Immature Survival Research Articles

Use of Minimal Residual Disease Status to Reduce Uncertainty in Estimating Long-term Survival Outcomes for Newly Diagnosed Multiple Myeloma Patients.

Background: Demonstrating the cost-effectiveness of new treatments for multiple myeloma (MM) often relies on the extrapolation of overall survival (OS) trial data. This method can introduce uncertainty in long-term survival estimates if OS data are immature, as is often the case in newly diagnosed MM (NDMM). We explore the use of the relationship between minimal residual disease (MRD) status and OS to reduce uncertainty of long-term survival outcomes. Objectives: To evaluate if uncertainty in long-term modeled outcomes in NDMM is reduced using a response-based partitioned survival model (PSM), whereby patients were categorized as MRD-positive or -negative, relative to a standard PSM, when OS data are immature. Methods: Standard and response-based PSMs, estimating patient life-years (LYs) over a lifetime horizon, were developed for NDMM patients treated with bortezomib, thalidomide, and dexamethasone (BTd) with or without daratumumab as induction and consolidation therapy. In the standard PSM, LYs were determined by extrapolations from individual patient data from CASSIOPEIA. In the response-based PSM, survival was dependent on MRD status at the time of the response assessment via a landmark analysis. Cox-proportional hazard ratios from external sources and CASSIOPEIA informed the relationship for OS between MRD-positive and MRD-negative, and between patients receiving BTd and daratumumab plus BTd, respectively. Uncertainty was assessed by comparing LYs and OS extrapolations from deterministic and probabilistic analyses. Results: This response-based PSM demonstrated reduced uncertainty in long-term survival outcomes compared with the standard PSM (range across extrapolations of 3.4 and 7.7 LYs for daratumumab plus BTd and BTd, respectively, vs 14.8 and 11.8 LYs for the standard PSM). It also estimated a narrower interquartile range of LYs in the probabilistic analyses for the majority of parametric extrapolations. Discussion: Alternative methods to estimate long-term survival outcomes, such as a response-based PSM, can reduce uncertainty in modeling predictions around cost-effectiveness estimates for health technology assessment bodies and payers, thereby supporting faster market access for novel therapies with immature survival data. Conclusions: Use of MRD status in a response-based PSM reduces uncertainty in modeling long-term survival in patients with NDMM and provides a greater number of clinically plausible extrapolations compared with a standard PSM.

Use of Minimal Residual Disease Status to Reduce Uncertainty in Estimating Long-term Survival Outcomes for Newly Diagnosed Multiple Myeloma Patients

Background: Demonstrating the cost-effectiveness of new treatments for multiple myeloma (MM) often relies on the extrapolation of overall survival (OS) trial data. This method can introduce uncertainty in long-term survival estimates if OS data are immature, as is often the case in newly diagnosed MM (NDMM). We explore the use of the relationship between minimal residual disease (MRD) status and OS to reduce uncertainty of long-term survival outcomes. Objectives: To evaluate if uncertainty in long-term modeled outcomes in NDMM is reduced using a response-based partitioned survival model (PSM), whereby patients were categorized as MRD-positive or -negative, relative to a standard PSM, when OS data are immature. Methods: Standard and response-based PSMs, estimating patient life-years (LYs) over a lifetime horizon, were developed for NDMM patients treated with bortezomib, thalidomide, and dexamethasone (BTd) with or without daratumumab as induction and consolidation therapy. In the standard PSM, LYs were determined by extrapolations from individual patient data from CASSIOPEIA. In the response-based PSM, survival was dependent on MRD status at the time of the response assessment via a landmark analysis. Cox-proportional hazard ratios from external sources and CASSIOPEIA informed the relationship for OS between MRD-positive and MRD-negative, and between patients receiving BTd and daratumumab plus BTd, respectively. Uncertainty was assessed by comparing LYs and OS extrapolations from deterministic and probabilistic analyses. Results: This response-based PSM demonstrated reduced uncertainty in long-term survival outcomes compared with the standard PSM (range across extrapolations of 3.4 and 7.7 LYs for daratumumab plus BTd and BTd, respectively, vs 14.8 and 11.8 LYs for the standard PSM). It also estimated a narrower interquartile range of LYs in the probabilistic analyses for the majority of parametric extrapolations. Discussion: Alternative methods to estimate long-term survival outcomes, such as a response-based PSM, can reduce uncertainty in modeling predictions around cost-effectiveness estimates for health technology assessment bodies and payers, thereby supporting faster market access for novel therapies with immature survival data. Conclusions: Use of MRD status in a response-based PSM reduces uncertainty in modeling long-term survival in patients with NDMM and provides a greater number of clinically plausible extrapolations compared with a standard PSM.

EE467 A Review of the Use of Clinical Expert Opinion to Inform Survival Curve Extrapolations in Single Technology Appraisals of New Cancer Drugs by NICE, UK

For immature survival data, extrapolation approaches are required to estimate the full survival benefit over a lifetime time horizon. Various extrapolation approaches are available; each will result in different survival estimates. Clinical expert opinion can be used to assess the plausibility of extrapolated curves.

Inheritance and Biological Characterization of an Orange-nymph Mutant in Orius laevigatus (Hemiptera: Anthocoridae).

A mutation showing a distinct orange color in the nymph stages was found in Orius laevigatus (Fieber) (Hemiptera: Anthocoridae), a key biological control agent in protected crops, used to control small pests, especially thrips. A laboratory strain carrying this body color mutation ambar was established. Genetic analysis determined that the mutation (ambar) was controlled by a single autosomal recessive allele. Some biological and ecological characteristics of this orange strain were compared to a normal population. Longevity, fecundity and fertility were similar in both populations, but immature survival, development rate, body size, starvation tolerance and predation capacity were inferior in the orange strain. The utility of the orange mutant as a visible marker for biological and ecological studies of this important biological control agent is discussed.

Comparative resistance and susceptibility of different chickpea (Cicer arietinum L.) seed cultivars to Callosobruchus maculatus (F.) (Coleoptera: Chrysomelidae)

Callosobruchus maculatus (F.) is a damaging insect pest of chickpea seeds (Cicer arietinum L.) in storage. Using chickpea seed cultivars that are resistant to C. maculatus is one of the best techniques to reduce the infestation risks of this pest. We studied the differences in the resistance and susceptibility of seven commercial chickpea cultivars (Adel, Ana, Ata, Mansour, Nosrat, Saeed, and Samin) to C. maculatus based on the free-choice oviposition preference, food consumption, life history/life table parameters, and digestive enzyme activity. Compared with other examined cultivars, C. maculatus oviposition preference and food consumption were highest on cultivars Ana and Adel, respectively. The developmental times were longest on cultivars Nosrat and Saeed, and shortest on cultivar Adel. Immature survival significantly differed among the cultivars, and was highest on cultivars Adel and Mansour, and lowest on cultivar Nosrat. The highest intrinsic rate of increase (r) was on cultivars Adel and Mansour, and lowest on cultivars Nosrat and Saeed. The amylolytic and proteolytic activities of fourth instar larvae were lowest on cultivar Ata. There were significant negative correlations between the seed hardness index with food consumption, immature survival, longevity, fecundity, r, and amylolytic activity of C. maculatus. As a result, the seed hardness is a main factor responsible for the resistance and susceptibility of the examined chickpea cultivars to C. maculatus, and this feature could be utilized to develop efficient control measures of the pest such as the production of transgenic seeds.

Biology of the Most Widely Distributed Sugarcane Stem Borers, Diatraea spp. (Lepidoptera: Crambidae), in Colombia.

Most studies on insect biology and ecology of sugarcane borers have focused on Diatraea saccharalis (Fabricius),the most widely distributed species in the Americas. Little information is available on the biology of other borer species present in Colombia, such as D. indigenellaDyar & Heinrich, D. busckella Dyar & heinrich,and D. tabernellaDyar, that present greater expansion and damage in sugarcane-growing regions. The biology of all four species was accordingly studied under laboratory conditions. Diatraea saccharalis presented the shortest development time (39.4days) and D. busckella the longest (58.2days). Immature survival was higher for D. saccharalis (83%) and D. tabernella (77%), with the latter also presenting the highest pupal weight (256.6mg). Observations on reproduction indicate that D. tabernella develops a larger number of egg masses per female (67.3) as compared with D. saccharalis (28.7). All three species spent more time in the pupal stage and resulted in greater pupal size than D. saccharalis; in particular, D. indigenella showed longer female longevity than D. saccharalis. High immature survival rate and greater reproductive success in D. tabernella could potentially generate a larger population in the field, whereas D. busckella takes longer to complete its development, thus increasing the chances of causing greater injury to sugarcane plants. Discussion on biology, ecology, and pest management of these little-known species is done using as model the better-known D. saccharalis.

Transgenerational effects of predation stress on prey survival, development, and offspring sex ratio: an experiment on Tyrophagus putrescentiae and predator Neoseiulus cucumeris

Predation stress can induce phenotypic plasticity in the life history traits of prey, especially early-life traits such as developmental time. Most previous transgenerational studies have focused on two generations and showed that the transgenerational effects induced by predation stress were negative on offspring fitness. Changes in sex ratio can also be an expression of transgenerational effects, influenced by many environmental and parental conditions. In this study, by using the prey–predator system of Tyrophagus putrescentiae and Neoseiulus cucumeris, we tested whether immature survival, developmental time, and sex ratio of offspring could be influenced by transgenerational exposure to predation stress. We tested the transgenerational effects of predation pressure on early life traits of the offspring over three generations. The results showed that parental effects interacting with grandparental effects increased the immature survival rates of F3 offspring, and that parental effects combined with offspring effects shortened the development duration of F2 offspring. However, neither grandparental exposure to predation stress nor parental experience had any influence on the sex ratio of offspring over three generations.

Oviposition preference and life-history parameters of Callosobruchus maculatus (Coleoptera: Chrysomelidae) on different soybean (Glycine max) cultivars.

Callosobruchus maculatus (F.) (Coleoptera: Chrysomelidae) is one of the most destructive pests of stored legume seeds in many regions of the world. Evaluation of varietal resistance of host seeds to C.maculatus infestation can be useful in preventing severe damage. We studied the susceptibility and resistance of eight conventional soybean cultivars (Caspian, Kosar, L17, Nekador, Sari, Tapour, Williams and Zane) based on the oviposition preference (choice and no-choice tests) and population growth parameters of the pest. Compared with other cultivars tested, oviposition preference of C.maculatus was the lowest on Nekador. The developmental time of C.maculatus differed from 40.34 days on Nekador to 48.35 days on L17, and was negatively correlated with the seed protein content. Other performance measures of C.maculatus did not match the oviposition preference. Immature survival and female longevity were highest on Caspian. The intrinsic rate of increase (rm ) was higher on Tapour, Nekador and Caspian than on Zane, Williams, and Kosar. A positive correlation was observed between the rm value of the pest and moisture content of the cultivars. Cluster analysis showed that cvs Nekador, Sari, Tapour, and Caspian were relatively susceptible, and cvs Kosar, Zane, Williams and L17 were partially resistant to this pest. Protein and moisture contents of soybean cultivars play an important role in the development and population growth of C.maculatus, and these traits could be used to develop safe and effective management strategies for this pest on stored soybean seeds. © 2022 Society of Chemical Industry.

Spatial patterns in age‐ and colony‐specific survival in a long‐lived seabird across 14 contrasting colonies

Demographic rates such as recruitment and survival probability can vary considerably among populations of the same species due to variation in underlying environmental processes. If environmental processes are spatially correlated, nearby populations are expected to have more similar demographic rates than those further apart. Breeding populations and foraging ranges are spatially segregated in colonial seabirds, making them ideal for studying spatial patterns in demographic rates and their effects on local population dynamics. Here we explored variation in age‐dependent survival probabilities across 14 colonies of Herring GullsLarus argentatusbreeding along the Dutch North Sea coast. We used long‐term mark–recapture data of marked fledglings to estimate survival, and estimated spatial autocorrelation of survival probabilities. We assessed whether survival until recruitment age or until 10 years old (close to their expected lifespan) explained variation in population trajectories of each colony. Juvenile and adult survival showed a strong, but different, north‐to‐south gradient in survival probability, with lower juvenile but higher adult survival in northern colonies than southern colonies, whereas the spatial pattern of immature survival was less distinct. Neither recruitment nor the proportion of 10‐year‐old adults alive predicted whether a colony collapsed, declined, remained stable or increased. The distinct spatial pattern in survival suggests variation in regional food availability, which do not seem to drive local population dynamics. The absence of a link between survival and colony trajectories implies that connectivity between populations plays an important role affecting population dynamics.

Overall Survival Benefits of Cancer Drugs Approved in China From 2005 to 2020

Of approximately 9 million patients with cancer in China in 2020, more than half were diagnosed with late-stage cancers. Recent regulatory reforms in China have focused on improving the availability of new cancer drugs. However, evidence on the clinical benefits of new cancer therapies authorized in China is not available. To characterize the clinical benefits of cancer drugs approved in China, as defined by the availability and magnitude of statistically significant overall survival (OS) results. This mixed-methods study comprising a systematic review and cross-sectional analysis identified antineoplastic agents approved in China between January 1, 2005, and December 31, 2020, using publicly available data and regulatory review documents issued by the National Medical Products Administration. The literature published up to June 30, 2021, was reviewed to collect results on end points used in pivotal trials supporting cancer drug approvals. The primary outcome measure was a documented statistically significant positive OS difference between a new cancer therapy and a comparator treatment. Secondary outcome measures were the magnitude of OS benefit and other primary efficacy measures in pivotal trials. Between 2005 and 2020, 78 cancer drugs corresponding to 141 indications were authorized in China, including 20 drugs (25.6%) (for 30 indications) approved in China only. Of all indications, 26 (18.4%) were evaluated in single-arm or dose-optimization trials, most of which were authorized after 2017. By June 30, 2021, 34 drug indications (24.1%) had a documented lack of OS gain. For 68 indications (48.2%) that had documented evidence of OS benefit, the median magnitude of OS improvement was 4.1 (range, 1.0-35.0) months. After a median follow-up of 1.9 (range, 1.0-11.1) years from approval, OS data for 13 indications (9.2%) were either not reported or were still not mature. Fewer than one-third of cancer drug indications approved in China only had documented evidence of OS benefits (9 of 30 [30.0%]), whereas more than one-half of the cancer drug indications also available in the US or Europe had OS benefits (59 of 111 [53.1%]). In this study, almost half of cancer drug indications approved in China had demonstrated OS gain. With the increase of cancer drug approvals based on single-arm trials or immature survival data in recent years, these findings highlight the need to routinely monitor the clinical benefits of new cancer therapies in China.

Demography of cape petrels in response to environmental changes

AbstractPredicting the responses of populations in changing environments is an important task for ecologists. Understanding the population dynamics of high‐latitude breeding species is critical given the particularly rapid environmental changes that occur in these regions. Using long‐term mark–resighting data acquired over 53‐years in Pointe Géologie, Terre Adélie, Antarctica, we estimated age‐specific demographic parameters and evaluated the effect of the environment on survival of a poorly known species, the cape petrel Daption capense. We then modeled the dynamics of this population using a life‐history model and performed prospective and retrospective analyses to estimate the sensitivity of the population growth rate to demographic parameters, and to quantify their relative contribution. Survival of cape petrel increased with age, being 0.610 (±0.193) for juveniles, 0.739 (±0.158) for individuals from 2 to 4, and 0.920 (±0.031) for older individuals. Minimum age at first reproduction was 3 years old, the age at which all birds were recruited was 14 years, and mean age at first reproduction was 9.05 (±2.06) years. Adult survival increased over time and was positively correlated with the southern annular mode (SAM). The stochastic population growth rate was estimated at 1.019, and adult survival over age 5 made the largest contribution to variance of the population growth rate. Sensitivity analyses revealed that population regulation was mainly driven by the SAM. Our results suggest that despite the decrease in breeding success, the population of cape petrels at Pointe Géologie increased due to the increase in immature and adult survival.

Disentangling thermal effects using life cycle simulation modelling on the biology and demographic parameters of Dolichogenidea gelechiidivoris, a parasitoid of Tuta absoluta

Dolichogenidea gelechiidivoris (Marsh) (Syn. Apanteles gelechiidivoris) (Hymenoptera: Braconidae), a konoibiont larval endoparasitoid of the South American tomato pinworm Tuta absoluta (Meyrick), was imported into Kenya in 2017 for the first classical biological control of T. absoluta in Africa. We determined the thermal thresholds of D. gelechiidivoris, with T. absoluta as host, using life cycle simulation modelling. Life-table data of D. gelechiidivoris were generated at six constant temperatures (10, 15, 20, 25, 30, and 35 °C, 65 ± 5% RH, and 12L: 12D photoperiod). Multiple non-linear functions were fitted to model some aspects of the biology of the parasitoid, including its longevity, mortality, reproduction, and senescence using Insect Life Cycle Modelling (ILCYM) software. The phenology models established were used to estimate life table parameters. Except at 35 °C, D. gelechiidivoris completed its development (i.e., egg-larval-pupa-adult) at all tested temperatures. The minimum temperature threshold from egg to cocoon was 7.0 °C and 5.9 °C from cocoon to adult wasp, while the maximum temperature thresholds were 34 °C and 36 °C, respectively. The optimal temperature for immature survival was 20–25 °C, while fecundity was optimum at 22.5 °C, with 69.5 eggs per female. Simulations of the population growth parameters indicated that the intrinsic rate of increase (rm) was maximum at 20 °C with 15 daughters per female per generation. Based on our findings the release of D. gelechiidivoris for inoculative augmentation in countries with temperatures ranging between 15 and 30 °C could be considered to control the pest.

Biology and life table parameters of Callosobruchus maculatus (F.) on Vigna unguiculata (L.) Walp. fertilized with some mineral- and bio-fertilizers

Callosobruchus maculatus (F.) (Coleoptera: Chrysomelidae), a major pest of stored cowpea Vigna unguiculata (L.) Walp., causes critical losses by decreasing the grain weight, germination ability and nutritional quality. Improving host plant resistance by the application of appropriate fertilizers would be effective in reducing C. maculatus infestation. The effects of some mineral- (triple superphosphate (TSP) and urea) and bio-fertilizers (Bradyrhizobium japonicum, Pseudomonas putida, mycorrhizal fungi, and a mixture of them) were evaluated on the susceptibility of stored cowpea grains to C. maculatus. Cowpeas fertilized with examined fertilizers were cultivated at farm conditions. Then, the mature, dry grains were harvested and used to investigate the pest's life cycle and life table characteristics under 28 ± 1 °C, 65 ± 5% R.H., and total darkness. Developmental time of C. maculatus on TSP-treated grains was shorter than on control and P. putida treated ones. However, the lowest immature survival and fecundity (number of deposited eggs) was on TSP-fertilized grains. The intrinsic rate of increase (r) and net reproductive rate (R0) were the lowest on the grains treated with TSP. The highest tannins and starch content in the grains fertilized with TSP may be the critical reasons for their resistance to C. maculatus in storage. Application of TSP fertilizer can be recommended to increase cowpea resistance to this pest.

Estimating the Demographic Parameters of Tuta absoluta (Lepidoptera: Gelechiidae) Using Temperature-Dependent Development Models and Their Validation under Fluctuating Temperature.

Simple SummaryTuta absoluta is an invasive insect pest that has spread widely and established itself in many countries since its first detection in Spain in 2006. The devastating moth originates in South America and attacks tomato and other solanaceous vegetables, leading to huge losses in yield and potential income particularly for small-scale farmers who often lack the resources and knowledge to manage the pest. In most cases, farmers have resorted to the indiscriminate application of broad-spectrum synthetic pesticides, which in most cases are not registered and are often used at high doses. This has resulted in the pest developing resistance to most major classes of pesticides. In addition, the non-selective use of toxic pesticides has resulted in negative effects on the health of users, consumers, and non-target organisms such as pollinators and natural enemies of insect pests. Various tactics aimed at controlling T. absoluta have been developed and are at different stages of adoption by farmers. To ensure that they are effective, sustainable, and friendly to both users and the environment, there is a need for a comprehensive understanding of the pest’s biology and ecology. To this effect, the present study developed models to predict intricate details of the pest’s development, survival, and reproduction using data generated in laboratory studies. Among other important findings, the study reports that temperatures between 20–25 °C are ideal for the development, survival, reproduction, and increase in the population of T. absoluta. These findings are vital in developing strategies in managing the pest, especially in light of global climate change.The tomato leafminer, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) is an invasive pest that devastates the production of tomatoes and other solanaceous vegetables. Since its trans-Atlantic invasion in 2006, T. absoluta has spread and established in many countries across the Afro-Eurasian Supercontinent, causing huge yield losses. This study aimed to determine the relationship between temperature and the life history traits of T. absoluta and provide the thermal thresholds for development using life cycle modelling. Linear and non-linear models were fitted to life table data collected at five constant temperatures of 15, 20, 25, 30, and 35 °C, with Relative Humidity 70 ± 5% and photoperiod 12L:12D. Another experiment was conducted at fluctuating temperatures to validate the laboratory results. Tuta absoluta completed its life cycle at temperatures between 15 and 35 °C. The development time ranged between 4.0–11 days, 6.3–16.0 days, and 5.4–20.7 days for egg, larva, and pupa, respectively. The lowest thermal threshold was estimated at 8.10, 7.83, and 11.62 °C, respectively for egg, larva, and pupa. While the optimum temperature for T. absoluta immature stages survival and female fecundity were predicted at a temperature range of 21–23 °C. The intrinsic rate of increase (rm), gross reproductive (GRR), and net reproductive (Ro) rates were significantly higher at temperatures between 20–25 °C. The model validation outcome showed similarities between observed and simulated values for development time, mortality rate, and life table parameters, attesting to the quality of the phenology model. Our results will help in predicting the effect of climate warming on the distribution and population dynamics of T. absoluta. Furthermore, the results could be used to develop management strategies adapted to different agroecological zones.

Plant Growth-Promoting Rhizobacteria Enhance Defense of Strawberry Plants Against Spider Mites.

Plants mediate interactions between below- and above-ground microbial and animal communities. Microbial communities of the rhizosphere commonly include mutualistic symbionts such as mycorrhizal fungi, rhizobia and free-living plant growth-promoting rhizobacteria (PGPR) that may influence plant growth and/or its defense system against aboveground pathogens and herbivores. Here, we scrutinized the effects of three PGPR, Azotobacter chroococcum, Azospirillum brasilense, and Pseudomonas brassicacearum, on life history and population dynamics of two-spotted spider mites, Tetranychus urticae, feeding on aboveground tissue of strawberry plants, and examined associated plant growth and physiology parameters. Our experiments suggest that these three species of free-living rhizobacteria strengthen the constitutive, and/or induce the direct, anti-herbivore defense system of strawberry plants. All three bacterial species exerted adverse effects on life history and population dynamics of T. urticae and positive effects on flowering and physiology of whole strawberry plants. Spider mites, in each life stage and in total, needed longer time to develop on PGPR-treated plants and had lower immature survival rates than those fed on chemically fertilized and untreated plants. Reduced age-specific fecundity, longer developmental time and lower age-specific survival rates of mites feeding on rhizobacteria treated plants reduced their intrinsic rate of increase as compared to mites feeding on chemically fertilized and control plants. The mean abundance was lower in spider mite populations feeding on PGPR-treated strawberries than in those feeding on chemically fertilized and untreated plants. We argue that the three studied PGPR systemically strengthened and/or induced resistance in above-ground plant parts and enhanced the level of biochemical anti-herbivore defense. This was probably achieved by inducing or upregulating the production of secondary plant metabolites, such as phenolics, flavonoids and anthocyanins, which were previously shown to be involved in induced systemic resistance of strawberry plants. Overall, our study emphasizes that PGPR treatment can be a favorable strawberry plant cultivation measure because providing essential nutrients needed for proper plant growth and at the same time decreasing the life history performance and population growth of the notorious herbivorous pest T. urticae.

P45 The Use of Historical Clinical Trial Data to Inform Survival Extrapolation

Standard parametric distributions are commonly used for the extrapolation of survival data in cost-effectiveness analyses. However, survival data is often immature and uncertainty remains around the survival extrapolations. Mature historical data can be used to better predict survival beyond trial data. This study assessed two methods to incorporate historical data in the extrapolation of immature survival data.

Physicochemical traits of Vicia faba L. seed cultivars affect oviposition preference and demographic parameters of Callosobruchus maculatus (F.) (Coleoptera: Chrysomelidae)

Callosobruchus maculatus (F.) is a common insect pest of stored leguminous seeds including faba bean (Vicia faba L.) in tropical and subtropical areas. In this study, differences in the seed resistance of seven faba bean cultivars (Barakat, Feiz, Luz de Otono, Mahta, Saraziri, Shadan, and Shakhbozi) to C. maculatus were studied using its oviposition preference, life history and life table parameters.Callosobruchusmaculatus showed the highest preference for egg-laying on cultivar Mahta as compared to other tested cultivars. Oviposition preference of the pest negatively correlated with the seed size and weight, and positively correlated with the starch content and the seed coat phenolics. Fecundity (number of eggs laid) of female weevils on cultivar Feiz was more than on cultivar Saraziri. High immature survival and delayed developmental time were on cultivar Barakat. The net reproductive rate (R0) of the insect feeding on cultivars Shakhbozi, Mahta and Shadan was higher than on cultivars Saraziri and Luz de Otono. The intrinsic rate of increase (r) and finite rate of increase (λ) were the highest on cultivar Shakhbozi and lowest on cultivar Saraziri. According to our results, Shadan, Barakat, Mahta, and Shakhbozi are the most suitable cultivars, and Saraziri is the least suitable cultivar to C. maculatus population increase. Findings of this research will help in developing management methods of C. maculatus such as the production of genetically engineered crops that are resistant to this insect.

Decreased bee emergence along an elevation gradient: Implications for climate change revealed by a transplant experiment.

Bees experience differences in thermal tolerance based on their geographical range; however, there are virtually no studies that examine how overwintering temperatures may influence immature survival rates. Here, we conducted a transplant experiment along an elevation gradient to test for climate-change effects on immature overwinter survival using movement along elevational gradient for a community of 26 cavity-nesting bee species in the family Megachilidae along the San Francisco Peaks, Arizona elevational gradient. In each of three years, we placed nest blocks at three elevations, to be colonized by native Megachilidae. Colonized blocks were then (1) moved to lower (warmer) elevations; (2) moved to higher (cooler) elevations; or (3) left in their natal habitat (no change in temperature). Because Megachilidae occupy high elevations with colder temperatures more than any other family of bees, we predicted that emergence would decrease in nest blocks moved to lower elevations, but that we would find no differences in emergence when nest blocks were moved to higher elevations. We found three major results: (1) Bee species moved to lower (warmer) habitats exhibited a 30% decrease in emergence compared with species moved within their natal habitat. (2) Habitat generalists were more likely than habitat specialists to emerge when moved up or down in elevation regardless of their natal life zones. (3) At our highest elevation treatment, emergence increased when blocks were moved to higher elevations, indicating that at least some Megachilidae species can survive at colder temperatures. Our results suggest that direct effects of warming temperatures will have negative impacts on the overall survival of Megachilidae. Additionally, above the tree line, low availability of wood-nesting resources is a probable limiting factor on bees moving up in elevation.

Genetic Ablation of the Inducible Form of Nitric Oxide in Male Mice Disrupts Immature Neuron Survival in the Adult Dentate Gyrus.

Inducible nitric oxide synthase (iNOS) is an enzyme upregulated in the brain during neuroimmune stimuli which is associated with an oxidative and pro-inflammatory environment in several brain regions, including the hippocampal formation and the prefrontal cortex. The dentate gyrus of the hippocampal formation is the site of a process known as adult hippocampal neurogenesis (AHN). Although many endogenous and extrinsic factors can modulate AHN, the exact participation of specific proinflammatory mediators such as iNOS in these processes remains to be fully elucidated. Here, we investigated how the total genetic ablation of iNOS impacts the hippocampal neurogenic niche and microglial phenotype and if these changes are correlated to the behavioral alterations observed in iNOS knockout (K.O.) mice submitted or not to the chronic unpredictable stress model (CUS - 21 days protocol). Contrary to our initial hypothesis, at control conditions, iNOS K.O. mice displayed no abnormalities on microglial activation in the dentate gyrus. However, they did exhibit impaired newborn cells and immature neuron survival, which was not affected by CUS. The reduction of AHN in iNOS K.O. mice was accompanied by an increased positive coping response in the tail suspension test and facilitation of anxiety-like behaviors in the novelty suppressed feeding. Next, we investigated whether a pro-neurogenic stimulus would rescue the neurogenic capacity of iNOS K.O. mice by administering in control and CUS groups the antidepressant escitalopram (ESC). The chronic treatment with ESC could not rescue the neurogenic capacity or the behavioral changes observed in iNOS K.O. mice. Besides, in the ventromedial prefrontal (vmPFC) cortex there was no change in the expression or the chronic activation of PV neurons (evaluated by double labeling PV with FOSB) in the prelimbic (PrL) or infralimbic subregions. FOSB expression, however, increased in the PrL of iNOS K.O. mice. Our results suggest that iNOS seems essential for the survival of newborn cells and immature neurons in the hippocampus and seem to partially explain the anxiogenic-like behavior observed in iNOS K.O. mice. On the other hand, the iNOS ablation appears to result in increased activity of the PrL which could explain the antidepressant-like behaviors of iNOS K.O mice.

Modelling approaches for histology-independent cancer drugs to inform NICE appraisals: a systematic review and decision-framework.

The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.