Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19.

BACKGROUND: Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19-related hospitalization or death from any cause by day 29. RESULTS: A total of 1035 patients underwent randomization and received an infusion of bamlanivimab-etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab-etesevimab group had a Covid-19-related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, -4.8 percentage points; 95% confidence interval [CI], -7.4 to -2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab-etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19-related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, -1.20; 95% CI, -1.46 to -0.94; P<0.001). CONCLUSIONS: Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19-related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.).

A Randomized, Placebo-Controlled Clinical Trial of Bamlanivimab and Etesevimab Together in High-Risk Ambulatory Patients With COVID-19 and Validation of the Prognostic Value of Persistently High Viral Load.

BACKGROUND: Based on interim analyses and modeling data, lower doses of bamlanivimab and etesevimab together (700/1400 mg) were investigated to determine optimal dose and expand availability of treatment. METHODS: This Phase 3 portion of the BLAZE-1 trial characterized the effect of bamlanivimab with etesevimab on overall patient clinical status and virologic outcomes in ambulatory patients ≥12 years old, with mild-to-moderate coronavirus disease 2019 (COVID-19), and ≥1 risk factor for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab and etesevimab together (700/1400 mg) or placebo were infused intravenously within 3 days of patients' first positive COVID-19 test. RESULTS: In total, 769 patients were infused (median age [range]; 56.0 years [12, 93], 30.3% of patients ≥65 years of age and median duration of symptoms; 4 days). By day 29, 4/511 patients (0.8%) in the antibody treatment group had a COVID-19-related hospitalization or any-cause death, as compared with 15/258 patients (5.8%) in the placebo group (Δ[95% confidence interval {CI}] = -5.0 [-8.0, -2.1], P < .001). No deaths occurred in the bamlanivimab and etesevimab group compared with 4 deaths (all COVID-19-related) in the placebo group. Patients receiving antibody treatment had a greater mean reduction in viral load from baseline to Day 7 (Δ[95% CI] = -0.99 [-1.33, -.66], P < .0001) compared with those receiving placebo. Persistently high viral load at Day 7 correlated with COVID-19-related hospitalization or any-cause death by Day 29 in all BLAZE-1 cohorts investigated. CONCLUSIONS: These data support the use of bamlanivimab and etesevimab (700/1400 mg) for ambulatory patients at high risk for severe COVID-19. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants will require continued monitoring to determine the applicability of this treatment. CLINICAL TRIALS REGISTRATION: NCT04427501.

A temporally stratified extension of space-for-time Cormack-Jolly-Seber for migratory animals.

Understanding drivers of temporal variation in demographic parameters is a central goal of mark-recapture analysis. To estimate the survival of migrating animal populations in migration corridors, space-for-time mark-recapture models employ discrete sampling locations in space to monitor marked populations as they move past monitoring sites, rather than the standard practice of using fixed sampling points in time. Because these models focus on estimating survival over discrete spatial segments, model parameters are implicitly integrated over the temporal dimension. Furthermore, modeling the effect of time-varying covariates on model parameters is complicated by unknown passage times for individuals that are not detected at monitoring sites. To overcome these limitations, we extended the Cormack-Jolly-Seber (CJS) framework to estimate temporally stratified survival and capture probabilities by including a discretized arrival time process in a Bayesian framework. We allow for flexibility in the model form by including temporally stratified covariates and hierarchical structures. In addition, we provide tools for assessing model fit and comparing among alternative structural models for the parameters. We demonstrate our framework by fitting three competing models to estimate daily survival, capture, and arrival probabilities at four hydroelectric dams for over 200 000 individually tagged migratory juvenile salmon released into the Snake River, USA.

Using a mechanistic framework to model the density of an aquatic parasite Ceratonova shasta.

Ceratonova shasta is a myxozoan parasite endemic to the Pacific Northwest of North America that is linked to low survival rates of juvenile salmonids in some watersheds such as the Klamath River basin. The density of C. shasta actinospores in the water column is typically highest in the spring (March-June), and directly influences infection rates for outmigrating juvenile salmonids. Current management approaches require quantities of C. shasta density to assess disease risk and estimate survival of juvenile salmonids. Therefore, we developed a model to simulate the density of waterborne C. shasta actinospores using a mechanistic framework based on abiotic drivers and informed by empirical data. The model quantified factors that describe the key features of parasite abundance during the period of juvenile salmon outmigration, including the week of initial detection (onset), seasonal pattern of spore density, and peak density of C. shasta. Spore onset was simulated by a bio-physical degree-day model using the timing of adult salmon spawning and accumulation of thermal units for parasite development. Normalized spore density was simulated by a quadratic regression model based on a parabolic thermal response with river water temperature. Peak spore density was simulated based on retained explanatory variables in a generalized linear model that included the prevalence of infection in hatchery-origin Chinook juveniles the previous year and the occurrence of flushing flows (≥171 m3/s). The final model performed well, closely matched the initial detections (onset) of spores, and explained inter-annual variations for most water years. Our C. shasta model has direct applications as a management tool to assess the impact of proposed flow regimes on the parasite, and it can be used for projecting the effects of alternative water management scenarios on disease-induced mortality of juvenile salmonids such as with an altered water temperature regime or with dam removal.

Identifying resting locations of a small elusive forest carnivore using a two-stage model accounting for GPS measurement error and hidden behavioral states.

BACKGROUND: Studies of animal movement using location data are often faced with two challenges. First, time series of animal locations are likely to arise from multiple behavioral states (e.g., directed movement, resting) that cannot be observed directly. Second, location data can be affected by measurement error, including failed location fixes. Simultaneously addressing both problems in a single statistical model is analytically and computationally challenging. To both separate behavioral states and account for measurement error, we used a two-stage modeling approach to identify resting locations of fishers (Pekania pennanti) based on GPS and accelerometer data. METHODS: We developed a two-stage modelling approach to estimate when and where GPS-collared fishers were resting for 21 separate collar deployments on 9 individuals in southern Oregon. For each deployment, we first fit independent hidden Markov models (HMMs) to the time series of accelerometer-derived activity measurements and apparent step lengths to identify periods of movement and resting. Treating the state assignments as given, we next fit a set of linear Gaussian state space models (SSMs) to estimate the location of each resting event. RESULTS: Parameter estimates were similar across collar deployments. The HMMs successfully identified periods of resting and movement with posterior state assignment probabilities greater than 0.95 for 97% of all observations. On average, fishers were in the resting state 63% of the time. Rest events averaged 5 h (4.3 SD) and occurred most often at night. The SSMs allowed us to estimate the 95% credible ellipses with a median area of 0.12 ha for 3772 unique rest events. We identified 1176 geographically distinct rest locations; 13% of locations were used on > 1 occasion and 5% were used by > 1 fisher. Females and males traveled an average of 6.7 (3.5 SD) and 7.7 (6.8 SD) km/day, respectively. CONCLUSIONS: We demonstrated that if auxiliary data are available (e.g., accelerometer data), a two-stage approach can successfully resolve both problems of latent behavioral states and GPS measurement error. Our relatively simple two-stage method is repeatable, computationally efficient, and yields directly interpretable estimates of resting site locations that can be used to guide conservation decisions.

Correlation of gene expression and contaminant concentrations in wild largescale suckers: a field-based study.

Toxic compounds such as organochlorine pesticides (OCs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ether flame retardants (PBDEs) have been detected in fish, birds, and aquatic mammals that live in the Columbia River or use food resources from within the river. We developed a custom microarray for largescale suckers (Catostomus macrocheilus) and used it to investigate the molecular effects of contaminant exposure on wild fish in the Columbia River. Using Significance Analysis of Microarrays (SAM) we identified 72 probes representing 69 unique genes with expression patterns that correlated with hepatic tissue levels of OCs, PCBs, or PBDEs. These genes were involved in many biological processes previously shown to respond to contaminant exposure, including drug and lipid metabolism, apoptosis, cellular transport, oxidative stress, and cellular chaperone function. The relation between gene expression and contaminant concentration suggests that these genes may respond to environmental contaminant exposure and are promising candidates for further field and laboratory studies to develop biomarkers for monitoring exposure of wild fish to contaminant mixtures found in the Columbia River Basin. The array developed in this study could also be a useful tool for studies involving endangered sucker species and other sucker species used in contaminant research.