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[...]to the trial in Tanzania,5 the authors now report in The Lancet Infectious Diseases that in Benin,6 the added benefit of the chlorfenapyr ITNs did not extend to the third year after distribution even though a considerably higher percentage of study nets remained in use at 36 months (52% in Benin vs 31% in Tanzania). Countries without substantial agricultural insecticide usage, such as Papua New Guinea, have not seen resistance emerge even after two decades of intensive ITN mass distributions on the same scale as in sub-Saharan Africa.9 As such, it seems worthwhile to explore opportunities to reserve specific insecticide classes for disease vector control; however, there is little economic incentive to develop new chemistries exclusively for public health. ITN coverage has remained largely unchanged since 2015, a trend that coincided with the stagnation of global malaria reduction.12 The work by Accrombessi and colleagues demonstrates that current chlorfenpyr ITNs have a stronger impact on malaria transmission in areas with pyrethroid resistance, but the added benefit is lost after 2 years, when the coverage, and therefore usage, of these nets becomes too low to exert population level effects on mosquitoes.

Plasmodium vivax poses unique challenges for malaria control and elimination, notably the potential for relapses to maintain transmission in the face of drug-based treatment and vector control strategies. We developed an individual-based mathematical model of P. vivax transmission calibrated to epidemiological data from Papua New Guinea (PNG). In many settings in PNG, increasing bed net coverage is predicted to reduce transmission to less than 0.1% prevalence by light microscopy, however there is substantial risk of rebounds in transmission if interventions are removed prematurely. In several high transmission settings, model simulations predict that combinations of existing interventions are not sufficient to interrupt P. vivax transmission. This analysis highlights the potential options for the future of P. vivax control: maintaining existing public health gains by keeping transmission suppressed through indefinite distribution of interventions; or continued development of strategies based on existing and new interventions to push for further reduction and towards elimination. Plasmodium vivax poses a unique challenge for malaria elimination worldwide. Here, White et al. develop an individual-based mathematical model of P. vivax transmission and evaluate intervention strategies in Papua New Guinea.

Papua New Guinea (PNG) has the highest malaria transmission outside of Africa. Long-lasting insecticidal nets (LLINs) are believed to have helped to reduce average malaria prevalence in PNG from 16% in 2008 to 1% in 2014. Since 2015 malaria in PNG has resurged significantly. Here, we present observations documenting decreased bioefficacy of unused LLINs with manufacturing dates between 2013 and 2019 collected from villages and LLIN distributors in PNG. Specifically, we show that of n  = 167 tested LLINs manufactured after 2013, only 17% are fulfilling the required World Health Organisation bioefficacy standards of ≥ 80% 24 h mortality or ≥ 95% 60 min knockdown in bioassays with pyrethroid susceptible Anopheles farauti mosquitoes. In contrast, all (100%, n  = 25) LLINs with manufacturing dates prior to 2013 are meeting these bioefficacy standards. These results suggest that decreased bioefficacy of LLINs is contributing to the malaria resurgence in PNG and increased scrutiny of LLIN quality is warranted. Malaria prevalence in Papua New Guinea has risen in recent years after almost a decade of decline. In this study, the authors demonstrate that long-lasting insecticidal nets used in the country that were manufactured since 2013 have significantly reduced bioefficacy.

A reduction in the number of digits has evolved many times in tetrapods, particularly in cursorial mammals that travel over deserts and plains, yet the underlying developmental mechanisms have remained elusive. Here we show that digit loss can occur both during early limb patterning and at later post-patterning stages of chondrogenesis. In the ‘odd-toed’ jerboa ( Dipus sagitta ) and horse and the ‘even-toed’ camel, extensive cell death sculpts the tissue around the remaining toes. In contrast, digit loss in the pig is orchestrated by earlier limb patterning mechanisms including downregulation of Ptch1 expression but no increase in cell death. Together these data demonstrate remarkable plasticity in the mechanisms of vertebrate limb evolution and shed light on the complexity of morphological convergence, particularly within the artiodactyl lineage. A study of limb development in multiple mammals reveals that evolutionary digit loss has occured in many different ways—at different stages and by different mechanisms, such as regulation of Shh in initial digit specification events or by removal of digits through cell death. Mechanisms of evolutionary limb loss The basic five-digit limb of tetrapods has been altered many times and in many ways during evolution, usually by the progressive loss of digits. Two papers published in this issue of Nature examine the developmental changes underlying digit reduction in mammals. Javier Lopez-Rios et al . look at cattle, where digits three and four are modified to form hooves; digits two and five are vestigial, and the first digit is lost. The first limb bud is shown to be progressively lost as it develops. The Ptch1 gene, which encodes a receptor for the limb-development morphogen Sonic hedgehog (SHH), is upregulated due to evolutionary alteration of a Ptch1 cis -regulatory module that no longer responds to graded SHH signalling during bovine handplate development. Kimberly Cooper et al . show, using a wide range of mammals, that mechanisms of digit loss vary in different lineages. In creatures as varied as the jerboa and the camel, cell death sculpts the tissue in the emerging limb to leave the remaining toes. In other creatures, such as the pig, digit loss is orchestrated by earlier limb patterning events with no increase in cell death. Taken together these findings demonstrate remarkable plasticity in the mechanisms of limb evolution in hooved mammals and rodents, yet reveal a degree of evolutionary convergence.

Background Long-lasting insecticidal nets (LLINs) play a key role in reducing malaria transmission in endemic countries. In a previous study, the authors demonstrated a substantial decrease in the bioefficacy of LLINs for malaria prevention delivered to Papua New Guinea (PNG) between 2013 and 2019. This coincided with a rise in malaria cases in the country. The present study was aimed at determining the underlying cause of the reduced bioefficacy observed in these LLINs. The main hypothesis was that a change in the coating formulation of the respective LLIN product was responsible, and had led to significantly altered product properties and performance. Methods A set of PermaNet ® 2.0 LLIN samples (n = 12) manufactured between 2007 and 2019 was subjected to combustion ion chromatography in order to understand the chemistry of the LLIN polymer coating formulation. In addition, World Health Organization (WHO) LLIN standard wash tests and cone bioassays were conducted to further characterize the change in product performance that occurred between 2012 and 2013. Results High polymer fluorine content (average 3.2 g/kg) was measured in PermaNet ® 2.0 manufactured up to 2012, whereas nets which were manufactured after 2012 contained very little polymer fluorine (average 0.04 g/kg) indicating a coating formulation change from a fluorocarbon (FC)-based to a non-FC-based formulation. The coating formulation change as part of the manufacturing process thus resulted in a significant reduction in bioefficacy. In addition, the manufacturing change affected wash resistance leading to a faster reduction in 24 h mosquito mortality in the non-FC-coated product with consecutive washes. Conclusion A change in coating formulation of PermaNet ® 2.0 resulted in reduced product performance in PNG. Post-2012 PermaNet ® 2.0 LLINs should not be considered to be the same product as PermaNet ® 2.0 LLINs produced prior to and in 2012. Coating formulation changes should be validated to not impact LLIN product performance.

Background Cross-border malaria transmission is an important problem for national malaria control programmes. The epidemiology of cross-border malaria is further complicated in areas where Plasmodium falciparum and Plasmodium vivax are both endemic. By combining passive case detection data with entomological data, a transmission scenario on the northwestern Thai–Myanmar border where P. falciparum is likely driven by importation was described, whereas P. vivax is also locally transmitted. This study highlights the differences in the level of control required to eliminate P. falciparum and P. vivax from the same region. Methods Malaria case data were collected from malaria clinics in Suan Oi village, Tak Province, Thailand between 2011 and 2014. Infections were diagnosed by light microscopy. Demographic data, including migrant status, were correlated with concomitantly collected entomology data from 1330 mosquito trap nights using logistic regression. Malaria infection in the captured mosquitoes was detected by ELISA. Results Recent migrants were almost four times more likely to be infected with P. falciparum compared with Thai patients (OR 3.84, p < 0.001) and cases were significantly associated with seasonal migration. However, P. falciparum infection was not associated with the Anopheles mosquito capture rates, suggesting predominantly imported infections. In contrast, recent migrants were equally likely to present with P. vivax as mid-term migrants. Both migrant groups were twice as likely to be infected with P. vivax in comparison to the resident Thai population (OR 1.96, p < 0.001 and OR 1.94, p < 0.001, respectively). Plasmodium vivax cases were strongly correlated with age and local capture rates of two major vector species Anopheles minimus and Anopheles maculatus (OR 1.23, p = 0.020 and OR 1.33, p = 0.046, respectively), suggesting that a high level of local transmission might be causing these infections. Conclusions On the Thai–Myanmar border, P. falciparum infections occur mostly in the recent migrant population with a seasonality reflecting that of agricultural activity, rather than that of the local mosquito population. This suggests that P. falciparum was mostly imported. In contrast, P. vivax cases were significantly associated with mosquito capture rates and less with migrant status, indicating local transmission. This highlights the different timelines and requirements for P. falciparum and P. vivax elimination in the same region and underlines the importance of multinational, cross-border malaria control.

Background Quality assurance (QA) of insecticide-treated nets (ITNs) delivered to malaria-endemic countries is conducted by measuring physiochemical parameters, but not bioefficacy against malaria mosquitoes. This study explored utility of cone bioassays for pre-delivery QA of pyrethroid ITNs to test the assumption that cone bioassays are consistent across locations, mosquito strains, and laboratories. Methods Double-blinded bioassays were conducted on twenty unused pyrethroid ITNs of 4 brands (100 nets, 5 subsamples per net) that had been delivered for mass distribution in Papua New Guinea (PNG) having passed predelivery inspections. Cone bioassays were performed on the same net pieces following World Health Organization (WHO) guidelines at the PNG Institute of Medical Research (PNGIMR) using pyrethroid susceptible Anopheles farauti sensu stricto ( s.s .) and at Ifakara Health Institute (IHI), Tanzania using pyrethroid susceptible Anopheles gambiae s.s . Additionally, WHO tunnel tests were conducted at IHI on ITNs that did not meet cone bioefficacy thresholds. Results from IHI and PNGIMR were compared using Spearman’s Rank correlation, Bland–Altman (BA) analysis and analysis of agreement. Literature review on the use of cone bioassays for unused pyrethroid ITNs testing was conducted. Results In cone bioassays, 13/20 nets (65%) at IHI and 8/20 (40%) at PNGIMR met WHO bioefficacy criteria. All nets met WHO bioefficacy criteria on combined cone/tunnel tests at IHI. Results from IHI and PNGIMR correlated on 60-min knockdown (KD60) (r s  = 0.6, p  = 0.002,n = 20) and 24-h mortality (M24) (r s  = 0.9, p  < 0.0001,n = 20) but BA showed systematic bias between the results. Of the 5 nets with discrepant result between IHI and PNGIMR, three had confidence intervals overlapping the 80% mortality threshold, with averages within 1–3% of the threshold. Including these as a pass, the agreement between the results to predict ITN failure was good with kappa = 0.79 (0.53–1.00) and 90% accuracy. Conclusions Based on these study findings, the WHO cone bioassay is a reproducible bioassay for ITNs with > 80% M24, and for all ITNs provided inherent stochastic variation and systematic bias are accounted for. The literature review confirms that WHO cone bioassay bioefficacy criteria have been previously achieved by all pyrethroid ITNs (unwashed), without the need for additional tunnel tests. The 80% M24 threshold remains the most reliable indicator of pyrethroid ITN quality using pyrethroid susceptible mosquitoes. In the absence of alternative tests, cone bioassays could be used as part of pre-delivery QA.

An argument with roots in ancient Greek philosophy claims that only humans are capable of a certain class of thought termed conceptual, as opposed to perceptual thought, which is common to humans, the higher animals, and some machines. We outline the most detailed modern version of this argument due to Mortimer Adler, who in the 1960s argued for the uniqueness of the human power of conceptual thought. He also admitted that if conceptual thought were ever manifested by machines, such an achievement would contradict his conclusion. We revisit Adler’s criterion in the light of the past five decades of artificial-intelligence (AI) research, and refine it in view of the classical definitions of perceptual and conceptual thought. We then examine two well-publicized examples of creative works (prose and art) produced by AI systems and show that evidence for conceptual thought appears to be lacking in them. Although clearer evidence for conceptual thought on the part of AI systems may arise in the near future, especially if the global neuronal workspace theory of consciousness prevails over its rival, integrated information theory, the question of whether AI systems can engage in conceptual thought appears to be still open.

Background Direct membrane feeding assays (DMFA) are an important tool to study parasite transmission to mosquitoes. Mosquito feeding rates in these artificial systems require optimization, as there are a number of factors that potentially influence the feeding rates and there are no standardized methods that apply to all anopheline species. Methods A range of parameters prior to and during direct membrane feeding (DMF) were evaluated for their impact on Anopheles farauti sensu stricto feeding rates, including the starving conditions and duration of starving prior to feeding, membrane type, DMF exposure time, mosquito age, feeding in the light versus the dark, blood volume, mosquito density and temperature of water bath. Results The average successful DMFA feeding rate for An. farauti s.s. colony mosquitoes increased from 50 to 85% when assay parameters were varied. Overnight starvation and Baudruche membrane yielded the highest feeding rates but rates were also affected by blood volume in the feeder and the mosquito density in the feeding cups. Availability of water during the pre-feed starvation period did not significantly impact feeding rates, nor did the exposure duration to blood in membrane feeders, the age of mosquitoes (3, 5 and 7 days post-emergence), feeding in the light versus the dark, or the temperature (34 °C, 38 °C, 42 °C and 46 °C) of the water bath. Conclusion Optimal feeding conditions in An. farauti s.s. DMFA were to offer 50 female mosquitoes in a cup (with a total surface area of ~ 340 cm 2 with 1 mosquito/6.8 cm 2 ) that were starved overnight 350–500 µL of blood (collected in heparin-coated Vacutainer tubes) per feeder in feeders with a surface area ~ 5 cm 2 (with a maximum capacity of 1.5 mL of blood) via a Baudruche membrane, for at least 10–20 min. Graphical Abstract