Search

Abstract Parturition timing has long been a topic of interest in ungulate research. However, few studies have examined parturition timing at fine scale (e.g.,

Abstract Background Information on reproduction of harvested species such as mule deer (Odocoileus hemionus) is vital for conservation and management. Furthermore, parturition in ungulates may be detected using patterns of movement logged by GPS transmitters. Several movement-based methods have been developed to detect parturition in ungulates including the Peterson method, behavioral change point analysis (BCPA), rolling minimum convex polygons (rMCP), individual-based method (IBM), and population-based method (PBM). Our objectives were to (1) test the accuracy and the precision of each previously described method and (2) develop an improved method optimized for mule deer that incorporated aspects of the other methods. Methods We determined parturition timing and status for female mule deer fitted with GPS collars and implanted with vaginal implant transmitters (VITs). We used movement patterns before and after parturition to set movement thresholds for each movement-based method. Following model training, we used location and birth date data from an external dataset to test the effectiveness of each movement-based method. Additionally, we developed a novel method for detecting parturition called the analysis of parturition indicators (API). We used two regression analyses to determine the accuracy and precision of estimates generated by each method. Results The six methods we employed varied in accuracy, with the API, rMCP, and BCPA being most accurate. Precision also varied among methods, with the API, rMCP, and PBM generating the most precise estimates of parturition dates. The API and the rMCP performed similarly and better overall than any of the other existing methods. Conclusions We found that movement-based methods could be used to accurately and precisely detect parturition in mule deer. Further, we determined that the API and rMCP methods had the greatest overall success at detecting parturition in mule deer. The relative success of the API and rMCP may be attributed to the fact that both methods use home range size to detect parturition and are validated using known parturition dates of collared deer. We present the API as an efficient method of estimating birth status and timing of parturition of mule deer fitted with GPS transmitters, as well as affirm the effectiveness of a previously developed method, rMCP.

Climate and land-use change are modifying the availability of food and water resources, which is driving more wildlife to the wildland-urban interface. For many wildlife populations, use of these areas still requires habitat connectivity both within the interface and/or to wildland habitats. However, navigating these areas can be difficult due to human development and sensory pollutants, such as artificial night light. Determining how these components of urbanization influence the behaviors and functional connectivity of species is important for managing wildlife within these mixed-use landscapes. Here we used a movescape approach based on graph theory to characterize functional uses of the landscape using metrics for behavior, connectivity, and space use intensity. We found that mule deer (Odocoileus hemionus; n = 43) functional uses of anthropogenic landscapes in the Intermountain West, USA, were dependent not only on physical barriers, terrain, and sensory factors, but also the local levels of light exposure and vegetative greenness. Remotely sensed artificial light levels had a strong influence on how mule deer used the landscape by reducing the intensity of use in the most illuminated areas given forage availability. In contrast, relatively high local light levels were associated with increased use intensity within less developed areas—highlighting the foraging tradeoffs for species using the wildland-urban interface. Corridor use was reduced in areas where road and housing density were higher, and within-corridor movement was faster when artificial light was high and vegetative greenness was low. Developing a more mechanistic understanding of how species functionally use the landscape in relation to features of urbanization can enhance conservation by delineating areas important for connectivity and foraging, while providing insights into how future development and climate change may alter movement and behavior. Spatially-explicit estimates of functional uses can directly guide management decisions to maintain species resiliency and improve land-use planning.

Background Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction. Methods and Results The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta‐Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin‐like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47–0.7]; P=3.13E‐05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44–0.69]; P=0.0001), and DNASE1 (deoxyribonuclease‐1) (HR, 0.5704 [95% CI, 0.46–0.71]; P=0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α‐1, collagen XV α‐1), metabolism (pancreatic α‐amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission. Conclusions Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Abstract Observed links between parasites, such as ticks, and climate change have aroused concern for human health, wildlife population dynamics, and broader ecosystem effects. The one‐host life history of the winter tick (Dermacentor albipictus) links each annual cohort to environmental conditions during three specific time periods when they are predictably vulnerable: spring detachment from hosts, summer larval stage, and fall questing for hosts. We used mixed‐effects generalized linear models to investigate the drivers of tick loads carried by moose (Alces alces) relative to these time periods and across 750 moose, 10 years, and 16 study areas in the western United States. We tested for the effects of biotic factors (moose density, shared winter range, vegetation, migratory behavior) and weather conditions (temperature, snow, humidity) during each seasonal period when ticks are vulnerable and off‐host. We found that warm climatic regions, warm seasonal periods across multiple partitions of the annual tick life cycle, and warm years relative to long‐term averages each contributed to increased tick loads. We also found important effects of snow and other biotic factors such as host density and vegetation. Tick loads in the western United States were, on average, lower than those where tick‐related die‐offs in moose populations have occurred recently, but loads carried by some individuals may be sufficient to cause mortality. Lastly, we found interannual variation in tick loads to be most correlated with spring snowpack, suggesting this environmental component may have the highest potential to induce change in tick load dynamics in the immediate future of this region.

Abstract Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on behavior, neurochemistry, and potential for addiction. Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKIIα, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release. Our results suggest a role for CaMKIIα in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine’s neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder.

ObjectivePatients with melanoma and early stable disease (SD) with pembrolizumab have unclear prognosis. We present post hoc analyses of long-term outcomes for patients with early SD, partial response (PR) or complete response (CR) with pembrolizumab.Patients and methodsPatients who received pembrolizumab in the KEYNOTE-001 and KEYNOTE-006 studies and had SD, PR or CR at weeks 12 or 24 were included.ResultsOf 294 patients in the week 12 analysis, 107 (36.4%) had SD at week 12, of whom 7 (6.5%) had a best overall response of CR, 43 (40.2%) had PR and 57 (53.3%) had SD. Forty-eight-month overall survival (OS) rates were 95.2%, 73.0% and 47.7%, respectively, for patients with CR, PR and SD at week 12. Similar results were observed in the 241 patients in the week 24 analysis. Forty-eight-month OS rates were 72.1% for patients with SD at week 12 followed by subsequent response and 75.0% for patients with PR at week 12 followed by no change in response or progression. Thirty-six-month and 48-month OS rates were 11.6% and not reached, respectively, for patients with SD at week 12 followed by progression before week 24.ConclusionsA substantial proportion of patients (46.7%) with early (week 12) SD with pembrolizumab achieved subsequent PR or CR. Patients with SD at week 12 and subsequent CR/PR had similar survival to those who maintained PR. In contrast, patients with SD at week 12 and subsequent progression had poor survival outcomes. These findings may guide treatment decisions for patients achieving early SD.Trial registrationClinicaltrials.gov: NCT01295827 (KEYNOTE-001); NCT01866319 (KEYNOTE-006).

Objective: Pulmonary artery reconstruction during comprehensive stage 2 (CS2) procedure can be challenging. Since 2017, we have employed preemptive left pulmonary artery (LPA) stenting. We hypothesized that LPA stenting promotes adequate growth and without compromising Fontan candidacy. Herewith, we report our midterm results. Methods: From 2002 to 2020, 159 patients underwent CS2. Patients were divided as follows: no stent (n = 122; Group 1) and perioperative LPA stent (n = 37; Group 2). Group 2 was subdivided according to unplanned stent (n = 17; Group 2a) or preemptive stent (n = 20; Group 2b). Relevant perioperative data was reviewed. Nonparametric statistics were utilized. Results: Median age and weight at surgery and hospital length of stay after CS2 did not differ between groups. Median cardiopulmonary bypass and crossclamp times were significantly greater in Group 1 (265 vs 243 minutes [P = .021] and 46 vs 26 minutes [P = .008]). In-hospital mortality was similar between Groups 1 and 2 (9.0% vs 18.9%, respectively [P = .1348]). Group 2b demonstrated a superior survival compared to Group 2a (P = .0335) but not Group 1 (P > .9999). Preemptive stenting significantly increased median hilar LPA diameter at CS2 exit angiogram compared with no stenting (P

ObjectiveLong-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.Patients and methodsAnalysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.ResultsAdverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.ConclusionsThese results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.Clinical trial registryNCT01295827, NCT01704287, NCT01866319.

Abstract The capture of neonate ungulates allows for the collection of valuable ecological data, including estimates of litter size. However, varied methods used to capture neonate ungulates can result in sampling biases. Our objective was to determine if opportunistic captures of neonate ungulates (i.e., locating neonates by visually scanning for adult females displaying postpartum behaviors) bias relative estimates of litter size and investigate potential causes if a bias does exist. We analyzed data from 161 litters of mule deer (Odocoileus hemionus) sampled using three different capture methods during 2019–2021 in Utah, USA. Estimates of litter size derived from opportunistic captures were smaller than estimates derived from movement-based captures or captures completed with the aid of vaginal implant transmitters (VITs). Age at capture was inversely related to estimates of litter size and likely influenced the detection bias associated with opportunistic captures. Neonates captured opportunistically were not older than neonates captured using movement-based methods, but were older than neonates captured with the aid of VITs. Distance between neonates from the same litter did not influence estimates of litter size. Researchers should be aware of the biases associated with different capture methods and use caution when interpreting data among multiple capture methods. Estimates of litter size derived from opportunistic captures should not be compared to estimates of litter size derived from alternative capture methods without accounting for the detection bias we observed.

Many of the larger US metropolitan regions promote polycentric development as a way of fostering livability, accessibility, and sustainability. Polycentric urban structures can increase transit ridership, promote active transportation, and decrease vehicle miles traveled (VMT) and CO2 emissions. Although many regions include ambitious polycentric aspirations in their plans, only a few follow up with rigorous implementation and see their efforts come to fruition. The topic of implementation is also widely omitted from scholarly inquiry. This research aims to explore three examples of successful implementation of urban polycentricity: Portland, Oregon; Seattle, Washington; and Denver, Colorado. Each region employs a very distinct polycentric development model, but each relies heavily on its regional governance organization for direction, guidance, and even command in the implementation process. To understand specific strategies and methods used by each region, the authors conducted interviews with metropolitan planning organizations, central cities, and transit agencies in the three regions and used qualitative techniques to analyze the interview transcripts and collected documents. As regional governance organizations play a crucial role in implementing regional plans, their policies and practices were also investigated by the authors. Based on collected data and insights, we conclude that the three regions are great examples of an advanced implementation of polycentric development. This research can be helpful to other US metropolitan regions that wish to promote polycentric development. The lessons learned from the three case studies can provide guidance and possible paths to successful implementation.

Abstract Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition that can lead to severe impairment of physical, psychological, cognitive, social, and occupational functions. The cause of ME/CFS remains incompletely understood. There is no clinical diagnostic test for ME/CFS. Although many therapies have been used off-label to manage symptoms of ME/CFS, there are limited, if any, specific therapies or cure for ME/CFS. In this study, we investigated the expression of genes specific to key immune functions, and viral infection status in ME/CFS patients with an aim of identifying biomarkers for characterization and/or treatment of the disease. Methods In 2021, one-hundred and sixty-six (166) patients diagnosed with ME/CFS and 83 healthy controls in the US participated in this study via a social media-based application (app). The patients and heathy volunteers consented to the study and provided self-collected finger-stick blood and first morning void urine samples from home. RNA from the fingerstick blood was tested using DxTerity’s 51-gene autoimmune RNA expression panel (AIP). In addition, DNA from the same fingerstick blood sample was extracted to detect viral load of 4 known ME/CFS associated viruses (HHV6, HHV7, CMV and EBV) using a real-time PCR method. Results Among the 166 ME/CFS participants in the study, approximately half (49%) of the ME/CFS patients reported being house-bound or bedridden due to severe symptoms of the disease. From the AIP testing, ME/CFS patients with severe, bedridden conditions displayed significant increases in gene expression of IKZF2, IKZF3, HSPA8, BACH2, ABCE1 and CD3D, as compared to patients with mild to moderate disease conditions. These six aforementioned genes were further upregulated in the 22 bedridden participants who suffer not only from ME/CFS but also from other autoimmune diseases. These genes are involved in T cell, B cell and autoimmunity functions. Furthermore, IKZF3 (Aiolos) and IKZF2 (Helios), and BACH2 have been implicated in other autoimmune diseases such as systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (RA). Among the 240 participants tested with the viral assays, 9 samples showed positive results (including 1 EBV positive and 8 HHV6 positives). Conclusions Our study indicates that gene expression biomarkers may be used in identifying or differentiating subsets of ME/CFS patients having different levels of disease severity. These gene targets may also represent opportunities for new therapeutic modalities for the treatment of ME/CFS. The use of social media engaged patient recruitment and at-home sample collection represents a novel approach for conducting clinical research which saves cost, time and eliminates travel for office visits.

Abstract Background Stress-induced mental illnesses (mediated by neuroinflammation) pose one of the world’s most urgent public health challenges. A reliable in vivo chemical biomarker of stress would significantly improve the clinical communities’ diagnostic and therapeutic approaches to illnesses, such as depression. Methods Male and female C57BL/6J mice underwent a chronic stress paradigm. We paired innovative in vivo serotonin and histamine voltammetric measurement technologies, behavioral testing, and cutting-edge mathematical methods to correlate chemistry to stress and behavior. Results Inflammation-induced increases in hypothalamic histamine were co-measured with decreased in vivo extracellular hippocampal serotonin in mice that underwent a chronic stress paradigm, regardless of behavioral phenotype. In animals with depression phenotypes, correlations were found between serotonin and the extent of behavioral indices of depression. We created a high accuracy algorithm that could predict whether animals had been exposed to stress or not based solely on the serotonin measurement. We next developed a model of serotonin and histamine modulation, which predicted that stress-induced neuroinflammation increases histaminergic activity, serving to inhibit serotonin. Finally, we created a mathematical index of stress, S i and predicted that during chronic stress, where S i is high, simultaneously increasing serotonin and decreasing histamine is the most effective chemical strategy to restoring serotonin to pre-stress levels. When we pursued this idea pharmacologically, our experiments were nearly identical to the model’s predictions. Conclusions This work shines the light on two biomarkers of chronic stress, histamine and serotonin, and implies that both may be important in our future investigations of the pathology and treatment of inflammation-induced depression.

Abstract Background Non-communicable diseases (NCDs) constitute the leading cause of mortality globally. Low and middle-income countries (LMICs) not only experience the largest burden of humanitarian emergencies but are also disproportionately affected by NCDs, yet primary focus on the topic is lagging. We conducted a systematic review on the effect of humanitarian disasters on NCDs in LMICs assessing epidemiology, interventions, and treatment. Methods A systematic search in MEDLINE, MEDLINE (PubMed, for in-process and non-indexed citations), Social Science Citation Index, and Global Health (EBSCO) for indexed articles published before December 11, 2017 was conducted, and publications reporting on NCDs and humanitarian emergencies in LMICs were included. We extracted and synthesized results using a thematic analysis approach and present the results by disease type. The study is registered at PROSPERO (CRD42018088769). Results Of the 85 included publications, most reported on observational research studies and almost half (48.9%) reported on studies in the Eastern Mediterranean Region (EMRO), with scant studies reporting on the African and Americas regions. NCDs represented a significant burden for populations affected by humanitarian crises in our findings, despite a dearth of data from particular regions and disease categories. The majority of studies included in our review presented epidemiologic evidence for the burden of disease, while few studies addressed clinical management or intervention delivery. Commonly cited barriers to healthcare access in all phases of disaster and major disease diagnoses studied included: low levels of education, financial difficulties, displacement, illiteracy, lack of access to medications, affordability of treatment and monitoring devices, and centralized healthcare infrastructure for NCDs. Screening and prevention for NCDs in disaster-prone settings was supported. Refugee status was independently identified both as a risk factor for diagnosis with an NCD and conferring worse morbidity. Conclusions An increased focus on the effects of, and mitigating factors for, NCDs occurring in disaster-afflicted LMICs is needed. While the majority of studies included in our review presented epidemiologic evidence for the burden of disease, research is needed to address contributing factors, interventions, and means of managing disease during humanitarian emergencies in LMICs.

Translocation of large mammals has become common practice for wildlife managers charged with conservation of animals and their genetic integrity on increasingly modified landscapes. Translocations of ungulates have occurred around the world with varying outcomes. Although translocations have been used to manage mule deer (Odocoileus hemionus) in western North America, only recently have the outcomes associated with this management practice been documented. Our objective was to evaluate survival of translocated mule deer in comparison to resident mule deer over multiple years following release and provide information useful in judging the relative value of translocation as a conservation strategy for this species. In January and March 2013, the Utah Division of Wildlife Resources (UDWR) captured and translocated 102 mule deer from winter range near Parowan, Utah to winter range near Holden, Utah (approximately 145 kilometers north of capture location). We fitted each deer with a radio transmitter (n = 102 total: 21 GPS collars, 81 VHF collars) prior to release. We also captured and marked a total of 70 resident deer (9 GPS collars, 61 VHF collars) to serve as a reference group. Survival of translocated deer in the first year was similar among release dates in January (0.51; 95% CI = 0.40–0.63) and March (0.53; 95% CI = 0.40–0.66). Annual survival of translocated deer, however, was lower than survival of resident deer (0.83; 95% CI = 0.72–0.90) in the first year after release. During the second year following release, however, survival of translocated animals (0.85; 95% CI = 0.71–0.93) was not different from that of resident deer (0.80; 95% CI = 0.69–0.88). Additionally, age strongly influenced the survival of translocated deer; young deer (e.g., 1.5 year olds) were more than twice as likely as old deer (e.g., 7.5 year olds) to survive the initial year following translocation. These data highlight the need to monitor translocated animals for multiple years following release and suggest that wildlife managers should expect to see higher survival rates during the second year following translocation and higher survival rates in younger deer compared to older deer.

Maternal effects are the influence of maternal phenotype and the maternally-provided environment on the phenotype (i.e., expression of traits) of offspring. Frequently, maternal effects are manifest both before and after parturition. Pre-parturition effects are primarily direct allocation of energy to the offspring that is in utero. Post-parturition effects can include direct (e.g., nursing and defending offspring) and indirect (e.g., selection of habitat that is relatively safe or has high nutritional value) influences. While both direct and indirect effects are often discussed, there is a paucity of information on the relative importance of each type on offspring due to the difficulty in monitoring mothers prior to parturition and mother-offspring relationships after parturition in free-ranging animals. Our objective was to determine the importance of direct maternal effects on birth weight, growth rates, and survival of mule deer (Odocoileus hemionus) fawns from birth through the first 18 months of life. We determined the effect of nutritional condition of the dam (mother) on birth weight (pre-parturition direct effect). We also examined the post-parturition direct effect of dam nutritional condition on growth rates and survival of fawns. Direct maternal effects were evident both before and after parturition; dams in better nutritional condition produced offspring with greater mass at birth, higher rates of growth, and increased survival. Our findings demonstrate that maternal nutritional condition influences fawn health from gestation through recruitment. These links highlight the importance of considering direct maternal effects when examining population dynamics and reproductive success in long-lived mammals. Management plans for ungulates should include assessment of nutritional condition of adult females to maximize likelihood of effective conservation.

BackgroundPembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.Patients and methodsPatients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).ResultsKEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.ConclusionsThis 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.Clinical trial registryClinicalTrials.gov, NCT01295827.

AimsTo assess whether nursing home (NH) residents with type 2 diabetes mellitus (T2D) preferentially received "T2D-friendly" (vs "T2D-unfriendly") β-blockers after acute myocardial infarction (AMI), and to evaluate the comparative effects of the two groups of β-blockers.Materials and methodsThis new-user retrospective cohort study of NH residents with AMI from May 2007 to March 2010 used national data from the Minimum Data Set and Medicare system. T2D-friendly β-blockers were those hypothesized to increase peripheral glucose uptake through vasodilation: carvedilol, nebivolol and labetalol. Primary outcomes were hospitalizations for hypoglycaemia and hyperglycaemia in the 90 days after AMI. Secondary outcomes were functional decline, death, all-cause re-hospitalization and fracture hospitalization. We compared outcomes using binomial and multinomial logistic regression models after propensity score matching.ResultsOf 2855 NH residents with T2D, 29% initiated a T2D-friendly β-blocker vs 24% of 6098 without T2D (P

Purpose: The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827).Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations.Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1-89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites; all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs. 23%; P < 0.001) and improved OS (HR, 0.38; P < 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS (P < 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1-positive tumors were independently associated with higher ORR and longer OS.Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma. Clin Cancer Res; 24(20); 4960-7. ©2018 AACR See related commentary by Warner and Postow, p. 4915.

Recent meta-analyses indicate that predator removal experiments result in marginal increases in prey abundance at best. However, most predator removal studies take place for less than the target prey’s generation time and lack a targeted spatial approach. Our objective was to determine how temporal and spatial aspects of predator control influenced neonate survival of a temperate ungulate. We conducted multiyear coyote (Canis latrans) removals using a crossover experimental design. We found that consecutive years of predator removal increased survival of neonate mule deer (Odocoileus hemionus) more than a single year of removal. We also found that removing coyotes from areas near fawn birth sites increased fawn survival, whereas removing coyotes from areas farther from birth sites did not influence fawn survival. Our results underscore the need for coyote removal programs to (1) employ removal efforts over consecutive years to maximize effectiveness, (2) conduct spatially explicit removal efforts targeting fawning habitat, and (3) occur when the likelihood of additive mortality is high and prey populations have the resources available to grow.

Gender-based violence (GBV) is a global public health and human rights problem that is exacerbated by social and environmental stressors for a multitude of interpersonal, cultural, and economic reasons. Through sudden disruptions in the microclimate of a region, climate shocks often have a negative impact on food security, which correlates with increases in GBV. Associations between the various combinations of GBV, climate change, and food insecurity have been documented in the growing international literature, but questions remain about these associations that require further clarification. The impact of the COVID-19 pandemic caused by SARS-CoV-2 provides insight through a real time demonstration into these interactions. This review of the global literature examines the interplay between GBV, climate change, and food insecurity-including recent literature regarding the COVID-19 pandemic. This review covers original research studies employing both quantitative and qualitative methodology, those that conducted secondary analyses of existing data sources and perspective pieces derived from observed evidence. An additional analytic layer of system dynamics modeling allowed for the integration of findings from the scoping review and discovery of additional insights into the interplay between disasters, food insecurity, and GBV. Findings from this review suggest that the development and adaptation of evidence-based, focused interventions and policies to reduce the effects of climate shocks and bolster food security may ultimately decrease GBV prevalence and impact.

Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.

INTRODUCTION:Urinary biomarkers are being developed to detect bladder cancer recurrence/progression in patients with non-muscle-invasive bladder cancer (NMIBC). We conducted a questionnaire-based study to determine what diagnostic accuracy and cost would such test(s) need for both patients and urologic oncologists to comfortably forgo surveillance cystoscopy in favour of these tests. METHODS:Surveys were administered to NMIBC patients at followup cystoscopy visit and to physician members of the Society of Urologic Oncology. Participants were questioned about acceptable false-negative (FN) rates and costs for such alternatives, in addition to demographics that could influence chosen error rates and costs. RESULTS:A total of 137 patient and 51 urologic oncologist responses were obtained. Seventy-seven percent of patients were not comfortable with urinary biomarker(s) alternatives to repeat cystoscopy, with a further 14% willing to accept such alternatives only if the FN rate were 0.5% or lower. Seventy-five percent of urologic oncologists were comfortable with an alternative urinary biomarker test(s), with 37% and 33% willing to accept FN rates of 5% and 1%, respectively. Forty-seven percent of patients were not willing to pay out-of-pocket for such tests, while 61% of urologic oncologists felt that a price range of $100-500 would be reasonable. CONCLUSIONS:This is the first survey evaluating patient and urologic oncologist perspectives on acceptable error rates and costs for urinary biomarker alternatives to surveillance cystoscopy for patients with NMIBC. Despite potential responder bias, this study suggests that urinary biomarker(s) will require sensitivity equivalent to that of cystoscopy in order to completely replace it in surveillance of patients with NMIBC.

Abstract Background Conservation and management of migratory animals has gained attention in recent years, but the majority of research has focused on stereotypical ‘migrant’ and ‘resident’ behaviors, often failing to incorporate any atypical behaviors or characterize migratory behaviors beyond distance and timing of the migration. With migration threatened by anthropogenic development and climate change, it is crucial that we understand the full range of migratory behaviors. Our objective was to demonstrate and characterize the variation in migration strategies, including typical and atypical migratory behaviors for mule deer (Odocoileus hemionus) in Utah, USA. Methods Because calculation of common metrics such as distance, timing, and use of stopovers during migration did not adequately describe the variation we observed in migratory behavior for this species—particularly when animals visited multiple (> 3) ranges for extended lengths of time—we developed additional methods and categories to describe observed variation in migratory behavior. We first categorized trajectories based on the number of discrete, separate ranges and range shifts between them. Then, we further characterized the variation in migration strategies by examining the timing, duration, and distance traveled within each of the categories. We also examined if and how frequently individual deer switched among categories from year to year. Results We classified 1218 movement trajectories from 722 adult female mule deer, and found that 54.4% were dual-range migrants, who made one round-trip to one distinct range. Multi-range migrants (23.6%) made one round-trip during which they stayed at multiple discrete ranges. Commuters (1.0%) traveled to the same range multiple times, and poly migrants (1.5%) made multiple round-trips to different ranges. Gradual movers (2.5%) did not show a discrete range shift but moved gradually between ranges, whereas residents (12.6%) never left their home ranges, and dispersers (4.4%) left but never returned. Of the deer that we monitored for multiple years, 51.2% switched among categories. Conclusion We conclude that the substantial number of atypical migratory strategies, as well as the number of deer that switched categories, underlines the importance of studying these less-stereotyped behaviors that may be exhibited by large proportions of populations. Acknowledging and investigating the full complexity and diversity in migratory strategies might uncover unknowns with respect to underlying factors and drivers of migration, and can help shape effective conservation strategies.

Introduction: Mortality and morbidity from Non-Communicable Diseases (NCDs) in Africa are expected to worsen if the status quo is maintained. Emergency care settings act as a primary point of entry into the health system for a spectrum of NCD-related illnesses, however, there is a dearth of literature on this population. We conducted a systematic review assessing available evidence on epidemiology, interventions and management of NCDs in acute and emergency care settings in Kenya, the largest economy in East Africa and a medical hub for the continent. Methods: All searches were run on July 15, 2015 and updated on December 11, 2020, capturing concepts of NCDs, and acute and emergency care. The study is registered at PROSPERO (CRD42018088621). Results: We retrieved a total of 461 references, and an additional 23 articles in grey literature. 391 studies were excluded by title or abstract, and 93 articles read in full. We included 10 articles in final thematic analysis. The majority of studies were conducted in tertiary referral or private/mission hospitals. Cancer, diabetes, cardiovascular disease and renal disease were addressed. Majority of the studies were retrospective, cross-sectional in design; no interventions or clinical trials were identified. There was a lack of access to basic diagnostic tools, and management of NCDs and their complications was limited. Conclusion: There is a paucity of literature on NCDs in Kenyan emergency care settings, with particular gaps on interventions and management. Opportunities include nationally representative, longitudinal research such as surveillance and registries, as well as clinical trials and implementation science to advance evidence-based, context-specific care.

Abstract Ecological context—the biotic and abiotic environment, along with its influence on population mixing dynamics and individual susceptibility—is thought to have major bearing on epidemic outcomes. However, direct comparisons of wildlife disease events in contrasting ecological contexts are often confounded by concurrent differences in host genetics, exposure histories, or pathogen strains. Here, we compare disease dynamics of a Mycoplasma ovipneumoniae spillover event that affected bighorn sheep populations in two contrasting ecological contexts. One event occurred on the herd's home range near the Rio Grande Gorge in New Mexico, while the other occurred in a captive facility at Hardware Ranch in Utah. While data collection regimens varied, general patterns of antibody signal strength and symptom emergence were conserved between the two sites. Symptoms appeared in the captive setting an average of 12.9 days postexposure, average time to seroconversion was 24.9 days, and clinical signs peaked at approximately 36 days postinfection. These patterns were consistent with serological testing and subsequent declines in symptom intensity in the free‐ranging herd. At the captive site, older animals exhibited more severe declines in body condition and loin thickness, higher symptom burdens, and slower antibody response to the pathogen than younger animals. Younger animals were more likely than older animals to clear infection by the time of sampling at both sites. The patterns presented here suggest that environment may not be a major determinant of epidemiological outcomes in the bighorn sheep—M. ovipneumoniae system, elevating the possibility that host‐ or pathogen‐factors may be responsible for observed variation.

FKRP mutations cause muscular dystrophies with varied clinical presentations. The target of FKRP is α-dystroglycan, but here the authors show that FKRP also directs sialylation of fibronectin, a process that is essential for recruitment o collagen to the muscle basement membrane.

Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

Bubble point tests are widely used for assessing the integrity of sterilizing-grade membrane cartridge filters. While many authors have considered the limitations of bubble point tests as applied to cartridge filters, the level of bacterial retention assurance provided by this test as conducted with automated integrity testers (AITs) has not, until now, been quantified. Contrary to the notion that filter leaks result in a depressed bubble point, it was shown that the bubble point as reported by AITs was insensitive to defect size up until the point where the AIT either determined a gross leak failure or was not able to return a valid result. For the three AITs used in this study, the minimum laser hole defect diameter in 10-inch (25.4 cm) sterilizing-grade cartridge filters that resulted in a failing bubble point test was between about 30 and 60 µm, depending on the filter type and test conditions. These defect sizes were associated with bacterial log reduction values in the 4.0 to 4.5 range. This study supports the generally recommended practice of pairing the bubble point test (which does confirm proper pore size rating) with a complementary gas–liquid diffusion test (better suited for detecting defects) to achieve a more comprehensive assessment of filter integrity.

Abstract Background The ChEMBL database is one of a number of public databases that contain bioactivity data on small molecule compounds curated from diverse sources. Incoming compounds are typically not standardised according to consistent rules. In order to maintain the quality of the final database and to easily compare and integrate data on the same compound from different sources it is necessary for the chemical structures in the database to be appropriately standardised. Results A chemical curation pipeline has been developed using the open source toolkit RDKit. It comprises three components: a Checker to test the validity of chemical structures and flag any serious errors; a Standardizer which formats compounds according to defined rules and conventions and a GetParent component that removes any salts and solvents from the compound to create its parent. This pipeline has been applied to the latest version of the ChEMBL database as well as uncurated datasets from other sources to test the robustness of the process and to identify common issues in database molecular structures. Conclusion All the components of the structure pipeline have been made freely available for other researchers to use and adapt for their own use. The code is available in a GitHub repository and it can also be accessed via the ChEMBL Beaker webservices. It has been used successfully to standardise the nearly 2 million compounds in the ChEMBL database and the compound validity checker has been used to identify compounds with the most serious issues so that they can be prioritised for manual curation.

Background. The evaluation of tumour-infiltrating lymphocytes (TILs) in solid malignancies has yielded insights into immune regulation within the tumour microenvironment and has also led to the development and optimisation of adoptive T cell therapies. Objectives. This study examined the in vitro expansion of TILs from prostate adenocarcinoma, as a preliminary step to evaluate the potential of TILs for adoptive T cell therapy. Design, Setting, and Participants. Malignant and adjacent nonmalignant tissues were obtained from fifteen men undergoing radical prostatectomy. Interventions. There were no study interventions. Outcome Measurements and Statistical Analysis. Expanded cells were analysed by flow cytometry, and the data was assessed for associations between cell subpopulations and expansion rate. Results. Tumour-infiltrating lymphocytes could be expanded to numbers that would be needed to generate a therapeutic infusion product from nine of 15 malignant specimens (60%). The CD4+ T cells predominated over CD8+ T cells (median 56.8% CD4+, 30.0% CD8+), and furthermore, faster TIL expansion was associated with a higher proportion of CD4+ T cells (median 69.8% in faster-growing cultures; 36.8% in slower-growing cultures). A higher proportion of CD3−CD56+ cells versus CD3+ cells was associated with slower TIL expansion in cultures from malignant specimens (median 13.3% in slower-growing cultures versus 2.05% in faster-growing cultures), but not from nonmalignant specimens. Conclusions. The expansion of TILs for potential therapeutic use is feasible. Our findings also indicate that further examination of TILs from prostate adenocarcinomas may yield insights into mechanisms of regulation of T cells within the tumour microenvironment. Further research is required to evaluate their therapeutic potential.

Next generation sequencing (NGS) assays with large targeted gene panels can comprehensively profile cancer somatic mutations in a tumor sample. Given the rapid adoption of such assays for circulating tumor DNA (ctDNA) analysis in clinical oncology, it is essential for the community to understand their analytical performance in liquid biopsy settings. Here, we directly compared five ctDNA NGS assays, most of which having a panel of 400 or more genes, with simulated samples harboring mutations relevant to solid tumors or myeloid malignancy. Our results indicate that the detection sensitivity and reproducibility of all five assays was 90% or higher when the mutations were at 0.5% or 1.0% allele frequency, and with optimal DNA input of 30 ng or 50 ng per vendor's protocol. The performances decreased and varied dramatically, when mutations were at a 0.1% allele frequency and/or when a lower genomic input of 10 ng DNA was used. Interestingly, one of the assays repeatedly showed higher rate of false positivity than the others across two different sample sets. Multiple intrinsic technical factors pertaining to the NGS assays were further investigated. Notable differences among the assays were seen for depth of coverage and background noise, which profoundly impacted assay performance. The results derived from this study are highly informative and provide a framework to assess and select suitable assays for specific application in cancer monitoring and potential clinical use.

The green wave hypothesis (GWH) states that migrating animals should track or 'surf' high-quality forage at the leading edge of spring green-up. To index such high-quality forage, recent work proposed the instantaneous rate of green-up (IRG), i.e. rate of change in the normalized difference vegetation index over time. Despite this important advancement, no study has tested the assumption that herbivores select habitat patches at peak IRG. We evaluated this assumption using step selection functions parametrized with movement data during the green-up period from two populations each of bighorn sheep, mule deer, elk, moose and bison, totalling 463 individuals monitored 1-3 years from 2004 to 2014. Accounting for variables that typically influence habitat selection for each species, we found seven of 10 populations selected patches exhibiting high IRG-supporting the GWH. Nonetheless, large herbivores selected for the leading edge, trailing edge and crest of the IRG wave, indicating that other mechanisms (e.g. ruminant physiology) or measurement error inherent with satellite data affect selection for IRG. Our evaluation indicates that IRG is a useful tool for linking herbivore movement with plant phenology, paving the way for significant advancements in understanding how animals track resource quality that varies both spatially and temporally.

PurposeWe evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827).Patients and methodsPatients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1.ResultsOf the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177).ConclusionAtypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment.

Histamine is well known for mediating peripheral inflammation; however, this amine is also found in high concentrations in the brain where its roles are much less known. In vivo chemical dynamics are difficult to measure, thus fundamental aspects of histamine’s neurochemistry remain undefined. In this work, we undertake the first in-depth characterization of real time in vivo histamine dynamics using fast electrochemical tools. We find that histamine release is sensitive to pharmacological manipulation at the level of synthesis, packaging, autoreceptors and metabolism. We find two breakthrough aspects of histamine modulation. First, differences in H3 receptor regulation between sexes show that histamine release in female mice is much more tightly regulated than in male mice under H3 or inflammatory drug challenge. We hypothesize that this finding may contribute to hormone-mediated neuroprotection mechanisms in female mice. Second, a high dose of a commonly available antihistamine, the H1 receptor inverse agonist diphenhydramine, rapidly decreases serotonin levels. This finding highlights the sheer significance of pharmaceuticals on neuromodulation. Our study opens the path to better understanding and treating histamine related disorders of the brain (such as neuroinflammation), emphasizing that sex and modulation (of serotonin) are critical factors to consider when studying/designing new histamine targeting therapeutics.