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Background Nets containing pyriproxyfen, an insect growth regulator that sterilizes adult mosquitoes, have become available for malaria control. Suitable methods for investigating vector susceptibility to pyriproxyfen and evaluating its efficacy on nets need to be identified. The sterilizing effects of pyriproxyfen on adult malaria vectors can be assessed by measuring oviposition or by dissecting mosquito ovaries to determine damage by pyriproxyfen (ovary dissection). Method Laboratory bioassays were performed to compare the oviposition and ovary dissection methods for monitoring susceptibility to pyriproxyfen in wild malaria vectors using WHO bottle bioassays and for evaluating its efficacy on nets in cone bioassays. Blood-fed mosquitoes of susceptible and pyrethroid-resistant strains of Anopheles gambiae sensu lato were exposed to pyriproxyfen-treated bottles (100 μg and 200 μg) and to unwashed and washed pieces of a pyriproxyfen long-lasting net in cone bioassays. Survivors were assessed for the sterilizing effects of pyriproxyfen using both methods. The methods were compared in terms of their reliability, sensitivity, specificity, resources (cost and time) required and perceived difficulties by trained laboratory technicians. Results The total number of An. gambiae s.l. mosquitoes assessed for the sterilizing effects of pyriproxyfen were 1745 for the oviposition method and 1698 for the ovary dissection method. Fertility rates of control unexposed mosquitoes were significantly higher with ovary dissection compared to oviposition in both bottle bioassays (99–100% vs. 34–59%, P < 0.05) and cone bioassays (99–100% vs. 18–33%, P < 0.001). Oviposition rates of control unexposed mosquitoes were lower with wild pyrethroid-resistant An. gambiae s.l . Cové, compared to the laboratory-maintained reference susceptible An gambiae sensu stricto Kisumu (18–34% vs. 58–76%, P < 0.05). Sterilization rates of the Kisumu strain in bottle bioassays with the pyriproxyfen diagnostic dose (100 μg) were suboptimal with the oviposition method (90%) but showed full susceptibility with ovary dissection (99%). Wild pyrethroid-resistant Cové mosquitoes were fully susceptible to pyriproxyfen in bottle bioassays using ovary dissection (> 99%), but not with the oviposition method (69%). Both methods showed similar levels of sensitivity (89–98% vs. 89–100%). Specificity was substantially higher with ovary dissection compared to the oviposition method in both bottle bioassays (99–100% vs. 34–48%) and cone tests (100% vs.18–76%). Ovary dissection was also more sensitive for detecting the residual activity of pyriproxyfen in a washed net compared to oviposition. The oviposition method though cheaper, was less reliable and more time-consuming. Laboratory technicians preferred ovary dissection mostly due to its reliability. Conclusion The ovary dissection method was more accurate, more reliable and more efficient compared to the oviposition method for evaluating the sterilizing effects of pyriproxyfen on adult malaria vectors in susceptibility bioassays and for evaluating the efficacy of pyriproxyfen-treated nets.

New classes of long-lasting insecticidal nets (LLINs) combining mixtures of insecticides with different modes of action could put malaria control back on track after rebounds in transmission across sub-Saharan Africa. We evaluated the relative efficacy of pyriproxyfen-pyrethroid LLINs and chlorfenapyr-pyrethroid LLINs compared with standard LLINs against malaria transmission in an area of high pyrethroid resistance in Benin. We conducted a cluster-randomised, superiority trial in Zou Department, Benin. Clusters were villages or groups of villages with a minimum of 100 houses. We used restricted randomisation to randomly assign 60 clusters to one of three LLIN groups (1:1:1): to receive nets containing either pyriproxyfen and alpha-cypermethrin (pyrethroid), chlorfenapyr and alpha-cypermethrin, or alpha-cypermethrin only (reference). Households received one LLIN for every two people. The field team, laboratory staff, analyses team, and community members were masked to the group allocation. The primary outcome was malaria case incidence measured over 2 years after net distribution in a cohort of children aged 6 months–10 years, in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03931473. Between May 23 and June 24, 2019, 53 854 households and 216 289 inhabitants were accounted for in the initial census and included in the study. Between March 19 and 22, 2020, 115 323 LLINs were distributed to 54 030 households in an updated census. A cross-sectional survey showed that study LLIN usage was highest at 9 months after distribution (5532 [76·8%] of 7206 participants), but decreased by 24 months (4032 [60·6%] of 6654). Mean malaria incidence over 2 years after LLIN distribution was 1·03 cases per child-year (95% CI 0·96–1·09) in the pyrethroid-only LLIN reference group, 0·84 cases per child-year (0·78–0·90) in the pyriproxyfen-pyrethroid LLIN group (hazard ratio [HR] 0·86, 95% CI 0·65–1·14; p=0·28), and 0·56 cases per child-year (0·51–0·61) in the chlorfenapyr-pyrethroid LLIN group (HR 0·54, 95% CI 0·42–0·70; p<0·0001). Over 2 years, chlorfenapyr-pyrethroid LLINs provided greater protection from malaria than pyrethroid-only LLINs in an area with pyrethroid-resistant mosquitoes. Pyriproxyfen-pyrethroid LLINs conferred protection similar to pyrethroid-only LLINs. These findings provide crucial second-trial evidence to enable WHO to make policy recommendations on these new LLIN classes. This study confirms the importance of chlorfenapyr as an LLIN treatment to control malaria in areas with pyrethroid-resistant vectors. However, an arsenal of new active ingredients is required for successful long-term resistance management, and additional innovations, including pyriproxyfen, need to be further investigated for effective vector control strategies. UNITAID, The Global Fund.

Long-lasting insecticidal nets (LLINs) have successfully reduced malaria in sub-Saharan Africa, but their effectiveness is now partly compromised by widespread resistance to insecticides among vectors. We evaluated new classes of LLINs with two active ingredients with differing modes of action against resistant malaria vectors. We did a four-arm, cluster-randomised trial in Misungwi, Tanzania. Clusters were villages, or groups of hamlets, with at least 119 households containing children aged 6 months to 14 years living in the cluster's core area. Constrained randomisation was used to allocate clusters (1:1:1:1) to receive one of four types of LLIN treated with the following: α-cypermethrin only (pyrethroid-only [reference] group); pyriproxyfen and α-cypermethrin (pyriproxyfen group); chlorfenapyr and α-cypermethrin (chlorfenapyr group); or the synergist piperonyl butoxide and permethrin (piperonyl butoxide group). At least one LLIN was distributed for every two people. Community members and the field team were masked to group allocation. Malaria prevalence data were collected through cross-sectional surveys of randomly selected households from each cluster, in which children aged 6 months to 14 years were assessed for Plasmodium falciparum malaria infection by rapid diagnostic tests. The primary outcome was malaria infection prevalence at 24 months after LLIN distribution, comparing each of the dual-active-ingredient LLINs to the standard pyrethroid-only LLINs in the intention-to-treat population. The primary economic outcome was cost-effectiveness of dual-active-ingredient LLINs, based on incremental cost per disability-adjusted life-year (DALY) averted compared with pyrethroid-only LLINs, modelled over a 2-year period; we included costs of net procurement and malaria diagnosis and treatment, and estimated DALYs in all age groups. This study is registered with ClinicalTrials.gov (NCT03554616), and is ongoing but no longer recruiting. 84 clusters comprising 39 307 households were included in the study between May 11 and July 2, 2018. 147 230 LLINs were distributed among households between Jan 26 and Jan 28, 2019. Use of study LLINs was reported in 3155 (72·1%) of 4378 participants surveyed at 3 months post-distribution and decreased to 8694 (40·9%) of 21 246 at 24 months, with varying rates of decline between groups. Malaria infection prevalence at 24 months was 549 (45·8%) of 1199 children in the pyrethroid-only reference group, 472 (37·5%) of 1258 in the pyriproxyfen group (adjusted odds ratio 0·79 [95% CI 0·54–1·17], p=0·2354), 512 (40·7%) of 1259 in the piperonyl butoxide group (0·99 [0·67–1·45], p=0·9607), and 326 [25·6%] of 1272 in the chlorfenapyr group (0·45 [0·30–0·67], p=0·0001). Skin irritation or paraesthesia was the most commonly reported side-effect in all groups. Chlorfenapyr LLINs were the most cost-effective LLINs, costing only US$19 (95% uncertainty interval 1–105) more to public providers or $28 (11–120) more to donors per DALY averted over a 2-year period compared with pyrethroid-only LLINs, and saving costs from societal and household perspectives. After 2 years, chlorfenapyr LLINs provided significantly better protection than pyrethroid-only LLINs against malaria in an area with pyrethroid-resistant mosquitoes, and the additional cost of these nets would be considerably below plausible cost-effectiveness thresholds ($292–393 per DALY averted). Before scale-up of chlorfenapyr LLINs, resistance management strategies are needed to preserve their effectiveness. Poor textile and active ingredient durability in the piperonyl butoxide and pyriproxyfen LLINs might have contributed to their relative lack of effectiveness compared with standard LLINs. Joint Global Health Trials scheme (UK Foreign, Commonwealth and Development Office; UK Medical Research Council; Wellcome; UK Department of Health and Social Care), US Agency for International Development, President's Malaria Initiative.

Background Long-lasting insecticidal nets (LLINs) are currently the primary method of malaria control in sub-Saharan Africa and have contributed to a significant reduction in malaria burden over the past 15 years. However, this progress is threatened by the wide-scale selection of insecticide-resistant malaria vectors. It is, therefore, important to accelerate the generation of evidence for new classes of LLINs. Methods This protocol presents a three-arm superiority, single-blinded, cluster randomized controlled trial to evaluate the impact of 2 novel dual-active ingredient LLINs on epidemiological and entomological outcomes in Benin, a malaria-endemic area with highly pyrethroid-resistant vector populations. The study arms consist of (i) Royal Guard® LLIN, a net combining a pyrethroid (alpha-cypermethrin) plus an insect growth regulator (pyriproxyfen), which in the adult female is known to disrupt reproduction and egg fertility; (ii) Interceptor G2® LLIN, a net incorporating two adulticides (alpha-cypermethrin and chlorfenapyr) with different modes of action; and (iii) the control arm, Interceptor® LLIN, a pyrethroid (alpha-cypermethrin) only LLIN. In all arms, one net for every 2 people will be distributed to each household. Sixty clusters were identified and randomised 1:1:1 to each study arm. The primary outcome is malaria case incidence measured over 24 months through active case detection in a cohort of 25 children aged 6 months to 10 years, randomly selected from each cluster. Secondary outcomes include 1) malaria infection prevalence (all ages) and prevalence of moderate to severe anaemia in children under 5 years old, measured at 6 and 18 months post-intervention; 2) entomological indices measured every 3 months using human landing catches over 24 months. Insecticide resistance intensity will also be monitored over the study period. Discussion This study is the second cluster randomised controlled trial to evaluate the efficacy of these next-generation LLINs to control malaria transmitted by insecticide-resistant mosquitoes. The results of this study will form part of the WHO evidence-based review to support potential public health recommendations of these nets and shape malaria control strategies of sub-Saharan Africa for the next decade. Trial registration ClinicalTrials.gov, NCT03931473 , registered on 30 April 2019.

In the last 2 decades, there has been an increase in the geographic range and frequency of vector-borne diseases. Management of mosquito populations has become challenging due to increasing rates of resistance to existing insecticidal products and formulations. Several alternative tools have emerged to suppress or replace mosquito populations. One of these tools is the In2Care Mosquito Station (In2Care station). This dual-action station contains the insect growth regulator pyriproxyfen which disrupts the development of immatures and the entomopathogenic fungus Beauveria bassiana (B. bassiana) strain GHA which kills exposed adult mosquitoes. The In2Care stations have previously been shown to effectively control Aedes aegypti in field settings at a density of 6 stations/acre rather than the label-recommended 10 stations/acre. To further test the efficacy of low station density deployment, we deployed In2Care stations in the Pleasant Street Historic District of Gainesville, Florida, at a density of 3 stations/acre over a period of 2 years in the presence or absence of ground larvicidal applications.The deployment of stations resulted in no measurable impact on Ae. aegypti and Culex quinquefasciatus adult or immature abundance suggesting that the low-density deployment of In2Care stations is insufficient to reduce Ae. aegypti and Cu. quinquefasciatus abundance within treatment areas. Graphical Abstract

The sweet potato (cotton) whitefly Bemisia tabaci is a major agricultural pest in various fields and vegetable crops worldwide. It causes extensive damage by direct feeding on plants, reducing quality, secreting honeydew and transmitting plant viruses. B. tabaci is known for its genetic diversity and considered a complex of biotypes or, as suggested, a complex of distinct cryptic species. Management of whiteflies relies mainly on the use of insecticides; however, its ability to develop resistance to major insecticide classes creates a serious challenge to farmers and pest control specialists. Among the cryptic species of B. tabaci , MED is considered more resistant than the MEAM1 to insecticides such as pyriproxyfen and neonicotinoids; however, in recent years there are other species of B. tabaci including MEAM1, Asia I and Asia II-1 that have developed high resistance to various groups of insecticides. Advanced methods based on molecular and gene sequence data obtained from resistant and susceptible field-collected B. tabaci populations resulted in a better understanding of resistance mechanisms in this pest. Several components of IPM-IRM (Integrated Pest Management-Insecticide Resistance Management) programs such as selective and biorational insecticides, insecticide rotation with different modes of action and nonchemical control methods are among the countermeasures of insecticide resistance management for this pest. In the current review, we concentrate on insecticide resistance and resistance management of B. tabaci, focusing on reports published mainly over the past 10 years.

A Zika virus epidemic emerged in northeast Brazil in 2015 and was followed by a striking increase in congenital microcephaly cases, triggering a declaration of an international public health emergency. This is the final report of the first case-control study evaluating the potential causes of microcephaly: congenital Zika virus infection, vaccines, and larvicides. The published preliminary report suggested a strong association between microcephaly and congenital Zika virus infection. We did a case-control study in eight public maternity hospitals in Recife, Brazil. Cases were neonates born with microcephaly, defined as a head circumference of 2 SD below the mean. Two controls without microcephaly were matched to each case by expected date of delivery and area of residence. We tested the serum of cases and controls and the CSF of cases for detection of Zika virus genomes with quantitative RT-PCR and for detection of IgM antibodies with capture-IgM ELISA. We also tested maternal serum with plaque reduction neutralisation assays for Zika and dengue viruses. We estimated matched crude and adjusted odds ratios with exact conditional logistic regression to determine the association between microcephaly and Zika virus infection. We screened neonates born between Jan 15 and Nov 30, 2016, and prospectively recruited 91 cases and 173 controls. In 32 (35%) cases, congenital Zika virus infection was confirmed by laboratory tests and no controls had confirmed Zika virus infections. 69 (83%) of 83 cases with known birthweight were small for gestational age, compared with eight (5%) of 173 controls. The overall matched odds ratio was 73·1 (95% CI 13·0–∞) for microcephaly and Zika virus infection after adjustments. Neither vaccination during pregnancy or use of the larvicide pyriproxyfen was associated with microcephaly. Results of laboratory tests for Zika virus and brain imaging results were available for 79 (87%) cases; within these cases, ten were positive for Zika virus and had cerebral abnormalities, 13 were positive for Zika infection but had no cerebral abnormalities, and 11 were negative for Zika virus but had cerebral abnormalities. The association between microcephaly and congenital Zika virus infection was confirmed. We provide evidence of the absence of an effect of other potential factors, such as exposure to pyriproxyfen or vaccines (tetanus, diphtheria, and acellular pertussis, measles and rubella, or measles, mumps, and rubella) during pregnancy, confirming the findings of an ecological study of pyriproxyfen in Pernambuco and previous studies on the safety of Tdap vaccine administration during pregnancy. Brazilian Ministry of Health, Pan American Health Organization, and Enhancing Research Activity in Epidemic Situations.

Pyriproxyfen is an insect growth regulator acting as larvicide against a large spectrum of public health insect pests, especially dipterans. It is also widely used in agriculture and horticulture for the control of many insect species. Disrupting the endocrine system by mimicking the activity of the juvenile hormone, pyriproxyfen interferes with metamorphosis in insects and prevents them from reaching maturity and reproducing. Because the aquatic ecosystems can be directly or indirectly contaminated by pyriproxyfen, the goal of this study was to establish the aquatic ecotoxicological profile of pyriproxyfen and to identify the gaps that need to be filled. Pyriproxyfen is photodegraded quickly in water. In the absence of organic matter, its persistence in aerobic water media is also limited especially with high temperature and sunlight. Analysis of the laboratory and in situ results for more than 60 aquatic algae, plants, invertebrates, and vertebrates shows that the toxicity of pyriproxyfen is highly variable including within a same taxonomical group. Abiotic and biotic factors can highly influence the toxicity of the molecule. Pyriproxyfen disrupts the development of numerous species and adversely impacts various physiological events. It can also disturb the behavior of the organisms such as their predatory and swimming performances. Although some experimental studies focus on the environmental fate of pyriproxyfen metabolites, those dealing with their aquatic ecotoxicity assessment are scarce. In the same way, the limited number of studies dealing with the search of pyriproxyfen residues in lake, river, and other natural aquatic media does not include the identification of the metabolites.

Culex quinquefasciatus is an important mosquito vector responsible for the transmission of filarial worms, arthropod-borne viruses like Oropouche, St. Louis encephalitis, and West Nile and protozoans that cause avian malaria. Due to insecticide resistance documented in Cx. quinquefasciatus populations worldwide, integrated vector management programs can benefit from new strategies to control this species. The In2Care Mosquito Station (In2Care station), a commercially available dissemination station containing pyriproxyfen (PPF) and Beauveria bassiana spores, has been shown to be effective against skip-ovipositing Aedes aegypti and Aedes albopictus in previously conducted semifield and field trials.To determine the potential of Cx. quinquefasciatus adult females to autodisseminate PPF and if the In2Care station could be used for Cx. quinquefasciatus control, we assessed its efficacy in a semifield setting against wild Cx. quinquefasciatus. We found that the In2Care station was attractive to gravid Cx. quinquefasciatus females, with a significantly higher percentage of egg rafts laid in the In2Care station compared to alternative ovipots. Adult females successfully autodisseminated PPF from the In2Care station to surrounding ovipots, leading to a significant increase in mosquito emergence inhibition. Additionally, adult Cx. quinquefasciatus exposure to B. bassiana spores significantly reduced mosquito survivorship. These results suggest that the In2Care station may be effective against Cx. quinquefasciatus in addition to Ae. aegypti and Ae. albopictus. Additional field evaluations are needed to assess impacts at the population level.