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The majority of landbird species feed their nestlings arthropods and variation in arthropod populations can impact reproductive outcomes in these species. Arthropod populations in turn are influenced by climate because temperature affects survival and reproduction, and larval development. Thus, climate factors have the potential to influence many bird species during their reproductive phases. In this study, we assessed climate factors that impact the diet of nestling White-headed Woodpecker ( Dryobates albolarvatus ), an at-risk keystone species in much of its range in western North America. To do this, we measured stable isotope signatures (δ 13 C and δ 15 N) in 152 nestlings across six years and linked variation in isotopic values to winter (December-February) and spring (June) precipitation and temperature using mixed effects models. We also explored habitat factors that may impact δ 13 C and δ 15 N and the relationship between δ 15 N and nest productivity. Last, we estimated isotopic niche width for nestlings in different watersheds and years using Bayesian standard ellipses, which allowed us to compare dietary niche width and overlap. We found that colder winter temperatures were associated with an increase in δ 15 N and δ 15 N levels had a weak positive relationship with nest productivity. We also found that sites with a more diverse tree community were associated with a broader isotopic niche width in nestlings. Our findings suggest that nestling diet is affected by climate, and under future warming climate scenarios, White-headed Woodpecker nestling diet may shift in favor of lower trophic level prey (prey with lower δ 15 N levels). The impact of such changes on woodpecker populations merits further study., Competing Interests: None declared., (© 2020 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

A juvenile White-headed woodpecker ( Dryobates albolarvatus ) fitted with a radio tag was located dead at approximately 22-days post-fledging in Yakima county in central Washington in July 2015. Postmortem examination revealed an enlarged liver and spleen plus evidence of iron sequestration. Microscopic examination observed young gametocytes within the cytoplasm of erythrocytes, and exo-erythrocytic meronts within the cytoplasm of capillary endothelial cells, hepatocytes, and myocytes, and free in the tissues. These attributes implicated a haemosporidian infection that likely resulted in mortality. Subsequent sampling results of local woodpecker species in the same area during the breeding season in June-July 2016 and May-July 2017 showed other individuals infected with Haemoproteus parasites. Nested Polymerase Chain Reaction (PCR), sequencing, and microscopic analyses for avian haemosporidians revealed infections with Haemoproteus velans (Haemosporida, Haemoproteidae). This parasite was characterized molecularly and morphologically. This is the first report of a haemosporidian infection in a White-headed woodpecker anywhere in its range, and the first reported suspected mortality from haemoproteosis for a woodpecker (Piciformes, Picidae). The use of radio-tagged birds is an asset in wildlife haemosporidian studies because the effect of the pathogen can be monitored in real time. Additionally, this methodology provides opportunities to collect fresh material for microscopic and histological examination from wild birds that have died from natural causes., Competing Interests: None.

Tree cavities provide critical roosting and breeding sites for multiple species, and thermal environments in these cavities are important to understand. Our objectives were to (1) describe thermal characteristics in cavities between June 3 and August 9, 2014, and (2) investigate the environmental factors that influence cavity temperatures. We placed iButtons in 84 different cavities in ponderosa pine (Pinus ponderosa) forests in central Washington, and took hourly measurements for at least 8 days in each cavity. Temperatures above 40 °C are generally lethal to developing avian embryos, and ~ 18% of the cavities had internal temperatures of ≥ 40 °C for at least 1 h of each day. We modeled daily maximum cavity temperature, the amplitude of daily cavity temperatures, and the difference between the mean internal cavity and mean ambient temperatures as a function of several environmental variables. These variables included canopy cover, tree diameter at cavity height, cavity volume, entrance area, the hardness of the cavity body, the hardness of the cavity sill (which is the wood below the cavity entrance which forms the barrier between the cavity and the external environment), and sill width. Ambient temperature had the largest effect size for maximum cavity temperature and amplitude. Larger trees with harder sills may provide more thermally stable cavity environments, and decayed sills were positively associated with maximum cavity temperatures. Summer temperatures are projected to increase in this region, and additional research is needed to determine how the thermal environments of cavities will influence species occupancy, breeding, and survival.

The marbled murrelet (Brachyramphus marmoratus) is a declining seabird that is well-known for nesting in coastal old-growth forests in the Pacific Northwest. Most studies of habitat selection have focused on modeling terrestrial nesting habitat even though marine habitat is believed to be a major contributor to population declines in some regions. To address this information gap, we conducted a 5-year study of marine resource selection by murrelets in Washington, which contains a population experiencing the steepest documented declines and where marine habitat is believed to be compromised. Across five years we tracked 157 radio-tagged murrelets during the breeding season (May to August), and used discrete choice models to examine habitat selection. Using an information theoretic approach, our global model had the most support, suggesting that murrelet resource selection at-sea is affected by many factors, both terrestrial and marine. Locations with higher amounts of nesting habitat (β = 21.49, P < 0.001) that were closer to shore (β = -0.0007, P < 0.001) and in cool waters (β = -0.2026, P < 0.001) with low footprint (β = -0.0087, P < 0.001) had higher probabilities of use. While past conservation efforts have focused on protecting terrestrial nesting habitat, we echo many past studies calling for future efforts to protect marine habitat for murrelets, as the current emphasis on terrestrial habitat alone may be insufficient for conserving populations. In particular, marine areas in close proximity to old-growth nesting habitat appear important for murrelets during the breeding season and should be priorities for protection., Competing Interests: The authors have declared that no competing interests exist.

Woodpeckers and other primary cavity excavators (PCEs) are important worldwide for excavating cavities in trees, and a large number of studies have examined their nesting preferences. However, quantitative measures of wood hardness have been omitted from most studies, and ecologists have focused on the effects of external tree- and habitat-level features on nesting. Moreover, information is lacking on the role of wood hardness in limiting nesting opportunities for this important guild. Here, we used an information theoretic approach to examine the role of wood hardness in multi-scale nest site selection and in limiting nesting opportunities for six species of North American PCEs. We found that interior wood hardness at nests (n = 259) differed from that at random sites, and all six species of PCE had nests with significantly softer interior wood than random trees (F1,517 = 106.15, P < 0.0001). Accordingly, interior wood hardness was the most influential factor in our models of nest site selection at both spatial scales that we examined: in the selection of trees within territories and in the selection of nest locations on trees. Moreover, regardless of hypothesized excavation abilities, all the species in our study appeared constrained by interior wood hardness, and only 4-14% of random sites were actually suitable for nesting. Our findings suggest that past studies that did not measure wood hardness counted many sites as available to PCEs when they were actually unsuitable, potentially biasing results. Moreover, by not accounting for nest site limitations in PCEs, managers may overestimate the amount of suitable habitat. We therefore urge ecologists to incorporate quantitative measures of wood hardness into PCE nest site selection studies, and to consider the limitations faced by avian cavity excavators in forest management decisions.

Objective: The PREVENT III study was a prospective, randomized, double-blinded, multicenter phase III trial of a novel molecular therapy (edifoligide; E2F decoy) for the prevention of vein graft failure in patients undergoing infrainguinal revascularization for critical limb ischemia (CLI)., Methods: From November 2001 through October 2003, 1404 patients with CLI were randomized to a single intraoperative ex vivo vein graft treatment with edifoligide or placebo. After surgery, patients underwent graft surveillance by duplex ultrasonography and were followed up for index graft and limb end points to 1 year. A blinded Clinical Events Classification committee reviewed all index graft end points. The primary study end point was the time to nontechnical index graft reintervention or major amputation due to index graft failure. Secondary end points included all-cause graft failure, clinically significant graft stenosis (>70% by angiography or severe stenosis by ultrasonography), amputation/reintervention-free survival, and nontechnical primary graft patency. Event rates were based on Kaplan-Meier estimates. Time-to-event end points were compared by using the log-rank test., Results: Demographics, comorbidities, and procedural details reflected a population with CLI and diffuse atherosclerosis. Tissue loss was the presenting symptom in 75% of patients. High-risk conduits were used in 24% of cases, including an alternative vein in 20% (15% spliced vein and 5% non-great saphenous vein) and 6% less than 3 mm in diameter; 14% of the cases were reoperative bypass grafts. Most (65%) grafts were placed to infrapopliteal targets. Perioperative (30-day) mortality occurred in 2.7% of patients. Major morbidity included myocardial infarction in 4.7% and early graft occlusion in 5.2% of patients. Ex vivo treatment with edifoligide was well tolerated. There was no significant difference between the treatment groups in the primary or secondary trial end points, primary graft patency, or limb salvage. A statistically significant improvement was observed in secondary graft patency (estimated Kaplan-Meier rates were 83% edifoligide and 78% placebo; P = .016) within 1 year. The reduction in secondary patency events was manifest within 30 days of surgery (the relative risk for a 30-day event for edifoligide was 0.45; 95% confidence interval, 0.27-0.76; P = .005). For the overall cohort at 1 year, the estimated Kaplan-Meier rate for survival was 84%, that for primary patency was 61%, that for primary assisted patency was 77%, that for secondary patency was 80%, and that for limb salvage was 88%., Conclusions: In this prospective, randomized, placebo-controlled clinical trial, ex vivo treatment of lower extremity vein grafts with edifoligide did not confer protection from reintervention for graft failure.

Objective: The study was done to determine whether eptifibatide, a platelet glycoprotein (GP) IIb/IIIa antagonist, prevents ischemic complications following percutaneous coronary interventions (PCIs) in women as well as in men., Background: Eptifibatide reduces ischemic complications after nonurgent coronary stent interventions., Methods: We compared outcomes in women (n = 562) and men (n = 1,502) enrolled in the Enhanced Suppression of the Platelet GP IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of double-bolus eptifibatide during PCI., Results: Women in the ESPRIT trial were older, and more frequently had hypertension, diabetes mellitus, or acute coronary syndromes, but were less likely to have prior PCI or coronary artery bypass graft surgery. The primary end point, a composite at 48 h of death, myocardial infarction (MI), urgent target vessel revascularization (TVR), and unplanned GP IIb/IIIa use, occurred in 10.5% of women and 7.9% of men (p = 0.082). The composite of death, MI, or TVR after one year occurred in 24.5% of women compared with 18% of men (p = 0.0008). At 48 h, eptifibatide reduced the composite of death, MI, and TVR from 14.5% to 6.0% in women versus 9.0% to 6.8% in men. At one year, these differences persisted: 28.9% versus 20.0% for women and 19.5% versus 16.6% for men. No statistical interaction existed between treatment and gender at either 48 h (p = 0.063) or one year (p = 0.2). Bleeding occurred more commonly in women (5.5% vs. 2.6%, p = 0.002), and was more common in eptifibatide-treated women. After adjustment for age, weight, and hypertension, no interaction between treatment and gender was present., Conclusion: Eptifibatide is effective to prevent ischemic complications of PCI in women and may eliminate gender-related differences in PCI outcomes.

Background: Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions., Methods and Results: Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and >80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later., Conclusions: A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains >90% inhibition of platelet aggregation in >90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.

Background: The platelet GP IIb/IIIa inhibitor eptifibatide improves outcomes in patients with acute coronary syndromes. Patients requiring emergent coronary artery bypass grafting, however, may be at increased risk for bleeding if exposed to eptifibatide. Data from the PURSUIT trial were reviewed to assess this risk in patients undergoing coronary surgery immediately after exposure to eptifibatide., Methods: In PURSUIT, 10,948 patients who presented with non-ST segment elevation acute coronary syndromes were prospectively randomized to receive eptifibatide (180 microg/kg bolus plus 2 microg/kg/min infusion) or placebo. A total of 78 patients underwent immediate coronary artery bypass surgery within 2 hours of cessation of study drug (placebo, n = 46; eptifibatide, n = 32). Clinical outcome, bleeding, and transfusion requirements within this subset were examined., Results: Major bleeding was not different between groups, occurring in 64% of patients receiving placebo and 63% of patients receiving eptifibatide. The incidence of blood transfusion was similar as well (57% vs 59%). Postoperative thrombocytopenia occurred less often after eptifibatide exposure. Perioperative myocardial infarction was significantly reduced in patients who received eptifibatide (46% vs 22%, p < 0.05). There was no difference in perioperative stroke (2.2% vs 6.3%) or mortality (6.3% vs 6.5%)., Conclusions: Patients may safely undergo coronary artery bypass surgery within 2 hours of discontinuation of eptifibatide. Eptifibatide infusion in the immediate preoperative period had no adverse clinical effects, but did significantly decrease the incidence of perioperative myocardial infarction. Additionally, platelet counts after surgery were higher in the group of patients who received eptifibatide, perhaps indicative of a platelet-sparing effect during cardiopulmonary bypass.

Background: Platelet glycoprotein (GP) IIb/IIIa antagonists prevent the composite end point of death or myocardial infarction (MI) in patients with acute coronary syndromes. There is uncertainty about whether this effect is confined to patients who have percutaneous coronary interventions (PCIs) and whether PCIs further prevent death or MI in patients already treated with GP IIb/IIIa antagonists., Methods and Results: PURSUIT patients were treated with the GP IIb/IIIa antagonist eptifibatide or placebo; PCIs were performed according to physician practices. In 2253 of 9641 patients (23.4%), PCI was performed by 30 days. Early (<72 hours) PCI was performed in 1228 (12.7%). In 34 placebo patients (5.5%) and 10 treated with eptifibatide (1.7%) (P=0.001), MI preceded early PCI. In patients censored for PCI across the 30-day period, there was a significant reduction in the primary composite end point in eptifibatide patients (P=0.035). Eptifibatide reduced 30-day events in patients who had early PCI (11.6% versus 16.7%, P=0.01) and in patients who did not (14.6% versus 15.6%, P=0.23). After adjustment for PCI propensity, there was no evidence that eptifibatide treatment effect differed between patients with or without early PCI (P for interaction=0.634). PCI was not associated with a reduction of the primary composite end point but was associated with a reduced (nonspecified) composite of death or Q-wave MI. This association disappeared after adjustment for propensity for early PCI., Conclusions: Eptifibatide reduced the composite rates of death or MI in PCI patients and those managed conservatively.

To investigate the effects of a recombinant endotoxin-binding protein, bactericidal/permeability-increasing protein (rBPI23), on cytokine release and neutrophil activation in endotoxemia in humans, 8 volunteers were challenged twice with endotoxin and concurrently received either rBPI23 or placebo in a randomized, placebo controlled, double-blind crossover study, rBPI23 treatment significantly lowered circulating endotoxin levels (P = .02) and resulted in a significant reduction in the release of tumor necrosis factor (TNF), soluble TNF receptors p55 and p75, interleukin (IL)-6, IL-8 (P < .01 for each), and IL-10 levels (P = .02) but did not prevent the endotoxin-induced rise in body temperature. The early endotoxin-induced leukopenia was blunted (P = .08), and neutrophil degranulation, as measured by circulating levels of elastase/alpha 1-antitrypsin complexes (P = .03) and lactoferrin (P < .01), was largely prevented by rBPI23. The results of this study indicate that rBPI23 is capable of neutralizing many of the biologic effects of endotoxin in humans.

Objective: To evaluate the safety and activity of an immunoconjugate of ricin A chain and anti-CD5 monoclonal antibody (anti-CD5 IC), with and without concomitant methotrexate and/or azathioprine, in the treatment of rheumatoid arthritis (RA)., Methods: Seventy-nine patients with active RA were enrolled in 2 prospective open-label protocols., Results: Using composite criteria, response rates were 50-68% at 1 month and 22-25% at 6 months. Transient depletion of CD3/CD5 T cells was observed on days 2 and 5 of treatment, with reconstitution on day 15 or day 29. Treatment-associated adverse effects were common but resolved rapidly without sequelae., Conclusion: These findings suggest activity of anti-CD5 IC in active RA and warrant confirmation in a multicenter randomized study (currently underway).