Estimating meaningful change thresholds for Skin Pain-Numeric Rating Scale, Sleep-Numeric Rating Scale and Dermatology Life Quality Index in patients with prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is characterized by intensely itchy nodules/lesions and skin pain, which can have a substantial impact on health-related quality of life (HRQoL). Treatment benefits on such symptoms and impacts are best assessed in trials using patient-reported outcome (PROs) instruments such as Skin Pain Numerical Rating Scale (NRS), Sleep-NRS and Dermatology Life Quality Index (DLQI). However, no guidance exists for interpreting meaningful changes in scores using these PROs in patients with PN. OBJECTIVES: The main objective was to derive within-patient (responder definition) and between-group improvement thresholds for interpreting Skin Pain-NRS, Sleep-NRS and DLQI total scores in patients with PN. The measurement properties of the three PROs were also evaluated. METHODS: Intention-to-treat (ITT), blinded and pooled data were used from the Phase 3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN. Anchor- and distribution-based methods were applied to derive responder definition and between-group thresholds for Skin Pain-NRS, Sleep-NRS and DLQI. Data were additionally used to examine the instrument measurement properties, including reliability, validity and responsiveness. RESULTS: A total of 311 patients (mean age 49.5 years, 65.3% female) were included in the pooled ITT population. The within-patient improvement threshold for Skin Pain-NRS was estimated as 4.0 points, 2.0 points for Sleep-NRS and 9.0 points for DLQI total score. A 1.5-point improvement in Skin Pain-NRS scores, 1.0-point in Sleep-NRS and 4.0-point in DLQI indicated a between-group meaningful change. Adequate to good psychometric properties were demonstrated for all three instruments. CONCLUSIONS: The results of this study can aid interpretation of Skin Pain-NRS, Sleep-NRS and DLQI scores in patients with PN in both clinical trials and clinical practice to better understand and treat PN-related skin pain and the impact of PN on sleep quality and HRQoL.

Global disparity in public awareness of the biological control potential of invertebrates.

Invertebrates make up over 95% of animal biodiversity on Earth and contribute to multiple ecosystem services (ES) in natural and human-dominated systems. One such service, biological control (BC) of herbivorous pests, is a core component of sustainable intensification of agriculture, yet its importance is routinely overlooked. Here we report a macro-scale, cross-cultural assessment of the public visibility (or 'salience') of BC invertebrates, using high-throughput analysis of large bodies of digitized text (i.e., 'culturomics'). Using binomial scientific name frequency as proxy for visibility, we compared the extent to which a given species featured in webpages within either scientific media or the entire worldwide web, and in total search volume at varying spatial scale. For a set of 339 BC invertebrate species, scientific and internet coverage averaged 1020 and 1735 webpages, respectively. Substantial variability was recorded among BC taxa with Coleoptera, Hemiptera and Nematoda having comparatively high visibility. Online visibility exhibited large geographical variability ranging from France covering BC invertebrates on average in 1050 webpages versus Thailand or Indonesia on just 31-38. This work represents the first extensive use of culturomics to assess public visibility of insect-mediated ES. As BC uptake is dictated by stakeholders' access to (agro-ecological) information, our work identifies geographically-delineated areas that are differentially attuned to the concept of invertebrate BC, pinpoints opportunities for focusing education campaigns and awareness-raising, enables real-time tracking of BC public appeal, and informs public policy.

Two sphingomyelin synthase homologues regulate body weight and sphingomyelin synthesis in female brown planthopper, N. lugens (Stål).

Although sphingomyelins known to be are lipid constituents of the plasma membrane in vertebrates, much remains obscure about the metabolism of sphingomyelins in insects. With ultra performance liquid chromatography-time-of-flight-tandem mass spectrometry analysis, we revealed for the first time that sphingomyelins are abundant in Nilaparvata lugens (Stål), the brown planthopper (BPH), and their biosynthesis is carried out by sphingomyelin synthase-like protein 2 (SMSL2), which is homologous to sphingomyelin synthase-related protein (SMSr). Unlike other insect species, high concentrations of sphingomyelins rather than ceramide phosphoethanolamines exist in the BPH. Two putative genes, which are homologous to SMSr, are named Nilaparvata lugens SMS-like 1 (NlSMSL1) and 2 (NlSMSL2). Knockdowns of both NlSMSL2 and NlSMSL1 were conducted but only the first decreased concentrations of sphingomyelins in the BPH, indicating that NlSMSL2 plays a role in the biosynthesis of sphingomyelins. Real-time quantitative PCR analysis revealed both NlSMSL1 and NlSMSL2 are highly expressed in BPH adults, with NlSMSL1 specifically highly expressed in reproductive organs (ovaries and testes) whereas NlSMSL2 was highly expressed in the malpighian tubules. The knockdown of NlSMSL1 or NlSMSL2 increased BPH female body weight but not that of males, suggesting sex-specific roles for SMSLs in influencing BPH body weight. The results suggest that NlSMSL2 catalyses the synthesis of sphingomyelins and maintains female BPH body weight through alteration of sphingolipid content.

Interspecific competition between two generalist parasitoids that attack the leafroller Epiphyas postvittana (Lepidoptera: Tortricidae).

Two generalist parasitoids, Dolichogenidea tasmanica (Cameron) (Hymenoptera: Braconidae) and Therophilus unimaculatus (Turner) (Hymenoptera: Braconidae) attack early instars of tortricid moths, including the light brown apple moth, Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae). The two parasitoids co-exist in natural habitats, while D. tasmanica is dominant in vineyards, whereas T. unimaculatus occurs mainly in adjacent native vegetation. This difference suggests possible competition between the two species, mediated by habitat. Here, we report on the extent of interspecific differences in host discrimination and the outcome of interspecific competition between the two parasitoids. The parasitoids did not show different behavioural responses to un-parasitized hosts or those that were parasitized by the other species. Larvae of D. tasmanica out-competed those of T. unimaculatus, irrespective of the order or interval between attacks by the two species. The host larvae that were attacked by two parasitoids died more frequently before a parasitoid completed its larval development than those that were attacked by a single parasitoid. Dissection of host larvae parasitized by both species indicated that first instars of D. tasmanica attacked and killed larval T. unimaculatus.

Un-nesting DNA Russian dolls - the potential for constructing food webs using residual DNA in empty aphid mummies.

Constructing food-web assemblages comprising parasitoid wasps involves large field collections of hosts followed by labour-intensive rearing of the insects to evaluate the rates of parasitism along with morphological or molecular identification of the parasitoid species. This article presents research towards a new molecular method for the practical and accurate construction of aphid-based food webs. We hypothesize that parasitoid and hyperparasitoid DNA left inside aphid mummies after emergence of these third and fourth trophic-level guilds can be simultaneously detected using universal polymerase chain reaction (PCR) primers for nonspecific DNA amplification in combination with single-stranded conformation polymorphism (SSCP) analysis. Such a protocol theoretically allows food-web construction to be performed with no a priori knowledge of the species present. Moreover, the use of empty mummies circumvents rearing and minimizes labour and time in the field and laboratory. To test our hypothesis, we conducted DNA analyses on laboratory-produced parasitized aphids (mummies) from Myzus persicae and Brevicoryne brassicae (two important aphid pest species) after exposure to the parasitoid Diaeretiella rapae and the hyperparasitoid Asaphes vulgaris. DNA is amplifiable in empty aphid mummies for as long as 3 weeks after parasitoid emergence. However, the simultaneous identification of several species in a single mummy sample was rare, which hinders the accurate inference of trophic links. DNA quality and relative quantity, together with preferential amplification, are potential explanations of current results. Technical refinements are needed to ensure full reliability and detection of complex trophic links. The use of PCR-SSCP for food-web construction is novel, and its potential to include an important number of different species is yet to be fully explored.

The impact of floral resources and omnivory on a four trophic level food web.

Omnivory is common among arthropods, but little is known about how availability of plant resources and prey affects interactions between species operating at the third and fourth trophic level. We used laboratory and field cage experiments to investigate how the provision of flowers affects an omnivorous lacewing, Micromus tasmaniae (Hemerobiidae) and its parasitoid Anacharis zealandica (Figitidae). The adult lacewing is a true omnivore that feeds on both floral resources and aphids, whereas the parasitoid is a life-history omnivore, feeding on lacewing larvae in the larval stage and floral nectar as an adult. We showed that the effect of floral resources (buckwheat) on lacewing oviposition depends on prey (aphid) density, having a positive effect only at low prey density and that buckwheat substantially increases the longevity of the adult parasitoid. In field cages, we tested how provision of flowering buckwheat affects the dynamics of a four trophic level system, comprising parasitoids, lacewings, pea aphids and alfalfa. We found that provision of buckwheat decreased the density of lacewings in the first phase of the experiment when the density of aphids was high. This effect was probably caused by increased rate of parasitism by the parasitoid, which benefits from the presence of buckwheat. Towards the end of the experiment when the aphid populations had declined to low levels, the effect of buckwheat on lacewing density became positive, probably because lacewings were starving in the no-buckwheat treatment. Although presence of buckwheat flowers did not affect aphid populations in the field cages, these findings highlight the need to consider multitrophic interactions when proposing provision of floral resources as a technique for sustainable pest management.

Effects of reduced rates of two insecticides on enzyme activity and mortality of an aphid and its lacewing predator.

By applying insecticides at lower rates of active ingredients per unit area, survival rates of the pests' natural enemies can be enhanced, whereas pest mortality can remain high. The effects of reduced application rates of the insecticides lambda-cyhalothrin and dimethoate on the mortality of bird cherry-oat aphid, Rhopalosiphon padi (L.), and lacewing Micromus tasmaniae Walker were determined in the laboratory and field. Cholinesterase (ChE) and glutathione S-transferase (GST) activities in survivors provided a measure of sublethal effects and general fitness. In the laboratory, lacewings were less sensitive than aphids to both insecticides, and dimethoate was more toxic than lambda-cyhalothrin. However, these results could not be recreated in the field, in part due to very low recapture rates. In summary, lambda-cyhalothrin seemed to have no effect on aphids, but it was toxic to lacewings. Dimethoate was far less toxic in the field, but aphids were still more sensitive than were lacewings. Cholinesterase activity was reduced by dimethoate exposure in the laboratory in both species, but there were species-specific differences. Dimethoate and lambda-cyhalothrin had no effects on GST activity in either species. The high mortality rate for lacewings and aphids exposed to dimethoate in the field suggests that the application rate could be reduced to as low as 10% of that recommended by manufacturers, and this should still be highly efficacious against aphids, while protecting the predatory lacewing. Measurement of enzyme activity could provide a useful indicator of "fitness" of survivors.

Evaluation of transgenic approaches for controlling tuber moth in potatoes.

A wide spectrum of strategies to genetically engineer potato plants resistant to potato tuber moth, Phthorimaea operculella (Zeller), have been investigated. The potato cv Iwa was transformed with a range of genes under the transcriptional control of the CaMV 35S promoter using Agrobacterium-mediated gene transfer. The transferred genes encode protease inhibitors (spleen inhibitor and alpha1-antitrypsin inhibitor), biotin-binding proteins (avidin and streptavidin) and Cry proteins (crylAc9, cry1Ba1, crylCa5 and cry9Aa2). Of these three transgenic approaches, cry genes have proved the most useful. In order to control the expression of the cry genes in foliage and not in the tubers a light-inducible Lhca3 promoter from potato was also used. The interaction of different cry genes was investigated using an experimental approach to simulate gene pyramiding in potato. Potato plants transgenic for both the crylAc9 and cryAa2 genes were developed and evaluated to help provide a more durable resistance to potato tuber moth.

Repellency of volatile oils from plants against three mosquito vectors.

Volatile oils extracted by steam distillation from four plant species (turmeric (Curcuma longa), kaffir lime (Citrus hystrix), citronella grass (Cymbopogon winterianus) and hairy basil (Ocimum americanum)), were evaluated in mosquito cages and in a large room for their repellency effects against three mosquito vectors, Aedes aegypti, Anopheles dirus and Culex quinquefasciatus. The oils from turmeric, citronella grass and hairy basil, especially with the addition of 5% vanillin, repelled the three species under cage conditions for up to eight hours. The oil from kaffir lime alone, as well as with 5% vanillin added, was effective for up to three hours. With regard to the standard repellent, deet alone provided protection for at least eight hours against Ae. aegypti and Cx. quinquefasciatus, but for six hours against An. dirus. However, deet with the addition of 5% vanillin gave protection against the three mosquito species for at least eight hours. The results of large room evaluations confirmed the responses for each repellent treatment obtained under cage conditions. This study demonstrates the potential of volatile oils extracted from turmeric, citronella grass and hairy basil as topical repellents against both day- and night-biting mosquitoes. The three volatile oils can be formulated with vanillin as mosquito repellents in various forms to replace deet (N,N-diethyl-3-methylbenzamide), the most common chemical repellent currently available.

Effects of benzimidazole and triazole fungicide use on epigeic species of Collembola in wheat.

Foliar sprays of the systemic fungicides carbendazim, propiconazole, and triadimenol were applied in summer to replicated barrier-enclosed and open plots in a field of winter wheat in southern England at dose rates equivalent to label recommendations. Surface-active Collembola (springtails) were sampled from the experimental plots by suction sampling and pitfall trapping before and after the fungicide applications. No consistent effects of the fungicides on collembolan activity were detected using pitfall trapping but suction sampling revealed a transient negative effect of propiconazole and triadimenol on the overall abundance of higher collembolan taxa. Among individual species, however, fungicide effects varied spatially. Fewer significant treatment effects were obtained in enclosed than in open plots and no consistent effects of carbendazim were detected. The relevance of these findings to current fungicide usage strategies in British arable crops, which include the use of complex tank mixes, is discussed.

Habitat management to conserve natural enemies of arthropod pests in agriculture.

Many agroecosystems are unfavorable environments for natural enemies due to high levels of disturbance. Habitat management, a form of conservation biological control, is an ecologically based approach aimed at favoring natural enemies and enhancing biological control in agricultural systems. The goal of habitat management is to create a suitable ecological infrastructure within the agricultural landscape to provide resources such as food for adult natural enemies, alternative prey or hosts, and shelter from adverse conditions. These resources must be integrated into the landscape in a way that is spatially and temporally favorable to natural enemies and practical for producers to implement. The rapidly expanding literature on habitat management is reviewed with attention to practices for favoring predators and parasitoids, implementation of habitat management, and the contributions of modeling and ecological theory to this developing area of conservation biological control. The potential to integrate the goals of habitat management for natural enemies and nature conservation is discussed.

Enzymatic synthesis of 4-amino-3,5-diethylphenyl sulfate, a rodent metabolite of alachlor.

Rat liver tissue homogenates were utilized for in vitro enzymatic conversion of 2,6-diethylaniline (DEA) to the important alachlor metabolite 4-amino-3,5-diethylphenyl sulfate (ADEPS), which was also generated as a radiolabeled standard for use in metabolism studies. ADEPS formation in rodents is associated with the production of other reactive metabolites implicated in alachlor rodent carcinogenesis, making dependable access to an ADEPS standard highly desirable. (14)C-DEA was oxidized by rat liver microsomes to (14)C-4-amino-3,5-diethylphenol, which was further converted to ADEPS via addition of the phosphosulfate transferase cofactor adenosine-3'-phosphate-5'-phosphosulfate. Microprobe NMR was used in conjunction with high-resolution mass spectrometry to fully characterize the resulting (14)C-ADEPS and confirm its structure. Because microgram quantities sufficed for full characterization, the enzymatic transformation provides a viable alternative to radiosynthesis of (14)C-ADEPS.

Wound-induced changes in tomato leaves and their effects on the feeding patterns of larval lepidoptera.

Several studies have shown changes in the patterns of damage from feeding insects associated with changes in palatability and overall consumption as a result of wound-induced chemical changes in plants. This paper describes how the pattern of feeding damage made by the larvae of Spodoptera littoralis Boisd. (Lepidoptera: Noctuidae) on tomato is affected by changes in palatability of the leaves. Two sorts of responses to leaves from plants that had received prior damage were observed. Larvae offered a choice of leaves tended to take fewer meals on leaves from previously-wounded plants than on control leaves, frequently rejecting the former after sampling them. On wounded plants this rejection behaviour was associated with a shift in feeding site towards the base of the plant. However, starved larvae offered only a single excised leaf readily ate leaves from wounded plants but took shorter meals on these leaves than on controls. Although it was not directly tested it is possible that this difference in response reflected changes in food selectivity with a differing level of satiation. The results are considered in relation to the adaptive significance of the plant of changes in within-plant distributions of herbivore damage.

An evaluation of the potential effects of ivermectin on the decomposition of cattle dung pats.

The parasiticide ivermectin has been administered to domestic livestock since 1981 to control internal and external parasites, including insects; some of the ivermectin is excreted unchanged in faeces. Concerns over the effects of ivermectin on dung-utilising insect populations and the potential for consequent persistence of dung on pastures have been raised. This paper presents the results of a study over two grazing seasons of the rate of decomposition of cattle dung pats exposed to normal environmental influences. The cattle had been treated at therapeutic levels with either an injectable or a sustained release bolus formulation of ivermectin. It was concluded that the rate of decomposition of the dung pats, the extent of their avoidance by the cows, the organic matter content of the soil and the populations of earthworms in the pastures were not affected by the use of ivermectin.

Hydroxamic acid glucosides in honeydew of aphids feeding on wheat.

DIMBOA glucoside (2-O-/gb-D-glucopyranosyl-4-hydroxy-7-meth-oxy-1,4-benzoxazin-3-one), the main hydroxamic acid (Hx) in intact wheat plants, was detected in the honey dew ofRhopalosiphum padi feeding on seedlings of six wheat cultivars that differed in their concentration of Hx, suggesting that the chemical circulates in the phloem. Neither the aglucone (DIMBOA) nor its main breakdown product were found in any of the honeydew samples. Honey dew production by aphids caged on seedlings of the wheat cultivars and DIMBOA glucoside concentrations in the honeydew followed biphasic curves when plotted against Hx concentration, suggesting passive ingestion of the chemical from the phloem at low Hx concentrations and limited ingestion due to feeding deterrency by Hx in mesophyll cells at high Hx concentrations. The presence of plant toxins such as Hx glucosides in the phloem sap, the main ingesta of aphids, and in the mesophyll cells, has major implications for plant defense, through a feeding deterrent effect during stylet penetration, and deterrency (antixenosis) along with antibiosis during feeding.

The ecological significance of rapid wound-induced changes in plants: insect grazing and plant competition.

This paper investigates the hypothesis that a rapidly induced phytochemical response to grazing damage, such as that seen in tomato, serves to deflect insect herbivores away from leaves soon after damaging them (the grazing dispersal hypothesis). As a result, grazing damage is more dispersed than it otherwise would be, and young leaves, which may be of particular importance to a plant in competition for light, are not damaged excessively. In the first experiment, artificial removal of c. 15% of leaf area led to a significant reduction in plant performance compared with undamaged controls, but only when the plants were grown together in competition for light. The second experiment demonstrated that the distribution of grazing damage within the plant was an important factor in the outcome of competition; in those plants in which grazing was applied to the lower leaves there was no effect of damage upon performance compared with undamaged controls, whereas grazing to the upper leaves significantly reduced plant performance. A third experiment provided some insight into how this interaction between damage and competition comes about. It was shown that damage to leaves led to a rapid drop in the rate of extension growth of the main shoot, especially when the upper leaves were damaged, and normal rates of growth were not resumed for at least 3 days. It is argued that in a rapidly growing canopy, such an effect may mean that a damaged plant loses its position in the height hierarchy. The final experiment showed that previous damage to plants can affect the distribution of subsequent grazing by larvae of Spodoptera littoralis, apparently through a wound-induced reduction in leaf palatability. Plants which had been artificially damaged 48 h previously were grazed significantly less than controls, and the avoidance effect was greatest in the young leaves. These results are consistent with the grazing dispersal hypothesis, and suggest that rapid wound-induced responses may be of greatest significance in species characteristic of fertile environments where competition for light is particularly intense.

Metabolism of alachlor by rat and mouse liver and nasal turbinate tissues.

The metabolism of alachlor was studied using in vitro incubations with microsomal fractions prepared from liver and nasal turbinates of rats and mice. Specifically, the transformation of alachlor to 3,5-diethylbenzoquinone-4-imine was examined. A key intermediate in this pathway was identified as 2,6-diethylaniline, the formation of which required catalysis by microsomal arylamidases. 2,6-Diethylaniline was oxidized to 4-amino-3,5-diethylphenol and the electrophilic 3,5-diethylbenzoquinone 4-imine. Rat nasal tissue possessed high enzymatic activity which can promote the formation of the reactive quinone imine. Whole body autoradiographic analysis demonstrated localization of radioactivity in the rat nasal tissue following oral administration of alachlor. A methylsulfide metabolite of alachlor was shown to be a precursor to 2,6-diethylaniline. The deposition of radioactivity in the rat nasal tissue was more pronounced following oral administration of the methylsulfide metabolite of alachlor.

Temporal and spatial variation in palatability of soybean and cotton leaves following wounding.

Leaves of soybean (Glycine max (L.) Merr.) and cotton (Gossypium hirsutum L.) were mechanically damaged with a single hole and offered to Spodoptera littoralis Boisd (Lep., Noctuidae) larvae in laboratory bioassays at intervals of between 0 and 7 days from damage. The subsequent within-leaf grazing patterns of damaged and undamaged areas were compared using an image-analysing computer, and estimations were made by eye of percentage, areas grazed at three spatial scales. Reduction in palatability of damaged areas of both plant species was detected, at time intervals ranging from 0 to 7 days after damage. This effect was strongest for the longer time intervals and the effect became weaker with increasing distance from the site of damage. These results are discussed in relation to possible defensive roles of wound-induced changes.

Palatability of British trees to insects: constitutive and induced defences.

Undamaged foliage of sixteen species of broadleaved trees was assessed for background (constitutive) palatability using larvae of Spodoptera littoralis (Lepidoptera) in laboratory bioassays. Palatability (dry weight consumed in 48 h) varied significantly between species and exhibited a four-fold range. Leaves of fifteen species were damaged artificially in the field and offered with control (undamaged) leaves to Spodoptera after 48 h and two weeks on the tree. Leaves adjacent to the damaged ones were similarly tested. Ten species exhibited significant (P<0.02) wound induced declines in palatability; damaged and adjacent foliage was involved. Although there was no significant relationship between the trees' constitutive palatability and the number of invertebrate herbivore species they support, this previously-demonstrated relationship closely approached significance when the species showing wound-induced effects were excluded from the regression. These results are discussed within the limitations of laboratory bioassays and the possible field consequences are briefly considered.