other research to understand motivations for social diffusion

Efficacy of a ‘lethal house lure’ against Culex quinquefasciatus from Bouaké city, Côte d’Ivoire

Background: Eave tube technology is a novel method of insecticide application that uses an electrostatic coating system to boost insecticide efficacy against resistant mosquitoes. A series of previous experiments showed encouraging insecticidal effects against malaria vectors. This study was undertaken to assess the effects of the eave tube approach on other Culicidae, in particular Culex quinquefasciatus, under laboratory and semi-field conditions. Methods: Larvae of Cx. quinquefasciatus from Bouaké were collected and reared to adult stage, and World Health Organization (WHO) cylinder tests were performed to determine their resistance status. WHO standard 3-min cone bioassays were conducted using PermaNet 2.0 netting versus eave tube-treated inserts. To assess the transient exposure effect on Cx. quinquefasciatus, eave tube assay utilizing smelly socks as attractant was performed with exposure time of 30 s, 1 min, and 2 min on 10% beta-cyfluthrin-treated inserts. Residual activity of these treated inserts was then monitored over 9 months. Field tests involving release–recapture of Cx. quinquefasciatus within enclosures around experimental huts fitted with windows and untreated or insecticide-treated eave tubes were conducted to determine house entry preference and the impact of tubes on the survival of this species. Results: Bouaké Cx. quinquefasciatus displayed high resistance to three out of four classes of insecticides currently used in public health. After 3 min of exposure in cone tests, 10% beta-cyfluthrin-treated inserts induced 100% mortality in Cx. quinquefasciatus, whereas the long-lasting insecticidal net (LLIN) only killed 4.5%. With reduced exposure time on the eave tube insert, mortality was still 100% after 2 min, 88% after 1 min, and 44% after 30 s. Mortality following 1 h exposure on 10% beta-cyfluthrin-treated insert was > 80% continuously up to 7 months post-treatment. Data suggest that Cx. quinquefasciatus have a stronger preference for entering a house through the eaves than through windows. Beta-cyfluthrin-treated inserts were able to kill 51% of resistant Cx. quinquefasciatus released within the enclosure. Conclusions: Eave tubes are a novel method for delivery of insecticide to the house. They attract nuisance host-seeking Cx. quinquefasciatus mosquitoes and are as effective in controlling them as they are against pyrethroid-resistant Anopheles gambiae, despite the high level of resistance Cx. quinquefasciatus have developed

Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3

Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups

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

Management of patients with advanced prostate cancer : the report of the Advanced Prostate Cancer Consensus Conference APCCC 2017

BACKGROUND: In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics. OBJECTIVE: To present the report of APCCC 2017. DESIGN, SETTING, AND PARTICIPANTS: Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; "oligometastatic" prostate cancer; castration-naïve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process. RESULTS AND LIMITATIONS: Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data. CONCLUSIONS: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them. PATIENT SUMMARY: The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process

Semi-field studies to better understand the impact of eave tubes on mosquito mortality and behaviour

Background: Eave tubes are a type of housing modification that provide a novel way of delivering insecticides to mosquitoes as they attempt to enter the house. The current study reports on a series of semi-field studies aimed at improving the understanding of how eave tubes might impact mosquito mortality and behaviour. Methods: Experiments were conducted using West African style experimental huts at a field site in M'be, Côte d'Ivoire. Huts were modified in various ways to determine: (i) whether mosquitoes in this field setting naturally recruit to eave tubes; (ii) whether eave tubes can reduce house entry even in the absence of screening; (iii) whether mosquitoes suffer mortality if they attempt to exit a house via treated eave tubes; and, (iv) whether screening and eave tubes might deflect mosquitoes into neighbouring houses without the intervention. Results: Ninety percent more mosquitoes (Anopheles gambiae sensu lato, and other species) entered huts through open eaves tubes compared to window slits. The addition of insecticide-treated eave tubes reduced mosquito entry by 60%, even when windows remained open. Those mosquitoes that managed to enter the huts exhibited a 64% reduction in blood feeding and a tendency for increased mortality, suggesting contact with insecticide-treated inserts prior to hut entry. When An. gambiae mosquitoes were deliberately introduced into huts with treated eave tubes, there was evidence of six times increase in overnight mortality, suggesting mosquitoes can contact treated eave tube inserts when trying to exit the hut. There was no evidence for deflection of mosquitoes from huts with screening, or screening plus eave tubes, to adjacent unmodified huts. Conclusions: Eave tubes are a potentially effective way to target Anopheles mosquitoes with insecticides. That treated eave tubes can reduce mosquito entry even when windows are open is a potentially important result as it suggests that eave tubes might not need to be combined with household screening to have an impact on malaria transmission. The absence of deflection is also a potentially important result as coverage of eave tubes and/or screening is unlikely to be 100% and it is important that households that do not have the technology are not disadvantaged by those that do

Visualization and Identification of IL-7 Producing Cells in Reporter Mice

Interleukin-7 (IL-7) is required for lymphocyte development and homeostasis although the actual sites of IL-7 production have never been clearly identified. We produced a bacterial artificial chromosome (BAC) transgenic mouse expressing ECFP in the Il7 locus. The construct lacked a signal peptide and ECFP (enhanced cyan fluorescent protein ) accumulated inside IL-7-producing stromal cells in thoracic thymus, cervical thymus and bone marrow. In thymus, an extensive reticular network of IL-7-containing processes extended from cortical and medullary epithelial cells, closely contacting thymocytes. Central memory CD8 T cells, which require IL-7 and home to bone marrow, physically associated with IL-7-producing cells as we demonstrate by intravital imaging