Immature Survival Research Articles

A GIS-coupled thermal response model for predicting the population growth potential of the red cotton bug, Dysdercus koenigii (Fabricius) (Hemiptera: Pyrrhocoridae) in India under climate change conditions

Recently, the red cotton bug has become a significant menace to cotton in India. With the potential for increased habitat suitability due to predicted temperature rise of 2.5°C under future climate change in India, this pest could become even more severe in certain regions. Addressing the knowledge gap on the temperature-driven population growth of this pest is crucial for developing a climate-resilient pest management strategy. In this study, life history data gathered at various constant temperatures (15°C to 35°C) were used to estimate temperature thresholds and thermal requirements for the red cotton bug development. Stochastic estimation of life table parameters and validation with real-time weather data were performed. The phenology model, integrated into a geographic information system, projected the future pest status based on SSP126 temperature change scenarios for the year 2050. The temperatures between 8.35 – 10.83 °C were estimated as lower developmental thresholds for various immature life stages. The optimum and upper threshold temperatures estimated for different life stages ranged between 22.14 – 28.32°C and 35.80 – 39.08°C, respectively. Thermal requirements of 447.97 degree days for life cycle completion were estimated. The optimum immature survival rates (>70%) were observed at temperatures between 25-30°C. The temperature-dependent decrease in generation times from 90.45 days (15 °C) to 25.44 days (35°C) was observed, whereas maximum fecundity was recorded at 32°C. Simulation at fluctuating temperatures across different cotton growing locations provided reasonably similar results on potential population increase (finite rate of increase: 0.99 - 1.04 females/female/day and a generation time of 44.25 – 83.97 days). Risk mapping highlighted moderate to high suitability (ERI >0.4, GI > 6, and AI >4) of various cotton growing areas under current climate, and projected shifts in suitability under future climate change. The study has generated information valuable for implementing effective and timely pest management strategies for RCB. Integrating the field observations with model outputs can enhance a practical understanding of red cotton bug dynamics.

Demographic toxicology of insect growth regulators on the nontarget ectolarval parasitoid Habrobracon hebetor

Habrobracon hebetor Say (Hymenoptera: Braconidae) is one of the most important parasitoids of many pyralid moths, including the olive leaf moth, Palpita unionalis Hubner (Lepidoptera: Pyralidae). The widespread use of insecticides threatens natural enemies. Assessing the side effects of insecticides on nontarget organisms supports the rational use of insecticides during field application. The present study evaluates the lethal and sublethal effects of three insect growth regulators (IGRs), novaluron, methoxyfenozide, and pyriproxyfen, on P. unionalis and the demographic toxicology of these IGRs on its parasitoid H. hebetor. The LC50 values of these IGRs on P. unionalis were 0.97, 0.176, and 0.00009 ppm, respectively, indicating that pyriproxyfen was the most toxic. When H. hebetor adults were exposed to these LC50 levels under laboratory conditions to determine possible side effects. The IGRs did not affect the paralysis and parasitism rates of the parasitoid nor the sex ratio of its offspring. IGR treatments slightly reduced hatching rates and immature survival by 15–25%, indicating moderate effects on the early developmental stages of H. hebetor. The longevity and fecundity of treated females were each reduced to < 50% of their respective values in untreated females. Additionally, some demographic parameters of the parasitoid were significantly affected by the IGRs. Nevertheless, despite these observed effects, the positive net reproductive rate (R0 > 0) and intrinsic rate of increase (rm > 1) of H. hebetor indicated an exponential population increase that reflects the compatibility of the IGRs with the parasitoid. Our results demonstrated that the tested IGRs could be categorized as relatively harmless compounds to the parasitoid. Following these laboratory assessments, field studies will be required to confirm the effects of the tested IGRs on H. hebetor as well as other nontarget organisms.

Differences in within-plant oviposition preferences and immature survival between Orius predators and the importance of spatial availability of prey.

Oviposition preferences of plant-feeding predators remain a complex topic, as such omnivores choose oviposition sites by assessing both plant characteristics and the quality and quantity of nearby animal food sources. Orius predators are omnivores that oviposit endophytically, thus plant characteristics play an important role in their oviposition choices. In this study, we assessed the oviposition and foraging preferences of O. laevigatus and O. majusculus on vegetative and flowering chrysanthemum plants, and assessed the survival of their offspring on differently aged tissues. Our results show a preference of O. laevigatus for young and tender chrysanthemum tissues, where the survival of the nymphs was longer on a plant diet. In contrast, O. majusculus selected older plant parts when laying its eggs, and nymphs did not survive long on any of the plant tissues offered. The foraging activity of Orius females for animal prey (Ephestia kuehniella eggs) did not reveal any specific pattern for either of the two predators. Furthermore, we tested the plasticity of the within-plant oviposition preferences of O. laevigatus, by offering sentinel prey (E. kuehniella eggs) on distinct plant parts. We found that more eggs were laid in older plant tissue when animal prey was offered lower on the plant. Overall, our findings show that oviposition choices of Orius predators are based on a dynamic interplay between plant characteristics, presence of animal and/or floral food sources among other factors, and that differences may well occur between closely related species based on the importance of plant resources in their diet.

Unveiling protein elicitor MoHrip2: A potent biocontrol agent extracted from Magnaporthe oryzae safeguards Australian tobacco (Nicotiana benthamiana) against tobacco aphid (Myzus nicotianae)

The tobacco aphid (Myzus nicotianae) poses a significant threat to global Australian tobacco (Nicotiana benthamiana) output by inflicting damage through leaf twisting and feeding during its early growth stages. To explore potential herbivore resistance in N. benthamiana, this study investigates the effects of the elicitor protein MoHrip2, derived from Magnaporthe oryzae, on the immature growth, survival, and lifespan of M. nicotianae. Compared to the control group, MoHrip2 treatments at three concentrations (85.24, 51.14, 25.57 μg/mL) reduced M. nicotianae population after 7 days, 14 days, and 21 days. All concentrations significantly reduced aphid colonization rate, except for the lowest elicitor concertation (25.57 μg/mL at 7D). Likewise compared to the control group, the highest concentration of MoHrip2 i.e. 85.24 μg/mL, resulted in a decrease in the growth rates of M. nicotianae (second and third-generation). M. nicotianae colonized control plants quicker than MoHrip2-treated N. benthamiana plants in a host selection test. MoHrip2 (85.24, 51.14, 25.57 μg/mL) concentrations extended M. nicotianae nymphal development. The trichomes and wax on MoHrip2-treated leaves made M. nicotianae environment hostile. M. nicotianae reproduction and colonization were reduced by MoHrip2's leaf surface changes. Electrical penetration graphs (EPGs) against M. nicotianae assessed adult reproductive efficiency and pest-pathogen interaction. MoHrip2-treated N. benthamiana seedlings exhibited increased amounts of expression of genes involved in jasmonic acid (JA), salicylic acid (SA) pathways indicating the activation of systemic defense against M. nicotianae. This study reveals a direct correlation between temperature variations and climatic shifts in N. benthamiana plants, highlighting the potential of MoHrip2 in revolutionizing agroecosystems through enhanced pest management and biocontrol strategies. In conclusion, the present study sheds new light on the potential of MoHrip2, derived from M. oryzae, as an effective biocontrol technique against M. nicotianae, infesting N. benthamiana. These findings provide valuable insights into developing innovative and sustainable solutions for pest management in agricultural practices, considering the evidence presented against M. nicotianae, it can be concluded that implementing integrated pest management and utilizing MoHrip2 for bio control in the agroecosystem is an appropriate approach.

Abstract PR010: Exploratory analysis of tumor tertiary lymphoid structures using a novel artificial intelligence–based approach in patients with muscle-invasive urothelial carcinoma from the CheckMate 274 trial

Abstract Introduction: The phase 3 randomized CheckMate 274 trial in patients (pts) with high-risk muscle-invasive urothelial carcinoma (MIUC) demonstrated improved disease-free survival (DFS) with nivolumab (NIVO) vs placebo (PBO) in intent-to-treat (ITT) and tumor programmed death ligand 1 expression ≥1% pts (primary endpoints). With extended follow-up, continued efficacy was observed, and immature overall survival favored NIVO in both populations. Extending from previous exploratory tumor biomarker analyses (Necchi et al. ESMO 2022), we conducted a post hoc analysis of tertiary lymphoid structures (TLS), which are ectopic lymphoid structures often found within the solid tumor microenvironment. A subset of TLS has been associated with improved outcomes to neoadjuvant immunotherapy in UC. Using artificial intelligence (AI)–based algorithms, we explored the biomarker utility of TLS from CheckMate 274. Methods: We used a reproducible AI-based algorithm to identify and classify TLS in situ using hematoxylin and eosin (H&amp;E) images from pretreatment tumor tissue specimens (n=272/699 treated pts). Images were scored for the presence or absence of lymphoid aggregate (LA), immature TLS (iTLS), and mature TLS (mTLS) and scored as either positive (+) or negative (−) for the respective TLS category. Relationships between TLS categories and DFS were explored (minimum follow-up, 5.9 months). Results: Most tumors exhibited some form of LA/TLS (245/272; 90.1%), with a higher incidence of LA (237/272; 87.1%) compared with mTLS (89/272; 32.7%). There was heterogeneity of TLS within the tumors, with most tumors demonstrating more than 1 form of TLS (198/272; 72.8%). In the PBO arm, median DFS was modest for most TLS categories (5.7–8.3 months) but was substantially improved for mTLS+ tumors (22.1 months; 95% CI, 5.4–not estimable [NE]); n=41), representing a 2.7- to 3.9-fold increase relative to any other category. In contrast, treatment with NIVO resulted in 2.1- to 4.0-fold improvements in median DFS relative to PBO across all but the mTLS+ category (22.9 months; 95% CI,11.9–NE; n=48), which was similar to the PBO arm. The largest increases in median DFS (95% CI) for NIVO vs PBO were observed for LA+ (27.6 [16.1–NE; n=114] vs 8.3 [5.6–11.9; n=123] months; HR, 0.56; 95% CI, 0.39–0.80; P=0.0015), iTLS+ (27.0 [16.1–NE; n=91] vs 8.2 [5.4–21.2; n=105] months; HR, 0.61; 95% CI, 0.41–0.91; P=0.0143), and mTLS− tumors (24.6 [11.4–NE; n=81] vs 6.1 [5.2–8.5; n=102] months; HR, 0.53; 95% CI, 0.36–0.78; P=0.0012]). Conclusion: These results suggest that a novel AI-based TLS maturity classification using H&amp;E images is feasible to investigate the tumor microenvironment in MIUC, with potential broad application in other studies. Citation Format: Johannes Alfred Witjes, Matthew D. Galsky, Jürgen E. Gschwend, Dean F. Bajorin, Matthew I. Milowsky, Gautam Jha, Roger Li, Jun Li, Vanessa Matos-Cruz, Scott Ely, George Lee, Vipul Baxi, Joshua Zhang, Saurabh Gupta, Justin M. David. Exploratory analysis of tumor tertiary lymphoid structures using a novel artificial intelligence–based approach in patients with muscle-invasive urothelial carcinoma from the CheckMate 274 trial [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR010.

Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis

New cancer drugs can be approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints while data on overall survival are still incomplete or immature, with too few deaths for meaningful analysis. We aimed to evaluate whether clinical trials with immature survival data generated evidence of overall survival benefit during the period after marketing authorisation, and where that evidence was reported. In this retrospective analysis, we searched Drugs@FDA to identify cancer drug indications approved between Jan 1, 2001, and Dec 31, 2018, on the basis of immature survival data. We systematically collected publicly available data on postapproval overall survival results in labelling (Drugs@FDA), journal publications (MEDLINE via PubMed), and clinical trial registries (ClinicalTrials.gov). The primary outcome was availability of statistically significant overall survival benefits during the period after marketing authorisation (until March 31, 2023). Additionally, we evaluated the availability and timing of overall survival findings in labelling, journal publications, and ClinicalTrials.gov records. During the study period, the FDA granted marketing authorisation to 223 cancer drug indications, 95 of which had overall survival as an endpoint. 39 (41%) of these 95 indications had immature survival data. After a minimum of 4·3 years of follow-up during the period after marketing authorisation (and median 8·2 years [IQR 5·3-12·0] since FDA approval), additional survival data from the pivotal trials became available in either revised labelling or publications, or both, for 38 (97%) of 39 indications. Additional data on overall survival showed a statistically significant benefit in 12 (32%) of 38 indications, whereas mature data yielded statistically non-significant overall survival findings for 24 (63%) indications. Statistically significant evidence of overall survival benefit was reported in either labelling or publications a median of 1·5 years (IQR 0·8-2·3) after initial approval. The median time to availability of statistically non-significant overall survival results was 3·3 years (2·2-4·5). The availability of overall survival results on ClinicalTrials.gov varied considerably. Fewer than a third of indications approved with immature survival data showed a statistically significant overall survival benefit after approval. Notable inconsistencies in timing and availability of information after approval across different sources emphasise the need for better reporting standards. None.

The effects of nano- and microplastic ingestion on the survivorship and reproduction of Aedes aegypti and Aedes albopictus (Diptera: Culicidae).

Microplastics (MPs) and nanoplastics (NPs) are pervasive environmental pollutants that are commonly ingested by organisms at different trophic levels. While the effects of MPs on aquatic organisms have been extensively studied, the impacts of MP ingestion on the host fitness of terrestrial organisms, mainly insects, have been relatively unexplored. This study investigates the effects of MP and NP ingestion on the survivorship and reproduction of 2 medically important mosquito species, Aedes aegypti Linnaeus (Diptera: Culicidae) and Aedes albopictus Skuse (Diptera: Culicidae). Larval and pupal survivorship of Ae. albopictus were not significantly affected by particle size or concentration, but there was a reduction of Ae. aegypti pupal survivorship associated with the ingestion of 0.03 µm NPs. In addition, there was little observed impact of 0.03 µm NP and 1.0 µm MP ingestion on adult survivorship, fecundity, and longevity. To further investigate the effects of MP ingestion on mosquito fitness, we also examined the effects of MPs of varying shape, size, and plastic polymer type on Ae. aegypti immature and adult survivorship. The data suggest that the polymer type and shape did not impact Ae. aegypti immature or adult survivorship. These findings highlight that understanding the effects of microplastic ingestion by mosquitoes may be complicated by the size, composition, and amount ingested.

Combining temperature-dependent life table data into Insect Life Cycle Model to forecast fall armyworm Spodoptera frugiperda (JE Smith) distribution in maize agro-ecological zones in Africa.

The fall armyworm (FAW), Spodoptera frugiperda (JE Smith) (Lepidoptera: Noctuidae), an invasive agricultural pest, has significantly impacted crop yields across Africa. This study investigated the relationship between temperature and FAW life history traits, employing life cycle modeling at temperatures of 20, 25, 28, 30, and 32°C. The development time for eggs, larvae, and pupae varied from 0-3 days, 10-18 days, and 7-16 days, respectively. The optimal temperature range for immature stage survival and female fecundity was identified as 21-25°C, with the intrinsic rate of increase (rm) and gross reproductive rate (GRR) peaking at 25-28°C. Model validation confirmed the accuracy of these findings. The research further projected the Establishment Risk Index (ERI), Activity Index (AI), and Generation Index (GI) for FAW under current and future climates (2050 and 2070) using RCP 2.6 and RCP 8.5 scenarios. Results indicate that RCP 2.6 leads to a reduction in high-risk FAW areas, particularly in central Africa. Conversely, RCP 8.5 suggests an increase in areas conducive to FAW activity. These findings highlight the impact of climate policy on pest dynamics and the importance of incorporating climatic factors into pest management strategies. The study predicts a potential decrease in FAW prevalence in West Africa by 2070 under aggressive climate mitigation, providing a basis for future FAW management approaches.

Exposure to low-concentration fipronil impairs survival, behavior, midgut morphology and physiology of Aedes aegypti larvae

The Aedes aegypti mosquito is a vector for various arboviruses, including dengue and yellow fever. Insecticides, such as pyrethroids and organophosphates, are widely used to manage and control these insects. However, mosquitoes have developed resistance to these chemicals. Therefore, this study aimed to investigate the effects of the commercial formulation of fipronil (Tuit® Florestal; 80% purity) on the survival, behavior, morphology, and proteins related to signaling pathways of the midgut in A. aegypti larvae under controlled laboratory conditions. Significant reductions in immature survival were observed in all concentrations of fipronil tested. Low insecticide concentration (0.5 ppb) led to decreased locomotor activity in the larvae and caused disorganization of the epithelial tissue in the midgut. Moreover, exposure to the insecticide decreased the activity of detoxifying enzymes such as catalase, superoxide dismutase, and glutathione-S-transferase. On the other hand, the insecticide increased protein oxidation and nitric oxide levels. The detection of LC3, caspase-3, and JNK proteins, related to autophagy and apoptosis, increased after exposure. However, there was a decrease in the positive cells for ERK 1/2. Furthermore, the treatment with fipronil decreased the number of positive cells for the proteins FMRF, Prospero, PH3, Wg, Armadillo, Notch, and Delta, which are related to cell proliferation and differentiation. These findings demonstrate that even at low concentrations, fipronil exerts larvicidal effects on A. aegypti by affecting behavior and enzymatic detoxification, inducing protein oxidation, free radical generation, midgut damage and cell death, and inhibiting cell proliferation and differentiation. Thus, this insecticide may represent a viable alternative for controlling the spread of this vector.

Mating disruption alters the rate of development in an aphidophagous ladybird Propylea dissecta (Mulsant)

Ladybird beetles like many other organisms show developmental rate polymorphism in response to various abiotic and biotic factors. Since mating disruption acts as a stressor, we decided to study its impact on the occurrence of developmental rate polymorphs in ladybird beetle, Propylea dissecta Mulsant, 1850 (Coleoptera: Coccinellidae). Ten-day-old females were subjected to mating disruptions at 120, 180 min, and complete mating (211 ± 8.1 min) and then provided with optimum diet of Aphis craccivora Koch. Larvae in each treatment were reared individually and newly emerged adults were assessed on the basis of their developmental durations. They were separated into two lines: slow and fast developers. Extended mating duration was found to be correlated to increased immature survival and reduced offspring development times. Also, in complete mating treatment, percentage of fast developers were more in numbers; thus, mating duration increased the availability of sperm for females and seminal fluid may have boosted maternal protein reserves, which can then be used to produce offspring of better quality. Mating disruption might be a factor reducing the chances of fertilization success and offspring development in P. dissecta.

Wolbachia Infection through Hybridization to Enhance an Incompatible Insect Technique-Based Suppression of Aedes albopictus in Eastern Spain.

The emergence of insecticide resistance in arbovirus vectors is putting the focus on the development of new strategies for control. In this regard, the exploitation of Wolbachia endosymbionts is receiving increasing attention due to its demonstrated effectiveness in reducing the vectorial capacity of Aedes mosquitoes. Here, we describe the establishment of a naïve Wolbachia infection in a wild Aedes albopictus population of eastern Spain through a hybridization approach to obtain males capable of sterilizing wild females. The obtained lines were compared with the Wolbachia donor, Ae. albopictus ARwP, previously artificially infected with Wolbachia wPip, regarding immature and adult survival, female fecundity, egg fertility, and level of induced sterility. Our results did not show significant differences between lines in any of the biological parameters analyzed, indicating the full suitability of the hybrids to be used as a control tool against Ae. albopictus. In particular, hybrid males induced 99.9% sterility in the eggs of wild females without the need for any preliminary treatment. Being harmless to non-target organisms and the environment, the use of this bacterium for the control of Ae. albopictus deserves further exploration. This is especially relevant in areas such as eastern Spain, where this mosquito species has recently spread and may represent a serious threat due to its competence as a vector for dengue, chikungunya, and Zika viruses.

Behavioral responses and life history traits of Taiwanese and Indonesian populations of Aedes aegypti surviving deltamethrin–clothianidin treatment

BackgroundIndoor residual spraying (IRS) capitalizes on the natural behavior of mosquitoes because Aedes aegypti commonly seeks indoor resting sites after a blood meal. This behavior allows mosquitoes to be exposed to insecticide-treated surfaces and subsequently killed. Combinations of deltamethrin and clothianidin with different modes of action have shown promise in IRS, effectively targeting both susceptible and pyrethroid-resistant malaria vectors. However, the effects of this approach on Aedes mosquitoes remain unclear. The present study tested the effects of deltamethrin–clothianidin mixture treatment on behavioral responses and life history traits of Taiwanese and Indonesian populations of Ae. aegypti.MethodsWe adopted an excito-repellent approach to explore the behavioral responses of pyrethroid-resistant Ae. aegypti populations from Indonesia and Taiwan to a deltamethrin–clothianidin mixture used in contact irritancy and non-contact repellency treatments. We further evaluated the life history traits of surviving mosquitoes (i.e., delayed mortality after 7-day post-treatment, longevity, fecundity, and egg hatching) and investigated the potential transgenerational hormetic effects of insecticide exposure (i.e., development rate and survival of immatures and adult mosquitos).ResultsAll tested field populations of Ae. aegypti displayed strong contact irritancy responses; the percentage of escape upon insecticide exposure ranged from 38.8% to 84.7%. However, repellent effects were limited, with the escape percentage ranging from 4.3% to 48.9%. We did not observe immediate knockdown or mortality after 24 h, and less than 15% of the mosquitoes exhibited delayed mortality after a 7-day exposure period. However, the carryover effects of insecticide exposure on the survival of immature mosquitoes resulted in approximately 25% higher immature mortality than that in the control. By contrast, we further documented stimulated survivor reproduction and accelerated transgenerational immature development resulting from the sublethal effects of the insecticide mixture. In particular, the number of eggs laid by treated (both treatments) female mosquitoes increased by at least 60% compared with that of eggs laid by control female mosquitoes.ConclusionsIRS with deltamethrin–clothianidin effectively deters Aedes mosquitoes from entering residential areas and thereby reduces mosquito bites. However, the application rate (deltamethrin: 25 mg/m2; clothianidin: 200 mg/m2) may be insufficient to effectively kill Aedes mosquitoes. Insecticide response appears to vary across mosquito species; their behavioral and physiological responses to sublethal doses have crucial implications for mosquito control programs.Graphical

Temperature-dependent development and life tables of Palpita unionalis (Lepidoptera: Pyralidae)

Abstract Palpita unionalis Hubner (Lepidoptera: Pyralidae) is one of the primary pests in olive orchards, damaging buds and fruits of the olive tree. The present study investigated the biology of P. unionalis across a temperature gradient and elaborated on the corresponding life tables for a better understanding of its population dynamics in the environment. The biology of the pest was studied at six temperatures (17, 20, 22, 25, 27, and 30 °C). The duration and survival of immature stages, sex ratio, and survival of emerged adults were evaluated. The female fecundity and longevity (pre-oviposition, oviposition, and post-oviposition periods) were calculated. The life tables were elaborated from these parameters. The life cycle of P. unionalis was significantly longer at 17 °C and shorter at 30 °C. Larval survival was significantly reduced at 30 °C, however, adult survival was at a maximum, yet their sex ratio was not affected by temperature. The lower temperature, 20 °C, was optimal for fecundity (586.3 eggs), which was reflected in the highest net reproductive rate (105.7 offspring per individual). The thermal constant (K) and the lower thermal threshold (t 0) for egg to adult period were 582.9° days and 7.1 °C, respectively. Based on the current study, it is concluded from the parameters of biology and life tables that temperature has a significant role in the population growth of P. unionalis. This should be considered throughout the monitoring and management of P. unionalis at different agro-ecologies in the context of global warming.

Latitudinal variation in survival and immature development of Ceratitis capitata populations reared in two key overwintering hosts

Ceratitis capitata, a major agricultural pest, is currently expanding its geographic distribution to northern, temperate areas of Europe. Its seasonal biology and invasion success depend on temperature, humidity and host availability. In coastal warmer Mediterranean regions and cooler temperature areas, bitter oranges and apples serve as overwintering hosts during the larval stage. We assessed the overwintering capacity of C. capitata populations obtained from different areas of the northern hemisphere by studying the survival and development rates of immature stages in both fruits under laboratory conditions. Eggs from each population were artificially inserted in the flesh of the two hosts and kept at 15, 20, or 25 °C until pupation and adult emergence. Climatic analysis of the area of the population origin showed combined effects of latitude, host and macroclimatic variables on immature survival and development rates. Egg to adult survival rates and developmental duration were longer in apples than in bitter oranges. For populations originated from southern-warmer areas, egg to adult developmental duration was prolonged and adult emergence reduced at 15 °C compared to those populations obtained from northern regions. Our findings reveal varying plastic responses of medfly populations to different overwintering hosts and temperatures highlighting the differential overwintering potential as larvae within fruits. This study contributes towards better understanding the medfly invasion dynamics in temperate areas of Northern Europe and other parts of the globe with similar climates.

An updated cost-effectiveness analysis of axicabtagene ciloleucel in second-line large B-cell lymphoma patients in the United States

Aims This economic evaluation of axicabtagene ciloleucel (axi-cel) versus previous standard of care (SOC; salvage chemotherapy followed by high-dose therapy with autologous stem cell rescue) in the second line (2L) large B-cell lymphoma population is an update of previous economic models that contained immature survival data. Methods This analysis is based on primary overall survival (OS) ZUMA-7 clinical trial data (median follow-up of 47.2 months), from a United States (US) payer perspective, with a model time horizon of 50 years. Mixture cure models were used to extrapolate updated survival data; subsequent treatment data and costs were updated. Patients who remained in the event-free survival state by 5 years were assumed to have achieved long-term remission and not require subsequent treatment. Results Substantial survival and quality of life benefits were observed despite 57% of patients in the SOC arm receiving subsequent cellular therapy: median model-projected (ZUMA-7 trial Kaplan–Meier estimated) OS was 78 months (median not reached) for axi-cel versus 25 months (31 months) for SOC, resulting in incremental quality-adjusted life year (QALY) difference of 1.63 in favor of axi-cel. Incrementally higher subsequent treatment costs were observed in the SOC arm due to substantial crossover to cellular therapies, thus, when considering the generally accepted willingness to pay threshold of $150,000 per QALY in the US, axi-cel was cost-effective with an incremental cost-effectiveness ratio of $98,040 per QALY. Conclusions Results remained consistent across a wide range of sensitivity and scenario analysis, including a crossover adjusted analysis, suggesting that the mature OS data has significantly reduced the uncertainty of axi-cel’s cost-effectiveness in the 2L setting in the US. Deferring treatment with CAR T therapies after attempting a path to transplant may result in excess mortality, lower quality of life and would be an inefficient use of resources relative to 2L axi-cel.

Salicylic acid and fertilizers affect the performance of Panonychus citri (McGregor) (Acari; Tetranychidae) on citrus seedlings

ABSTRACT The citrus red mite, Panonychus citri (McGregor), is one of the most important pests of citrus trees. The use of non-selective and wide-spectrum insecticides leads to a reduction in the natural enemy presence against this pest and turns P. citri into a serious pest in citrus orchards. In the present study, the induction of resistance was carried out in two-year-old citrus seedlings using a foliar application of amino acid, humic acid, potassium, vermiwash, and salicylic acid (SA) against P. citri. The data indicated a lower survival rate, longer immature duration, shorter adult longevity, and lower fecundity due to an increase in the resistance of citrus. The developmental time of immature stages, survival, and fecundity was lowest in combined treatments, intermediate in individual treatments, and highest in control and vermiwash treatments. Population growth parameters of P. citri including net reproductive rate, intrinsic rate of increase, finite rate of increase, and generation time were lower when the mites fed on combined treatments, especially on potassium+SA. These results suggest that the application of a combination of fertilizer and SA on citrus trees can lead to a significant reduction in caused damage by citrus red mites. http://www.zoobank.org/urn:lsid:zoobank.org:pub:unique-alpha-numeric-id

MSR77 Can Bayesian Informative Priors Improve Extrapolation of Immature Overall Survival? A Case Study in Advanced Melanoma

MSR77 Can Bayesian Informative Priors Improve Extrapolation of Immature Overall Survival? A Case Study in Advanced Melanoma

Compatibility of pesticides with the predatory mite Neoseiulus barkeri.

Multiple arthropod pests can affect the same crop in agricultural systems, requiring the integration of control methods. In the present study, the effects of residual exposure to four broad-spectrum insecticides/acaricides (azadiractin, abamectin, chlorfenapyr, and fenpyroximate) on immature (development and survival time) and adult females (longevity, fecundity, and fertility life table parameters) of the predatory mite Neoseiulus barkeri were evaluated. Additionally, the insecticides/acaricides were categorized according to their selectivity based on the classification proposed by the International Organization for Biological Control (IOBC) for assessing the susceptibility of arthropods in laboratory experiments. Method 004, proposed by the Insecticide Resistance Action Committee (IRAC), was adopted for the bioassays with predators exposed to insecticide-acaricide residues. Among the insecticides/acaricides studied, azadirachtin had minimal effects on immature and adult N. barkeri (all non-significant) and was considered harmless based on the classification of toxicity according to the standards/categories proposed by the IOBC. All other insecticides/acaricides affected immature and adult N. barkeri and were considered slightly harmful in terms of toxicity, according to the IOBC.

Statistical Challenges from Trials of Potentially Curative Treatments: Validation of Cure Assumptions When Analyzing Zuma-7 Follow-up Data of Axi-Cel and Standard of Care Therapy

Introduction: ZUMA-7 is the largest randomized controlled trial (RCT) for chimeric antigen receptor (CAR) T-cell therapy which compared axicabtagene ciloleucel (Axi-cel) to standard of care (SoC) including autologous stem cell transplant (ASCT) for the treatment of relapsed or refractory DLBCL. Both arms of ZUMA-7 contained potentially curative treatments; however, differences in the treatment completion rate (94% received axi-cel and 36% received ASCT) and timing to receive definitive treatment led to differences in the extent and timing of cure. Furthermore, 57% of the SoC arm received potentially curative CAR-T therapies in subsequent lines of therapy leading to a delayed cure in that fraction of the population. The resulting event-free survival (EFS) and overall survival (OS) curves can pose challenges in interpretation and extrapolation for the purpose of simulations of long-term treatment effects and cost-effectiveness. Mixture cure modeling (MCM) has been suggested as a superior method to evaluate treatments of a curative nature to allow for part of the population to achieve long-term remission. This method has been shown to be useful both in designing and powering clinical studies of curative therapies but also for extrapolation of long-term outcomes in simulation studies. However previous iterations of this method did not account for differences in timing of curative therapies. ZUMA-7 had two pivotal analyses separated by nearly 2-years of follow-up: a primary EFS (datacut 1) and a primary OS analyses (data cut 2). The aim of this study was to use the two data cuts of ZUMA-7 to validate MCM in 2L LBCL and describe differences that may have arisen due to treatment specific timing and extent of cure. Methods: Overall survival individual patient-level data from the ZUMA-7 trial for axi-cel and SoC from both data cut 1 (median follow-up: 24.9 months) and data cut 2 (median follow-up: 47.2 months) were used in this analysis. Three different parametric modeling approaches were applied and compared in both data cuts: standard parametric model, spline-based model, and MCMs. Modeling approaches were evaluated for plausibility across a range of metrics, across the two data cuts, including visual fit, plausibility of long-term estimates, statistical goodness of fit, inspection of hazard plots, point-estimate accuracy, and conditional survival estimates. Additionality, the ability of the early data cut extrapolation to predict the actual data was assessed by comparing the model predictions with the latest KM estimator in both trial arms. Differences between trial arms were evaluated. Results: Cure-based and spline models provided the best fit based on the percentage inaccuracy of extrapolations fitted with data cut 1 in comparison to 5-year OS Kaplan-Meier estimates confirmed by data cut 2. In the axi-cel treatment arm, the percentage inaccuracy range between 2% and 27% (Figure 1). Based on data cut 1, cure fractions ranged considerably across the MCM extrapolation forms considered for both treatment arms (range: 24-54% [Figure 2] and 35-49% for axi-cel and SoC, respectively). Notably, the range of cure fractions narrowed considerably based on extrapolations performed on the more mature data cut 2 (range: 50-54% [Figure 2] and 41-50% for axi-cel and SoC, respectively). Overall, the uncertainty in the estimate of cure fractions based on MCMs was reduced from data cut 1 to data cut 2 for axi-cel vs. SoC, suggesting clinical input is needed to validate early extrapolations using less mature data cuts. Conclusion: Our analysis suggests that MCMs are helpful in making accurate predictions of survival based on immature data when a plateau in the survival curve is clinically plausible. However, this analysis also highlights the importance of considering clinical plausibility to guide specific curve selection in the presence of immature survival data, as there was a high degree of variability in the early extrapolations which was reduced with the longer-term follow-up. The ability to reliably extrapolate from early data may improve clinical decision making and reduce delays in patient access to potentially lifesaving treatments as more mature follow-up data are being collected.

TLR4 signalling protects Sertoli cells from cell stress via reprogramming inflammasome and autophagy pathways in MAPK1/ERK2 dependent way

Sertoli cells constitutively maintain the spermatogonial stem cell niche and blood-testis barrier via impenetrable tight junctions under hormonal, growth factor and cytokine control. Immature Sertoli cell proliferation and survival benefit from FSH, NF-κB, and IL-1α-dependent signalling effective via the MAPK family of pathways and related to p38 MAPK dependent Ca2+ and K+ fluxes. Little is known about how the NF-κB and MAPK axis interact with pro-inflammatory NOD1/TLR4 and different voltage-gated channels. Silencing MAPK1, we found that MAPK1/ERK2 has a synergistic role with TLR4 in restricting the pro-inflammatory NF-κB/Caspase-1/IL-1β axis while having an antagonistic effect on TLR4 in promoting adult 15 P-1 Sertoli cell line proliferation and migration. In MAPK1/ERK2 absence, there was an unexpected TLR4-NF-κB behaviour, showing a strong NF-κB transactivation, assessed using a pNIFTY-SEAP reporter plasmid, accompanied by significantly activated cell migration and proliferation, as demonstrated by the wound healing assay. Voltage-gated potassium flux, most likely via Kv1.3, was significantly increased after TLR4 and NOD1 challenge in ATP DAMP signal presence, associated with inflammasome activation. TLR4 challenge also activated macroautophagy while inhibiting mitophagy. Thus, TLR4 activation restricted the NF-κB and Caspase-1/IL-1β pro-inflammatory axis, cell migration and proliferation, voltage-gated potassium efflux, and shifted mitophagy to macroautophagy (towards an inflammasome pathway-related cell death), promoting cell survival. MAPK1/ERK2 had a differential effect, as in its absence, TLR4 activation had the opposite effect on NF-κB transactivation and cell migration and proliferation. Thus, TLR4/MAPK1/NF-κB/Kv1.3 interaction provides optimal Sertoli cell maintenance conditions and allows cell death only in extreme circumstances of cumulative DAMP/PAMP signalling stimulation.