https://doi.org/10.1371/journal.pcbi.1005327.g004. The scientific name "saccharin" suggests that they are consumers of foodstuffs rich in polysaccharides, such as: sugar, starch, glue found in book covers, upholstery, glues, but they also consume textiles made from cotton and silk. The results are given on Table 5. Understanding the geographic . Insecticide exposure had the greatest influence in all strategies with their PRCC coefficients of absolute magnitude greater than 0.75. cit. Seq both is the time until resistance has exceeded 50% to both insecticides that were deployed in sequence. After recovering the results of Curtis, we moved on to a sensitivity analysis of strategy choice in our parameter space. The next step is to allow for mating among the survivors to produce the next mosquito generation. How to get rid of Silverfish - Nexles Similarly, when HCH is deployed in a sequence, resistance to DDT spreads very rapidly from its relatively high frequency so it is the time taken for HCH resistance to reach 50% that largely determines the lifespan of the sequential deployment. The flexibility lies in how the niche exposures are defined and how previous analyses may be run as sub-sets of the whole model with different calibrations, e.g. Although a rich source of literature is available on the lethal effects of . https://doi.org/10.1371/journal.pcbi.1005327.g001. In every case, irrespective of whether mixtures or sequential use was eventually favoured, each insecticide lasted longer when deployed as part of a mixture than when deployed on its own. Parameter names are as defined on Table 4. https://doi.org/10.1371/journal.pcbi.1005327.g008. The Curtis model also made several assumptions, presumably dictated by computing restrictions at the time that we will relax in the development of our current model. [8]) but is surprisingly poorly developed for IR in human disease vectors. [parameter combinations are as used for Curtis in his Fig 2 in [17] (our Fig 2B) with the exception that each effectiveness was reduced by 0.2 to 0.53 for insecticide1 and to 0.8 for insecticide2], https://doi.org/10.1371/journal.pcbi.1005327.g011. No, Is the Subject Area "Public and occupational health" applicable to this article? Yes So far, we have looked at the absolute difference in time to resistance between the sequential and mixture strategies. It shows how the model can generate Fig 2 in [17] and allows the user to change parameter values to examine the consequences of doing so. For example, strict seasonal-rotations of different insecticides can be proposed and enforced. Such considerations could be added to our modelling framework but we have avoided doing so, in the interest of simplicity and brevity. Curtis reported calculations and results for a single generation of selection under a range of assumptions in his Table 1 (note: this table is absent from many current electronic reprints). We do this as follows. Larval pesticide exposure impacts monarch butterfly performance - Nature Yes The symbols (c) and (r) in the genotypes indicate whether the double heterozygotes are in coupling or repulsion, respectively. The use of drug combinations to treat malaria was therefore predicted on the type of population genetic models described above for insecticide resistance (see [6] for access to the literature) which showed that drug combinations should slow the input and subsequent spread of drug-resistant mutations. As for Table 3 but investigating the Curtis example based on field and laboratory data on gamma-hexachlorocyclohexane (HCH) and dichlorodiphenyltrichloroethane (DDT) deployment (Fig 2 in [17]). The Mendelian output of the four gamete types from each parental genotype are indicted in bold where r is the recombination rate between the loci. The first superscript to F indicates gender (male of female) while the second superscript indicates genotype at loci 1 and 2 so, for example, Fm, SS1SR2 is the relative frequency, among males, of the genotype SS at locus 1 and SR at locus 2, and Ff, RR1SR2 is the relative frequency, among females, of the genotype RR at locus 1 with SR at locus 2. Structure and function of an insect -carboxylesterase ( It is interpreted in the standard manner: a value of zero indicates no relationship between variable and outcome, values close to +1 or -1 indicate a variable with a high impact on the outcome, and the signs of the coefficients indicate the direction of the relationship. Two insecticides are deployed i.e. As in other animals, the gut-associated microbiota of mosquitoes affect host fitness and other phenotypes. 600 500 . Curtis used single examples to illustrate and develop his arguments. HCH resistance is the rarer of the resistance alleles when deployment is initiated so is invariably the rate-limiting factor in the dynamics and the time for that allele to reach 50% in a mixture determines the lifespan of the mixture i.e. Insecticide effectiveness (which will later be shown to be important for determining whether sequential use or mixtures are optimal) has a negative impact on times to resistance in sequential use (PRCC -0.5), but has less of an impact in mixtures. These fitnesses are determined by the effectiveness of the insecticides , (i.e. DDT was widely used until environmental concerns plus increasing resistance curtailed its used. The key point is that we do not need to know anything about the resistant SR and RR genotypes (fitness, dominance) which would be impossible to predict prior to them emerging in the population after the strategy decision has been made. [11]) investigated plant-encoded insecticidal toxins rather than insecticides but the models are analogous). His figure incorporates a period of relaxed selection when insecticide is not present, so the simulations must be stopped at generation 3, the genotype frequencies at time of stopping (generation 3) be retained, the exposure variables altered so that no insecticides are encountered, the model run until generation 12, the genotypes values retained and exposure variables changed back to reflect renewed insecticide deployment. The results were obtained from the sensitivity analysis described on Table 4. We can take this into account by making a requirement that time to resistance must be >20% longer in the mixture and this is shown on Fig 8B. Midgut microbiota can participate in the detoxification and metabolism processes in insects, but there are few reports on the relationship between midgut microbiota and insecticide resistance in mosquitoes. Nutrient-rich and well-fertilized soil boosts the growth of plants. i.e. We demonstrate this application by re-deriving the results from previous analyses primarily by Curtis [17] who investigated IR in public health, and, as discussed later, other 2-locus models applied to agriculture; the intention is to show consistency between our simulations and to investigate how robust are the conclusion from that Curtis paper. The model allows differential exposure of males and females, allows them to encounter high or low concentrations of insecticide, and allows selection pressures and dominance values to differ depending on the concentration of insecticide encountered. Our results (see later) suggest this statement is open to a different interpretation but this assertion has influenced public-health insecticide deployment policy for nearly 30 years. Gould [11] assumed additive fitness effects (rather than multiplicative as used here) and assumed mortality of SS homozygotes to be 24% to 48%. The variable names on the X axis are as described and defined on Table 4, except for resist_start_1_div_2 which is the starting frequency of the resistance allele at locus 1 divided by the starting frequency of the resistance allele at locus 2. Malaria is somewhat different, and more similar to insecticide resistance, in that drug-resistant mutations arise relatively rarely and then spread throughout the population (although this depends on the drug: resistance to atovaquone arises very easily from within the infection but, interestingly, has a lethal fitness cost in the insect vector [33]). https://doi.org/10.1371/journal.pcbi.1005327.s002, https://doi.org/10.1371/journal.pcbi.1005327.s003. Encounter insecticides. With the aim of selecting potential botanical insecticides, seven plant extracts (Daphne mucronata (Family: Thymelaeaceae), Tagetes minuta (Asteraceae), Calotropis procera (Apocynaceae), Boenninghausenia albiflora (Rutaceae), Eucalyptus sideroxylon (Myrtaceae), Cinnamomum camphora (Lauraceae) and Isodon rugosus (Lamiaceae)) were screened for their toxic effects against four important . In addition, the paper contained results based on both single-generation and multi-generation arguments. These problems are particularly acute in resource- and infrastructure-poor regions of sub-Saharan Africa. (6) the proportion of SS genotypes killed after contact with the insecticide); setting <1 allows a proportion of SS genotypes to survive contact with the insecticide, h is the dominance coefficient, s is selection coefficient favouring IR, and z is fitness cost of carrying resistance alleles in the absence of insecticide. We also allowed a more flexible description of how mosquitoes encounter insecticides. The paper of Curtis (1985) is extensively discussed above. The distributions of times to resistance in the sensitivity analysis differed for each deployment strategy but with considerable overlap between them (Fig 4). Three deployment policies are investigated as follows. We have assumed that the insecticide with lower levels of resistance would be a newer insecticide replacing an older insecticide where resistance had already reached relatively high frequencies; we therefore assume the new insecticide is the one deployed second in a sequential deployment. Substantial improvements in computer power and simulation software in the subsequent 30+ years enable more sophisticated investigations to be undertaken. mosquitoes surviving contact with an insecticide subsequently produce fewer viable offspring). Their values are their weighted average fitness across the nine different niches, the weighting reflecting the extent of their exposures () in each niche. For example, Tabashnik [15] discussed the impact of mutations encoding cross-resistance to both insecticides and noted that mixtures (and presumably mosaics) would constitute intense selection for cross resistance; this cross resistance can be incorporated using the antagonist/synergistic functions on our S1 Table. For example, the level of insecticide effectivenesses are the primary determinant of whether a mixture or sequential strategy is favoured in the tree shown Fig 8. Panel (C) is time to resistance as a function of the dominance of the resistance alleles, the dominance values being summed to construct the X-axis variable. We develop a flexible, two-locus model for the spread of insecticide resistance applicable to mosquito species that transmit human diseases such as malaria. Many simplifications made by us have been noted in the previous literature. Corn and cotton account for the largest shares of insecticide use in the United States. Frontiers | Interaction of Insecticides and Fungicides in Bees To avoid overfitting, the number of levels in the classification trees was restricted to the minimum where the relative error plus the standard error was less than the cross-validation error. In contrast, in public health there are severe operational difficulties that dictate that robust, simple polices be implemented. The model is implemented in the statistical environment R [28] and the sensitivity analysis uses the packages sensitivity and rpart. (A) Mixtures are deemed superior to sequential deployment if their time to resistance is longer than Sequential deployment (B) Mixtures are only deemed superior to sequential deployment if their time to resistance is at least 20% longer than Sequential. [1116]). The option to allow a locus to be sex-linked was included in the model because Anopheles gambiae has only 2 autosomes and one sex chromosome. The red dotted lines indicate the parameter values used by Curtis in Fig 2 in [17]. Concerns over the potential impact of IR has led the WHO to produce comprehensive plans to try and maintain their effectiveness in malaria control [4] and the influential Insecticide Resistance Action Committee (IRAC; http://www.irac-online.org/) has produced similar, but more general guidelines for controlling vectors of other human vector-borne disease [5]. Our simulations will assume that the effects of insecticides in a mixture are multiplicative e.g. One of the main drawbacks of previous models, at least in our opinions, is that insecticide deployment is assumed to be perfect, i.e. This follows conventional population genetic methodology and is achieved by assigning the fitness of each genotype at each locus, assuming that Locus 1 encodes resistance to insecticide A and Locus 2 encodes resistance to insecticide B. If "male exposure" is 0.6, then male exposure to niches AB, A, and B are 0.56*0.6 = 0.336, 0.12*0.6 = 0.072 and 0.12*0.6 = 0.072 respectively and the proportion unexposed rises to 0.2 + (0.8*0.40) = 0.52. The use of drug combinations for TB and HIV were driven by clinical observations that resistance almost inevitably arose in patients given monotherapies. [27]), but see Gould [11] for an example of thresholds based on mosquito viability. X axis parameters are as defined in Table 4 except from resist_start_1_div_2 and resist_start_hi_div_lo which are defined in the caption to Fig 5. https://doi.org/10.1371/journal.pcbi.1005327.g007, Classification trees based on the sensitivity analysis are shown on Fig 8. In this case we can assume a single, randomly mating mosquito population that can be investigated simply by using two of the single-insecticide niches in Table 1 in conjunction with the unexposed -, -niche. A mismatch in initial gene frequencies will therefore be inevitable, with resistance to the new insecticide being lower than that to the old insecticides. Yes Panel (A) is time to resistance as a function of mosquito exposure to insecticide. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Much of that work is relevant to public health in the tropics but there are two important differences. The one model that did allow relatively low selection pressures against malaria parasites with both resistant and sensitive alleles [27] had selection pressures that depended on the fraction of infected persons who are treated, dosage, and so on; in our terminology this confounded exposure and effectiveness. However the calibration used to replicate Fig 1 in [17] allows us to extend the one-generation argument presented in Table 1(vi) in [17] over the numerous generations required to simulate the spread of resistance (see later discussion of our Table 3). Note that we use females in this summation as we assume sufficient males survive to ensure all eggs are fertilised. The second quote has been extremely influential in guiding deployment of new insecticides. In between these extremes mean time to resistance was slightly shorter for the adaptive mixture strategy, as would be expected because removing the failing insecticide removes any lingering small-scale protection it may have afforded in the mixture. Carbamates may be used as IRS but are expensive. eight in each sex) are calculated in the same way. These values lie between 0 and 1, representing the proportion of the population likely to contact that niche. Finally, the poor deployment pattern is constant over the whole simulation time whereas in reality poor deployment is more likely to occur as random fluctuations over time depending on temporal problems in insecticide supply chain management. The most convenient way to do this is to calculate the relative frequencies of the four possible gametes from each sex (gamete outputs have to be calculated separately for each sex because survival of males and female genotypes may differ depending on their patterns of exposure to insecticides). The reasoning underlying mixtures is that using two different insecticides means that mosquitoes must be resistant to both insecticides to survive. Consequently, it is impossible at present to easily duplicate his work nor to re-calibrate and re-run his models to assess whether his assertions are robust across all parameter values. The second step is to define the fitness of the different genotypes (Table 2); these are all scaled relative to the fully sensitive mosquito in the absence of insecticide (as in a previous single-locus model of resistance evolution [24]) whose fitness is denoted 1. Malaria results in hundreds of thousands of deaths annually. The second caveat is more subjective. One insecticide is deployed until its resistance frequency reaches the 50% threshold, at which point it is replaced by the second insecticide until its resistance allele frequency also reaches the threshold. 9/20 The following corn herbicides* cannot be applied at timings listed below with COUNTER 20G Insecticide: Manufacturer Corn Herbicide Timing Manufacturer Corn Herbicide Timing Within the parameter space investigated mixture strategies can provide greater benefits with time to resistance being more than 200 generations longer than in sequential strategy (upper left of Fig 9). Insecticides can be classified in any of several ways, on the basis of their chemistry, their toxicological action, or their mode of penetration. if exposure is 0.8 and "correct mixture deployment" is 0.7 then 0.8 x 0.7 = 0.56 are exposed to the mixture, while [0.8x0.3]/2 = 0.12 are exposed to insecticide 1 and 0.12 to insecticide 2. Catholic Daily Mass - Daily TV Mass - June 2, 2023 - Facebook However some works did explicitly apply 2-locus models and it is important to reconcile their results with those presented here. The frequency of IR alleles at each locus and the extent of linkage disequilibrium (LD) between the loci. If the current generation is Generation 1 it takes the user-defined input values (which can, if desired, be genotypes that are not in HWE or LE), if not it takes the updated estimates of F produced in the previous generation of the simulation (see below). Risks of large-scale use of systemic insecticides to ecosystem The microbiome and mosquito vectorial capacity: rich potential for The German cockroach (Blattella germanica L.) is a major urban pest worldwide and is known for its ability to resist insecticides. In reality, poor deployment will result in exposure to different concentrations of insecticides in both mixture and sequential applications and our model could be used to investigate these implications further. The impact of this re-analysis of Curtiss results for insecticide deployment strategy depends on the context. insecticide, any toxic substance that is used to kill insects. Rotations are a strategy where one insecticide is periodically withdrawn from use and replaced by another, irrespective of its resistance profile; this has been used in agriculture but not, to our knowledge, in public health. by setting z>0 in column -of Table 2 and these costs may exhibit different levels of dominance quantified by the associated h parameter; fitness costs can be easily ignored (i.e. If we do care about pre-existing insecticides, for example pyrethroids, then a decision has to made that maximises the duration of effectiveness for both insecticides and that decision depends on a variety of factors (Figs 7 to 10). Resistance allele frequency to insecticide 1 deployed alone required 53 generations to exceed 50% (at which point it was replaced by insecticide 2 as indicated by the vertical dotted line). Both loci are assumed to be autosomal in the analyses presented here, although the model is structured to allow sex-linkage to be investigated, see later. Notably, the abstract of this paper states. (B) time to resistance in adaptive mixture minus that under sequential. An obvious question is how can sequential use sometimes be favoured even though resistance to individual insecticides always spreads faster if the insecticide is deployed on its own? The results consistently showed that deploying insecticides as mixtures increases their time to resistance compared to sequential deployment, with time to resistance being ~2.5 fold to ~4 fold longer when deploying insecticides as mixtures. This appears to be the most obvious interpretation given the context, but it has two drawbacks. We therefore . [19] and resistance in other organisms (e.g. The first step is to obtain the genotype frequencies for the current mosquito generation. First, it conflicts with our results (which appear consistent in every other aspect). insecticide effectiveness and exposure (e.g. Unripe olives are rich in oleuropein, a bitter tasting phenolic glycoside that is the main secondary metabolite of the unripe fruit. Yes Hence Curtiss statement could be interpreted as suggesting that deploying a new insecticide as a mixture with an existing insecticide would be counter-productive for the new insecticide because resistance to the new insecticide would spread faster if used in a mixture compared to if it was used alone. 2-loci, resistance to each of two insecticides encoded by different loci, equal exposure of sexes to the insecticide, and perfect deployment of insecticides (we denote insecticide in inverted commas because some studies (e.g. Our analyses suggested that insecticide effectiveness and levels of insecticide exposure were key determinants of whether mixtures outperformed sequential deployment, or vice versa. Other niches were omitted simply by setting exposure levels, , to be zero for the five unrequired niches (Table 1). Mix 1st is the time until resistance reaches 50% against either insecticide deployed in a mixture. One strategy to increase tree stability would be to prune the tree based on cross validation error as described in the methods but in our parameter space this resulted in a tree whose decision structure was based only on insecticide effectiveness; this is a neat result but lacks the illustrative advantages of the unpruned trees we show on Fig 8. The output from females parents is calculated in the same way except that the superscript m in the symbols below is replaced by f. that insecticide effectiveness now has a large coefficient and hence a large influence on determining which deployment strategy is optimal under any given set of parameters. The two most effective malaria control interventions have been insecticide treated bed nets and indoor residual spraying of insecticides but their successes are now threatened by insecticide resistance in mosquitoes.
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