High coverage of conventional and long-lasting insecticide treated nets (ITNs and LLINs) in parts of E Africa are associated with reductions in local malaria burdens. Shifts in malaria vector species ...ratio have coincided with the scale-up suggesting that some species are being controlled by ITNs/LLINs better than others.
Between 2005-2006 six experimental hut trials of ITNs and LLINs were conducted in parallel at two field stations in northeastern Tanzania; the first station was in Lower Moshi Rice Irrigation Zone, an area where An. arabiensis predominates, and the second was in coastal Muheza, where An. gambiae and An. funestus predominate. Five pyrethroids and one carbamate insecticide were evaluated on nets in terms of insecticide-induced mortality, blood-feeding inhibition and exiting rates.
In the experimental hut trials mortality of An. arabiensis was consistently lower than that of An. gambiae and An. funestus. The mortality rates in trials with pyrethroid-treated nets ranged from 25-52% for An. arabiensis, 63-88% for An. gambiae s.s. and 53-78% for An. funestus. All pyrethroid-treated nets provided considerable protection for the occupants, despite being deliberately holed, with blood-feeding inhibition (percentage reduction in biting rates) being consistent between species. Veranda exiting rates did not differ between species. Percentage mortality of mosquitoes tested in cone bioassays on netting was similar for An. gambiae and An. arabiensis.
LLINs and ITNs treated with pyrethroids were more effective at killing An. gambiae and An. funestus than An. arabiensis. This could be a major contributing factor to the species shifts observed in East Africa following scale up of LLINs. With continued expansion of LLIN coverage in Africa An. arabiensis is likely to remain responsible for residual malaria transmission, and species shifts might be reported over larger areas. Supplementary control measures to LLINs may be necessary to control this vector species.
Attractive toxic sugar bait (ATSB) sprayed onto vegetation has been successful in controlling Anopheles mosquitoes outdoors. Indoor application of ATSB has yet to be explored. The purpose of this ...study was to determine whether ATSB stations positioned indoors have the potential to kill host-seeking mosquitoes and constitute a new approach to control of mosquito-borne diseases.
Insecticides were mixed with dyed sugar solution and tested as toxic baits against Anopheles arabiensis, An. Gambiae s.s. and Culex quinquefasciatus in feeding bioassay tests to identify suitable attractant-insecticide combinations. The most promising ATSB candidates were then trialed in experimental huts in Moshi, Tanzania. ATSB stations were hung in huts next to untreated mosquito nets occupied by human volunteers. The proportions of mosquitoes killed in huts with ATSB treatments relative to huts with non-insecticide control treatments huts were recorded, noting evidence of dye in mosquito abdomens.
In feeding bioassays, chlorfenapyr 0.5% v/v, boric acid 2% w/v, and tolfenpyrad 1% v/v, mixed in a guava juice-based bait, each killed more than 90% of pyrethroid-susceptible An. Gambiae s.s. and pyrethroid-resistant An. arabiensis and Cx. quinquefasciatus. In the hut trial, mortality rates of the three ATSB treatments ranged from 41-48% against An. arabiensis and 36-43% against Cx. quinquefasciatus and all were significantly greater than the control mortalities: 18% for An. arabiensis, 7% for Cx. quinquefasciatus (p<0.05). Mortality rates with ATSB were comparable to those with long lasting insecticidal nets previously tested against the same species in this area.
Indoor ATSB shows promise as a supplement to mosquito nets for controlling mosquitoes. Indoor ATSB constitute a novel application method for insecticide classes that act as stomach poisons and have not hitherto been exploited for mosquito control. Combined with LLIN, indoor use of ATSB has the potential to serve as a strategy for managing insecticide resistance.
The first comprehensive guide to distributional reinforcement learning, providing a new mathematical formalism for thinking about decisions from a probabilistic perspective.Distributional ...reinforcement learning is a new mathematical formalism for thinking about decisions. Going beyond the common approach to reinforcement learning and expected values, it focuses on the total reward or return obtained as a consequence of an agent's choices—specifically, how this return behaves from a probabilistic perspective. In this first comprehensive guide to distributional reinforcement learning, Marc G. Bellemare, Will Dabney, and Mark Rowland, who spearheaded development of the field, present its key concepts and review some of its many applications. They demonstrate its power to account for many complex, interesting phenomena that arise from interactions with one's environment.The authors present core ideas from classical reinforcement learning to contextualize distributional topics and include mathematical proofs pertaining to major results discussed in the text. They guide the reader through a series of algorithmic and mathematical developments that, in turn, characterize, compute, estimate, and make decisions on the basis of the random return. Practitioners in disciplines as diverse as finance (risk management), computational neuroscience, computational psychiatry, psychology, macroeconomics, and robotics are already using distributional reinforcement learning, paving the way for its expanding applications in mathematical finance, engineering, and the life sciences. More than a mathematical approach, distributional reinforcement learning represents a new perspective on how intelligent agents make predictions and decisions.
There is an urgent need for new insecticides for indoor residual spraying (IRS) which can provide improved and prolonged control of malaria vectors that have developed resistance to existing ...insecticides. The neonicotinoid, clothianidin represents a class of chemistry new to public health. Clothianidin acts as an agonist on nicotinic acetyl choline receptors. IRS with a mixture of Clothianidin and another WHO approved insecticide such as deltamethrin could provide improved control of insecticide resistant malaria vector populations and serve as a tool for insecticide resistance management.
The efficacy and residual activity of a novel IRS mixture of deltamethrin and clothianidin was evaluated against wild pyrethroid resistant An. gambiae sl in experimental huts in Cove, Benin. Two application rates of the mixture were tested and comparison was made with clothianidin and deltamethrin applied alone. To assess the residual efficacy of the treatments on different local wall substrates, the inner walls of the experimental huts were covered with either cement, mud or plywood.
Clothianidin demonstrated a clear delayed expression in mortality of wild pyrethroid resistant An. gambiae sl in the experimental huts which reached its full effect 120 hours after exposure. Overall mortality over the 12-month hut trial was 15% in the control hut and 24-29% in the deltamethrin-treated huts. The mixture of clothianidin 200mg/m2 and deltamethrin 25mg/m2 induced high overall hut mortality rates (87% on mud walls, 82% on cement walls and 61% on wooden walls) largely due to the clothianidin component and high hut exiting rates (67-76%) mostly due to the deltamethrin component. Mortality rates remained >80% for 8-9 months on mud and cement walls. The residual activity trend was confirmed by results from monthly in situ cone bioassays with laboratory susceptible An. gambiae Kisumu strain.
IRS campaigns with the mixture of clothianidin plus deltamethrin have the potential to provide prolonged control of malaria transmitted by pyrethroid resistant mosquito populations.
The pyrethroid knockdown resistance gene (kdr) has become widespread in Anopheles gambiae in West Africa. A trial to test the continuing efficacy of insecticide-treated nets (ITN) and indoor residual ...spraying (IRS) was undertaken in experimental huts at 2 sites in Benin, the first where kdr is present at high frequency (Ladji), the second-where An. gambiae is susceptible (Malanville). Holes were made in the nets to mimic worn nets. At Malanville, 96% of susceptible An. gambiae were inhibited from blood-feeding, whereas at Ladji feeding was uninhibited by ITNs. The mortality rate of An. gambiae in ITN huts was 98% in Malanville but only 30% at Ladji. The efficacy of IRS was equally compromised. Mosquitoes at Ladji had higher oxidase and esterase activity than in a laboratory-susceptible strain, but this fact did not seem to contribute to resistance. Pyrethroid resistance in An. gambiae appears to threaten the future of ITN and IRS in Benin.
We introduce α-Rank, a principled evolutionary dynamics methodology, for the evaluation and ranking of agents in large-scale multi-agent interactions, grounded in a novel dynamical game-theoretic ...solution concept called Markov-Conley chains (MCCs). The approach leverages continuous-time and discrete-time evolutionary dynamical systems applied to empirical games, and scales tractably in the number of agents, in the type of interactions (beyond dyadic), and the type of empirical games (symmetric and asymmetric). Current models are fundamentally limited in one or more of these dimensions, and are not guaranteed to converge to the desired game-theoretic solution concept (typically the Nash equilibrium). α-Rank automatically provides a ranking over the set of agents under evaluation and provides insights into their strengths, weaknesses, and long-term dynamics in terms of basins of attraction and sink components. This is a direct consequence of the correspondence we establish to the dynamical MCC solution concept when the underlying evolutionary model's ranking-intensity parameter, α, is chosen to be large, which exactly forms the basis of α-Rank. In contrast to the Nash equilibrium, which is a static solution concept based solely on fixed points, MCCs are a dynamical solution concept based on the Markov chain formalism, Conley's Fundamental Theorem of Dynamical Systems, and the core ingredients of dynamical systems: fixed points, recurrent sets, periodic orbits, and limit cycles. Our α-Rank method runs in polynomial time with respect to the total number of pure strategy profiles, whereas computing a Nash equilibrium for a general-sum game is known to be intractable. We introduce mathematical proofs that not only provide an overarching and unifying perspective of existing continuous- and discrete-time evolutionary evaluation models, but also reveal the formal underpinnings of the α-Rank methodology. We illustrate the method in canonical games and empirically validate it in several domains, including AlphaGo, AlphaZero, MuJoCo Soccer, and Poker.
Malaria control through use of long-lasting insecticidal nets (LN) is threatened by the selection of anopheline mosquitoes strongly resistant to pyrethroid insecticides. To sustain future ...effectiveness it is essential to identify and evaluate novel insecticides suitable for nets. Mixtures of two insecticides with contrasting mode of action have the potential to kill resistant vectors and restore transmission control provided the formulation can withstand regular washing over the net's life span.
The efficacy of a novel mixture LN, Interceptor® G2, that combines the pyrrole chlorfenapyr and pyrethroid alpha-cypermethrin was evaluated under controlled household conditions (experimental hut trial) and by laboratory bioassay against pyrethroid resistant An. gambiae in Benin before and after standardized washing. Comparison arms included standard alpha-cypermethrin LN, nets hand-treated with chlorfenapyr-only and untreated nets.
The chlorfenapyr-alphacypermethrin LN demonstrated improved efficacy and wash resistance compared to a standard alpha-cypermethrin LN against pyrethroid resistant mosquitoes (resistance ratio 207). In experimental hut trial alpha-cypermethrin LN killed only 20% (95% CI 15-26%) of host-seeking An. gambiae whilst mixture LN killed 71% (95% CI 65-77%). Mixture LN washed 20 times killed 65% (95% CI 58-71%), and thus intensive washing reduced efficacy by only 6% (95% CI 1.3-11%). The chlorfenapyr net killed 76% (95% CI 70-81%). Personal protection and blood feeding inhibition did not differ between mixture and pyrethroid LN; however, the mixture LN was 2.5 (95% CI: 2.1-3.1) times more protective than untreated nets. Standard WHO cone bioassays conducted during day time hours failed to anticipate field efficacy but overnight tunnel tests successfully predicted mixture LN and chlorfenapyr net efficacy in field trials.
Interceptor® G2 LN demonstrates the potential to control transmission and provide community protection over the normal lifespan of long lasting nets where standard pyrethroid LN show signs of failing due to resistance.
Novel chemistry for vector control is urgently needed to counter insecticide resistance in mosquitoes. Here a new meta-diamide insecticide, broflanilide (TENEBENALTM), was evaluated in East African ...experimental huts in Moshi, northern Tanzania. Two consecutive experimental hut trials with broflanilide 50WP were conducted; the first evaluating the efficacy of three concentrations, 50 mg/m2, 100 mg/m2, and 200 mg/m2 using a prototype formulation, and the second trial evaluating an improved formulation. The IRS treatments were applied on both mud and concrete surfaces and efficacy was monitored over time. The mortality, blood-feeding inhibition and exiting behaviour of free-flying wild mosquitoes was compared between treatment arms. Additionally, cone assays with pyrethroid-susceptible and resistant mosquito strains were conducted in the huts to determine residual efficacy. The first trial showed a dosage-mortality response of the prototype formulation and 3-8 months of residual activity, with longer activity on concrete than mud. The second trial with an improved formulation showed prolonged residual efficacy of the 100 mg/m2 concentration to 5-6 months on mud, and mosquito mortality on the concrete surface ranged between 94-100% for the full duration of the trial. In both trials, results with free-flying, wild Anopheles arabiensis echoed the mortality trend shown in cone assays, with the highest dose inducing the highest mortality and the improved formulation showing increased mortality rates. No blood-feeding inhibition or insecticide-induced exiting effects were observed with broflanilide. Broflanilide 50WP was effective against both susceptible and pyrethroid-resistant mosquito strains, demonstrating an absence of cross resistance between broflanilide and pyrethroids. The improved formulation, which has now been branded VECTRONTM T500, resulted in a prolonged residual efficacy. These results indicate the potential of this insecticide as an addition to the arsenal of IRS products needed to maintain both control of malaria and resistance management of malaria-transmitting mosquitoes.
The effectiveness of long-lasting insecticidal nets (LLIN), the primary method for preventing malaria in Africa, is compromised by evolution and spread of pyrethroid resistance. Further gains require ...new insecticides with novel modes of action. Chlorfenapyr is a pyrrole insecticide that disrupts mitochrondrial function and confers no cross-resistance to neurotoxic insecticides. Interceptor® G2 LN (IG2) is an insecticide-mixture LLIN, which combines wash-resistant formulations of chlorfenapyr and the pyrethroid alpha-cypermethrin. The objective was to determine IG2 efficacy under controlled household-like conditions for personal protection and control of wild, pyrethroid-resistant Anopheles funestus mosquitoes.
Experimental hut trials tested IG2 efficacy against two positive controls-a chlorfenapyr-treated net and a standard alpha-cypermethrin LLIN, Interceptor LN (IG1)-consistent with World Health Organization (WHO) evaluation guidelines. Mosquito mortality, blood-feeding inhibition, personal protection, repellency and insecticide-induced exiting were recorded after zero and 20 washing cycles. The trial was repeated and analysed using multivariate and meta-analysis.
In the two trials held in NE Tanzania, An. funestus mortality was 2.27 (risk ratio 95% CI 1.13-4.56) times greater with unwashed Interceptor G2 than with unwashed Interceptor LN (p = 0.012). There was no significant loss in mortality with IG2 between 0 and 20 washes (1.04, 95% CI 0.83-1.30, p = 0.73). Comparison with chlorfenapyr treated net indicated that most mortality was induced by the chlorfenapyr component of IG2 (0.96, CI 0.74-1.23), while comparison with Interceptor LN indicated blood-feeding was inhibited by the pyrethroid component of IG2 (IG2: 0.70, CI 0.44-1.11 vs IG1: 0.61, CI 0.39-0.97). Both insecticide components contributed to exiting from the huts but the contributions were heterogeneous between trials (heterogeneity Q = 36, P = 0.02). WHO susceptibility tests with pyrethroid papers recorded 44% survival in An. funestus.
The high mortality recorded by IG2 against pyrethroid-resistant An. funestus provides first field evidence of high efficacy against this primary, anthropophilic, malaria vector.
The rotational use of insecticides with different modes of action for indoor residual spraying (IRS) is recommended for improving malaria vector control and managing insecticide resistance. ...Insecticides with new chemistries are urgently needed. Broflanilide is a newly discovered insecticide under consideration. We investigated the efficacy of a wettable powder (WP) formulation of broflanilide (VECTRON T500) for IRS on mud and cement wall substrates in laboratory and experimental hut studies against pyrethroid-resistant malaria vectors in Benin, in comparison with pirimiphos-methyl CS (Actellic 300CS). There was no evidence of cross-resistance to pyrethroids and broflanilide in CDC bottle bioassays. In laboratory cone bioassays, broflanilide WP-treated substrates killed > 80% of susceptible and pyrethroid-resistant An. gambiae sl for 6-14 months. At application rates of 100 mg/m
and 150 mg/m
, mortality of wild pyrethroid-resistant An. gambiae sl entering experimental huts in Covè, Benin treated with VECTRON T500 was similar to pirimiphos-methyl CS (57-66% vs. 56%, P > 0.05). Throughout the 6-month hut trial, monthly wall cone bioassay mortality on VECTRON T500 treated hut walls remained > 80%. IRS with broflanilide shows potential to significantly improve the control of malaria transmitted by pyrethroid-resistant mosquito vectors and could thus be a crucial addition to the current portfolio of IRS insecticides.
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