Decoupling of bird migration from the changing phenology of spring green-up.

The green-up of vegetation in spring brings a pulse of food resources that many animals track during migration. However, green-up phenology is changing with climate change, posing an immense challenge for species that time their migrations to coincide with these resource pulses. We evaluated changes in green-up phenology from 2002 to 2021 in relation to the migrations of 150 Western-Hemisphere bird species using eBird citizen science data. We found that green-up phenology has changed within bird migration routes, and yet the migrations of most species align more closely with long-term averages of green-up than with current conditions. Changing green-up strongly influenced phenological mismatches, especially for longer-distance migrants. These results reveal that bird migration may have limited flexibility to adjust to changing vegetation phenology and emphasize the mounting challenge migratory animals face in following en route resources in a changing climate.

Predicting Hydrocarbon Primary Biodegradation in Soil and Sediment Systems Using System Parameterization and Machine Learning.

Technical complexity associated with biodegradation testing, particularly for substances of unknown or variable composition, complex reaction products, or biological materials (UVCB), necessitates the advancement of non-testing methods such as quantitative structure-property relationships (QSPRs). Models for describing the biodegradation of petroleum hydrocarbons (HCs) have been previously developed. A critical limitation of available models is their inability to capture the variability in biodegradation rates associated with variable test systems and environmental conditions. Recently, the Hydrocarbon Biodegradation System Integrated Model (HC-BioSIM) was developed to characterize the biodegradation of HCs in aquatic systems with the inclusion of key test system variables. The present study further expands the HC-BioSIM methodology to soil and sediment systems using a database of 2195 half-life (i.e., degradation time [DT]50) entries for HCs in soil and sediment. Relevance and reliability criteria were defined based on similarity to standard testing guidelines for biodegradation testing and applied to all entries in the database. The HC-BioSIM soil and sediment models significantly outperformed the existing biodegradation HC half-life (BioHCWin) and virtual evaluation of chemical properties and toxicities (VEGA) quantitative Mario Negri Institute for Pharmacological Research (IRFMN) models in soil and sediment. Average errors in predicted DT50s were reduced by up to 6.3- and 8.7-fold for soil and sediment, respectively. No significant bias as a function of HC class, carbon number, or test system parameters was observed. Model diagnostics demonstrated low variability in performance and high consistency of parameter usage/importance and rule structure, supporting the generalizability and stability of the models for application to external data sets. The HC-BioSIM provides improved accuracy of Persistence categorization, with correct classification rates of 83.9%, and 90.6% for soil and sediment, respectively, demonstrating a significant improvement over the existing BioHCWin (70.7% and 58.6%) and VEGA (59.5% and 18.5%) models. Environ Toxicol Chem 2024;43:1352-1363. © 2024 Concawe. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

In Silico Acute Aquatic Hazard Assessment and Prioritization Using a Grouped Target Site Model: A Case Study of Organic Substances Reported in Permian Basin Hydraulic Fracturing Operations.

Hydraulic fracturing (HF) is commonly used to enhance onshore recovery of oil and gas during production. This process involves the use of a variety of chemicals to support the physical extraction of oil and gas, maintain appropriate conditions downhole (e.g., redox conditions, pH), and limit microbial growth. The diversity of chemicals used in HF presents a significant challenge for risk assessment. The objective of the present study is to establish a transparent, reproducible procedure for estimating 5th percentile acute aquatic hazard concentrations (e.g., acute hazard concentration 5th percentiles [HC5s]) for these substances and validating against existing toxicity data. A simplified, grouped target site model (gTSM) was developed using a database (n = 1696) of diverse compounds with known mode of action (MoA) information. Statistical significance testing was employed to reduce model complexity by combining 11 discrete MoAs into three general hazard groups. The new model was trained and validated using an 80:20 allocation of the experimental database. The gTSM predicts toxicity using a combination of target site water partition coefficients and hazard group-based critical target site concentrations. Model performance was comparable to the original TSM using 40% fewer parameters. Model predictions were judged to be sufficiently reliable and the gTSM was further used to prioritize a subset of reported Permian Basin HF substances for risk evaluation. The gTSM was applied to predict hazard groups, species acute toxicity, and acute HC5s for 186 organic compounds (neutral and ionic). Toxicity predictions and acute HC5 estimates were validated against measured acute toxicity data compiled for HF substances. This case study supports the gTSM as an efficient, cost-effective computational tool for rapid aquatic hazard assessment of diverse organic chemicals. Environ Toxicol Chem 2024;43:1161-1172. © 2024 ExxonMobil Petroleum and Chemical BV. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

US and international per- and polyfluoroalkyl substances surface water quality criteria: A review of the status, challenges, and implications for use in chemical management and risk assessment.

Regulation of per- and polyfluorinated substances (PFAS) in surface water is a work-in-progress with relatively few criteria promulgated in the United States and internationally. Surface water quality criteria (SWQC) or screening values derived for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) by Australia, Canada, the European Union (EU), and four US states (Florida, Michigan, Minnesota, and Wisconsin), and the San Francisco Bay Regional Water Quality Control Board (SFB RWQCB; California) were compared. Across these eight jurisdictions, promulgated numeric criteria for the same compound and receptor span over five orders of magnitude as a result of different approaches and data interpretations. Human health criteria for PFOS range from 0.0047 to 600 ng/L depending on route of exposure (e.g., fish consumption or drinking water) and are lower than most ecological criteria for protection of aquatic and wildlife receptors. Data gaps and uncertainty in chronic toxicity and bioaccumulation of PFOS and PFOA, as well as the use of conservative assumptions regarding intake and exposure, have resulted in some criteria falling at or below ambient background concentrations and current analytical detection limits (around 1 ng/L for commercial laboratories). Some jurisdictions (e.g., Australia, Canada) have deemed uncertainty in quantifying water-fish bioaccumulation too great and set fish tissue action levels in lieu of water criteria. Current dynamics associated with the emerging and evolving science of PFAS toxicity, exposure, and environmental fate (i.e., data gaps and uncertainty), as well as the continuous release of scientific updates, pose a challenge to setting regulatory limits. Integr Environ Assess Manag 2024;20:36-58. © 2023 AECOM Technical Services, Inc and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Climate change causes declines and greater extremes in wetland inundation in a region important for wetland birds.

Wetland ecosystems are vital for maintaining global biodiversity, as they provide important stopover sites for many species of migrating wetland-associated birds. However, because weather determines their hydrologic cycles, wetlands are highly vulnerable to effects of climate change. Although changes in temperature and precipitation resulting from climate change are expected to reduce inundation of wetlands, few efforts have been made to quantify how these changes will influence the availability of stopover sites for migratory wetland birds. Additionally, few studies have evaluated how climate change will influence interannual variability or the frequency of extremes in wetland availability. For spring and fall bird migration in seven ecoregions in the south-central Great Plains of North America, we developed predictive models associating abundance of inundated wetlands with a suite of weather and land cover variables. We then used these models to generate predictions of wetland inundation at the end of the century (2069-2099) under future climate change scenarios. Climate models predicted the average number of inundated wetlands will likely decline during both spring and fall migration periods, with declines being greatest in the eastern ecoregions of the southern Great Plains. However, the magnitude of predicted declines varied considerably across climate models and ecoregions, with uncertainty among climate models being greatest in the High Plains ecoregion. Most ecoregions also were predicted to experience more-frequent extremely dry years (i.e., years with extremely low wetland abundances), but the projected change in interannual variability of wetland inundation was relatively small and varied across ecoregions and seasons. Because the south-central Great Plains represents an important link along the migratory routes of many wetland-dependent avian species, future declines in wetland inundation and more frequent periods of only a few wetlands being inundated will result in an uncertain future for migratory birds as they experience reduced availability of wetland stopover habitat across their migration pathways.

Exploratory analyses of treatment subgroup interaction by PD-L1 status and according to PD-L1 expression in the JAVELIN Bladder 100 trial.

PURPOSE: Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC). METHODS: JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay). RESULTS: No significant interaction between treatment and PD-L1 status was observed for OS. Clinically meaningful and robust survival data were observed in favor of avelumab using the different ≥ 1% TC/IC PD-L1 expression cutoff. CONCLUSIONS: These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels.

A Review of Mechanistic Models for Predicting Adverse Effects in Sediment Toxicity Testing.

Since recognizing the importance of bioavailability for understanding the toxicity of chemicals in sediments, mechanistic modeling has advanced over the last 40 years by building better tools for estimating exposure and making predictions of probable adverse effects. Our review provides an up-to-date survey of the status of mechanistic modeling in contaminated sediment toxicity assessments. Relative to exposure, advances have been most substantial for non-ionic organic contaminants (NOCs) and divalent cationic metals, with several equilibrium partitioning-based (Eq-P) models having been developed. This has included the use of Abraham equations to estimate partition coefficients for environmental media. As a result of the complexity of their partitioning behavior, progress has been less substantial for ionic/polar organic contaminants. When the EqP-based estimates of exposure and bioavailability are combined with water-only effects measurements, predictions of sediment toxicity can be successfully made for NOCs and selected metals. Both species sensitivity distributions and toxicokinetic and toxicodynamic models are increasingly being applied to better predict contaminated sediment toxicity. Furthermore, for some classes of contaminants, such as polycyclic aromatic hydrocarbons, adverse effects can be modeled as mixtures, making the models useful in real-world applications, where contaminants seldomly occur individually. Despite the impressive advances in the development and application of mechanistic models to predict sediment toxicity, several critical research needs remain to be addressed. These needs and others represent the next frontier in the continuing development and application of mechanistic models for informing environmental scientists, managers, and decisions makers of the risks associated with contaminated sediments. Environ Toxicol Chem 2023;00:1-17. © 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Variation among arthropod taxa in the amino acid content of exoskeleton and digestible tissue.

Arthropod consumption provides amino acids to invertebrates and vertebrates alike, but not all amino acids in arthropods may be digestible as some are bound in the exoskeleton. Consumers may not be able to digest exoskeleton in significant amounts or avoid it entirely (e.g., extraoral digestion). Hence, measures that do not separate digestible amino acids from those in exoskeleton may not accurately represent the amino acids available to consumers. Additionally, arthropods are taxonomically diverse, and it remains unclear if taxonomic differences also reflect differences in amino acid availability. Thus, we tested: (1) if there were consistent differences in the content and balance of amino acids between the digestible tissue and exoskeleton of arthropods and (2) if arthropod Orders differ in amino acid content and balance. We measured the amino acid content (mg/100 mg dry mass) and balance (mg/100 mg protein) of whole bodies and exoskeleton of a variety of arthropods using acid hydrolysis. Overall, there was higher amino acid content in digestible tissue. There were also significant differences in the amino acid balance of proteins in digestible tissue and exoskeleton. Amino acid content and balance also varied among Orders; digestible tissues of Hemiptera contained more of some essential amino acids than other Orders. These results demonstrate that arthropod taxa vary in amino acid content, which could have implications for prey choice by insectivores. In addition, exoskeleton and digestible tissue content differ in arthropods, which means that whole body amino acid content of an arthropod is not necessarily a predictor of amino acid intake of a predator that feeds on that arthropod.

Review of range-wide vital rates quantifies eastern wild Turkey population trajectory.

Recent declines in eastern wild turkeys (Meleagris gallopavo silvestris) have prompted increased interest in management and research of this important game species. However, the mechanisms underlying these declines are unclear, leaving uncertainty in how best to manage this species. Foundational to effective management of wildlife species is understanding the biotic and abiotic factors that influence demographic parameters and the contribution of vital rates to population growth. Our objectives for this study were to (1) conduct a literature review to collect all published vital rates for eastern wild turkey over the last 50 years, (2) perform a scoping review of the biotic and abiotic factors that have been studied relative to wild turkey vital rates and highlight areas that require additional research, and (3) use the published vital rates to populate a life-stage simulation analysis (LSA) and identify the vital rates that make the greatest contribution to population growth. Based on published vital rates for eastern wild turkey, we estimated a mean asymptotic population growth rate (λ) of 0.91 (95% CI = 0.71, 1.12). Vital rates associated with after-second-year (ASY) females were most influential in determining population growth. Survival of ASY females had the greatest elasticity (0.53), while reproduction of ASY females had lower elasticity (0.21), but high process variance, causing it to explain a greater proportion of variance in λ. Our scoping review found that most research has focused on the effects of habitat characteristics at nest sites and the direct effects of harvest on adult survival, while research on topics such as disease, weather, predators, or anthropogenic activity on vital rates has received less attention. We recommend that future research take a more mechanistic approach to understanding variation in wild turkey vital rates as this will assist managers in determining the most appropriate management approach.

Using weight of evidence to assess degradation potential of UVCB hydrocarbon solvents.

Hydrocarbon solvents are a diverse group of petrochemical substances that are identified as unknown or variable composition, complex reaction products, or biological materials (UVCBs) and may contain tens of thousands of individual chemical constituents. As such, it is generally not possible to analytically resolve every chemical constituent in a hydrocarbon solvent. This, along with the low water solubility and/or high vapor pressure of constituents, precludes the use of many standardized tests designed to determine biodegradation in the environment (e.g., Organization for Economic Co-operation and Development [OECD] 309). A weight of evidence approach may be needed to reduce uncertainty to an acceptable level such that a determination on the biodegradation of the substance can be drawn. Based on the OECD 2019 weight of evidence guidance, we present a framework using various lines of evidence that can be used to evaluate the biodegradation of a UVCB solvent in a weight of evidence approach. The lines of evidence include whole substance testing, data on representative constituents, quantitative structure activity relationship (QSAR) models, and biological plausibility. Using these lines of evidence, "Hydrocarbon, C11-C14, normal alkane, isoalkane, cyclic, <2% aromatics" (EC# 926-141-6) was evaluated in a case study. Data from three whole substance tests, 43 constituents (representing 152 data points), three QSAR models and evidence of microbial degradation pathways were evaluated. Based on the available data, it is concluded that the solvent for the case study is not expected to persist in the environment. This framework sets out a real-world example of how the weight of evidence can be used to evaluate hydrocarbon solvents. While focused on persistence, similar approaches can be used to evaluate other endpoints such as bioaccumulation and toxicity. Integr Environ Assess Manag 2023;19:1120-1130. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Climate Change and Wetlands in the Southern Great Plains: How Are Managers Dealing with an Uncertain Future?

Little guidance is available to assist wetland managers in developing climate adaptation plans. To facilitate development of recommendations for adaptation strategies, it is essential to first determine if or how wetland managers are addressing these challenges. We used an online survey to solicit feedback from wetland managers and biologists in the Southern Great Plains of North America to gain information on perceptions of wetland managers regarding climate change; assess how the effects of climate change are being addressed through management; and identify barriers to implementing climate change adaptation. The majority of wetland managers (63%) agreed they are currently experiencing effects of climate change in wetlands, and most respondents (76%) reported that changes in the timing of water availability throughout the year was the most likely impact. Managers reported using a diversity of approaches in managing for changing precipitation, with management of native and invasive plant species being the two most common practices. Lack of funding and personnel were the most commonly identified factors limiting manager's response to changing precipitation patterns. In addition, >50% of managers indicated uncertainty about the effects of climate change on wetlands as a barrier to management, which may relate to limited access to peer-reviewed science. While most of the management practices reported were short-term measures and may not reflect long-term adaptation for climate change, the fact that many managers are considering climate change in their management suggests that there is considerable opportunities to continue developing capacity for climate change adaptation in the region.

Bison movements change with weather: Implications for their continued conservation in the Anthropocene.

Animal movement patterns are affected by complex interactions between biotic and abiotic landscape conditions, and these patterns are being altered by weather variability associated with a changing climate. Some animals, like the American plains bison (Bison bison L.; hereafter, plains bison), are considered keystone species, thus their response to weather variability may alter ecosystem structure and biodiversity patterns. Many movement studies of plains bison and other ungulates have focused on point-pattern analyses (e.g., resource-selection) that have provided information about where these animals move, but information about when or why these animals move is limited. For example, information surrounding the influence of weather on plains bison movement in response to weather is limited but has important implications for their conservation in a changing climate. To explore how movement distance is affected by weather patterns and drought, we utilized 12-min GPS data from two of the largest plains bison herds in North America to model their response to weather and drought parameters using generalized additive mixed models. Distance moved was best predicted by air temperature, wind speed, and rainfall. However, air temperature best explained the variation in distance moved compared to any other single parameter we measured, predicting a 48% decrease in movement rates above 28°C. Moreover, severe drought (as indicated by 25-cm depth soil moisture) better predicted movement distance than moderate drought. The strong influence of weather and drought on plains bison movements observed in our study suggest that shifting climate and weather will likely affect plains bison movement patterns, further complicating conservation efforts for this wide-ranging keystone species. Moreover, changes in plains bison movement patterns may have cascading effects for grassland ecosystem structure, function, and biodiversity. Plains bison and grassland conservation efforts need to be proactive and adaptive when considering the implications of a changing climate on bison movement patterns.

Utomilumab in Patients With Immune Checkpoint Inhibitor-Refractory Melanoma and Non-Small-Cell Lung Cancer.

Section Head: Clinical/translational cancer immunotherapy. Background: The goal of this study was to estimate the objective response rate for utomilumab in adults with immune checkpoint inhibitor (ICI)-refractory melanoma and non-small-cell lung cancer (NSCLC). Methods: Utomilumab was dosed intravenously every 4 weeks (Q4W) and adverse events (AEs) monitored. Tumor responses by RECIST1.1 were assessed by baseline and on-treatment scans. Tumor biopsies were collected for detection of programmed cell death ligand 1, CD8, 4-1BB, perforin, and granzyme B, and gene expression analyzed by next-generation sequencing. CD8+ T cells from healthy donors were stimulated with anti-CD3 ± utomilumab and compared with control. Results: Patients with melanoma (n=43) and NSCLC (n=20) received utomilumab 0.24 mg/kg (n=36), 1.2 mg/kg (n=26), or 10 mg/kg (n=1). Treatment-emergent AEs (TEAEs) occurred in 55 (87.3%) patients and serious TEAEs in 18 (28.6%). Five (7.9%) patients discontinued owing to TEAEs. Thirty-two (50.8%) patients experienced treatment-related AEs, mostly grade 1-2. Objective response rate: 2.3% in patients with melanoma; no confirmed responses for patients with NSCLC. Ten patients each with melanoma (23.3%) or NSCLC (50%) had stable disease; respective median (95% confidence interval, CI) progression-free survival was 1.8 (1.7-1.9) and 3.6 (1.6-6.5) months. Utomilumab exposure increased with dose. The incidences of antidrug and neutralizing antibodies were 46.3% and 19.4%, respectively. Efficacy was associated with immune-active tumor microenvironments, and pharmacodynamic activity appeared to be blunted at higher doses. Conclusions: Utomilumab was well tolerated, but antitumor activity was low in patients who previously progressed on ICIs. The potential of 4-1BB agonists requires additional study to optimize efficacy while maintaining the tolerable safety profile.

Changes in waterfowl migration phenologies in central North America: Implications for future waterfowl conservation.

Globally, migration phenologies of numerous avian species have shifted over the past half-century. Despite North American waterfowl being well researched, published data on shifts in waterfowl migration phenologies remain scarce. Understanding shifts in waterfowl migration phenologies along with potential drivers is critical for guiding future conservation efforts. Therefore, we utilized historical (1955-2008) nonbreeding waterfowl survey data collected at 21 National Wildlife Refuges in the mid- to lower portion of the Central Flyway to summarize changes in spring and autumn migration phenology. We examined changes in the timing of peak abundance from survey data at monthly intervals for each refuge and species (or species group; n = 22) by year and site-specific temperature for spring (Jan-Mar) and autumn (Oct-Dec) migration periods. For spring (n = 187) and autumn (n = 194) data sets, 13% and 9% exhibited statistically significant changes in the timing of peak migration across years, respectively, while the corresponding numbers for increasing temperatures were 4% and 9%. During spring migration, ≥80% of significant changes in the timing of spring peak indicated advancements, while 67% of significant changes in autumn peak timing indicated delays both across years and with increasing temperatures. Four refuges showed a consistent pattern across species of advancing spring migration peaks over time. Advancements in spring peak across years became proportionally less common among species with increasing latitude, while delays in autumn peak with increasing temperature became proportionally more common. Our study represents the first comprehensive summary of changes in spring and autumn migration phenology for Central Flyway waterfowl and demonstrates significant phenological changes during the latter part of the twentieth century.

Climate alters the movement ecology of a non-migratory bird.

Global climate change is causing increased climate extremes threatening biodiversity and altering ecosystems. Climate is comprised of many variables including air temperature, barometric pressure, solar radiation, wind, relative humidity, and precipitation that interact with each other. As movement connects various aspects of an animal's life, understanding how climate influences movement at a fine-temporal scale will be critical to the long-term conservation of species impacted by climate change. The sedentary nature of non-migratory species could increase some species risk of extirpation caused by climate change. We used Northern Bobwhite (Colinus virginianus; hereafter bobwhite) as a model to better understand the relationship between climate and the movement ecology of a non-migratory species at a fine-temporal scale. We collected movement data on bobwhite from across western Oklahoma during 2019-2020 and paired these data with meteorological data. We analyzed movement in three different ways (probability of movement, hourly distance moved, and sinuosity) using two calculated movement metrics: hourly movement (displacement between two consecutive fixes an hour apart) and sinuosity (a form of tortuosity that determines the amount of curvature of a random search path). We used generalized linear-mixed models to analyze probability of movement and hourly distance moved, and used linear-mixed models to analyze sinuosity. The interaction between air temperature and solar radiation affected probability of movement and hourly distance moved. Bobwhite movement increased as air temperature increased beyond 10°C during low solar radiation. During medium and high solar radiation, bobwhite moved farther as air temperature increased until 25-30°C when hourly distance moved plateaued. Bobwhite sinuosity increased as solar radiation increased. Our results show that specific climate variables alter the fine-scale movement of a non-migratory species. Understanding the link between climate and movement is important to determining how climate change may impact a species' space use and fitness now and in the future.

Predicting Primary Biodegradation of Petroleum Hydrocarbons in Aquatic Systems: Integrating System and Molecular Structure Parameters using a Novel Machine-Learning Framework.

Quantitative structure-property relationship (QSPR) models for predicting primary biodegradation of petroleum hydrocarbons have been previously developed. These models use experimental data generated under widely varied conditions, the effects of which are not captured adequately within model formalisms. As a result, they exhibit variable predictive performance and are unable to incorporate the role of study design and test conditions on the assessment of environmental persistence. To address these limitations, a novel machine-learning System-Integrated Model (HC-BioSIM) is presented, which integrates chemical structure and test system variability, leading to improved prediction of primary disappearance time (DT50) values for petroleum hydrocarbons in fresh and marine water. An expanded, highly curated database of 728 experimental DT50 values (181 unique hydrocarbon structures compiled from 13 primary sources) was used to develop and validate a supervised model tree machine-learning model. Using relatively few parameters (6 system and 25 structural parameters), the model demonstrated significant improvement in predictive performance (root mean square error = 0.26, R2 = 0.67) over existing QSPR models. The model also demonstrated improved accuracy of persistence (P) categorization (i.e., "Not P/P/vP"), with an accuracy of 96.8%, and false-positive and -negative categorization rates of 0.4% and 2.7%, respectively. This significant improvement in DT50 prediction, and subsequent persistence categorization, validates the need for models that integrate experimental design and environmental system parameters into biodegradation and persistence assessment. Environ Toxicol Chem 2022;41:1359-1369. © 2022 ExxonMobil Biomedical Sciences, Inc. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Why did the chicken not cross the road? Anthropogenic development influences the movement of a grassland bird.

Movement and selection are inherently linked behaviors that form the foundation of a species' space-use patterns. Anthropogenic development in natural ecosystems can result in a variety of behavioral responses that can involve changes in either movement (speed or direction of travel) or selection (resources used), which in turn may cause population-level consequences including loss of landscape connectivity. Understanding how a species alters these different behaviors in response to human activity is essential for effective conservation. In this study, we investigated the effects of anthropogenic development such as roads, power lines and oil wells on the greater prairie-chicken (Tympanuchus cupido) movement and selection behaviors in the post-nesting and non-breeding season. Our first objective was to assess using integrated step selection analysis (iSSA) if greater prairie-chickens altered their movement behaviors or their selection patterns when encountering oil wells, power lines, or roads. Our second objective was to determine whether prairie-chickens avoided crossing linear features such as roads or power lines by comparing the number of crossing events in greater prairie-chicken movement tracks to the number of movements that crossed these features in simulated movement tracks. Based on the iSSA analysis, we found that greater prairie-chickens avoided oil wells, power lines, and roads in both seasons, and altered their rate of movement when near anthropogenic structures. However, changes in speed varied by season, with prairie-chickens increasing their movement rates in the post-nesting season when near to development and decreasing movement rates in the non-breeding season. Furthermore, prairie-chickens crossed roads and power lines at much lower rates than expected. These changes in behavior can result in habitat loss for greater prairie-chickens, as well as the potential loss of landscape connectivity. By considering both movement and selection, we were able to develop an ecological understanding of how increasing human activity may influence the space use of this species of conservation concern. Furthermore, this research provides insight into the decision-making processes by animals when they encounter anthropogenic development.

Clinical Impact of Pitolisant on Excessive Daytime Sleepiness and Cataplexy in Adults With Narcolepsy: An Analysis of Randomized Placebo-Controlled Trials.

BACKGROUND: Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, is indicated for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. The efficacy and safety of pitolisant have been demonstrated in randomized placebo-controlled trials. When evaluating the results of randomized placebo-controlled trials, the clinical impact of a treatment can be assessed using effect size metrics that include Cohen's d (the standardized mean difference of an effect) and number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person). OBJECTIVE: The objective of this study was to evaluate the clinical impact of pitolisant for the reduction in excessive daytime sleepiness or cataplexy in adults with narcolepsy. METHODS: This post hoc analysis incorporated data from two 7-week or 8-week randomized placebo-controlled trials (HARMONY 1, HARMONY CTP). Study medication was individually titrated, with a maximum possible pitolisant dose of 35.6 mg/day. Efficacy was assessed using the Epworth Sleepiness Scale (ESS) and weekly rate of cataplexy (HARMONY CTP only). Cohen's d was derived from the least-squares mean difference between treatment groups (pitolisant vs placebo), and NNTs were calculated from response rates. Treatment response was defined for excessive daytime sleepiness in two ways: (a) reduction in ESS score ≥ 3 or final ESS score ≤ 10 and (b) final ESS score ≤ 10. Treatment response was defined for cataplexy as a ≥ 25%, ≥ 50%, or ≥ 75% reduction in weekly rate of cataplexy. RESULTS: The analysis population included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). For pitolisant vs placebo, Cohen's d effect size values were 0.61 (HARMONY 1) and 0.86 (HARMONY CTP) based on changes in ESS scores, and 0.86 (HARMONY CTP) based on changes in weekly rate of cataplexy. NNTs for pitolisant were 3-5 for the treatment of excessive daytime sleepiness and 3-4 for the treatment of cataplexy. CONCLUSIONS: The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction in both excessive daytime sleepiness and cataplexy. These large effect sizes and low NNTs provide further evidence supporting the strength of the clinical response to pitolisant in the treatment of adults with narcolepsy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01067222 (February 2010), NCT01800045 (February 2013).

Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial.

In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432 ), avelumab/best supportive care (BSC) significantly prolonged overall survival relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fcγ receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment.

Time to Onset of Response to Pitolisant for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Patients With Narcolepsy: An Analysis of Randomized, Placebo-Controlled Trials.

BACKGROUND: Pitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. OBJECTIVE: Analyses evaluated the time to onset of clinical response during treatment with pitolisant. METHODS: Data were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo. RESULTS: The analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]). CONCLUSIONS: Onset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2-3 weeks of pitolisant treatment in patients with narcolepsy. CLINICALTRIALS. GOV IDENTIFIER: NCT01067222 (February 2010), NCT01800045 (February 2013).