Abstract: Background: Monoclonal Antibody Therapy (MAbs) has been shown to reduce rates of ED visits and hospitalizations in patients at risk for severe Covid-19 infection in clinical trials. Since November, three Mabs received emergency use authorization: Bamlanivimab (Bam), Bamlanivimab/Etesevimab (Bam/Ete) and Casirivimab/Imdevimab (Casi/imdevi). We describe here the real-world effectiveness of implementing early MAb therapy in the outpatient setting for individuals with Covid-19 at high risk of progression. Methods: We examined the records of 808 UCLA Health patients with a confirmed positive SARS-CoV2 PCR test who were either referred for outpatient Mab therapy or received Mab treatment in the emergency department (ED) between December 10, 2020, and May 3, 2021. The primary outcome of our analysis was the combined 30-day incidence of emergency department visits, hospitalizations, or death following the date of referral. SARS-CoV2 isolates of hospitalized patients who had received Mabs were sequenced to determine the presence of variants. Results: Of 808 patients, 383 were referred for treatment but did not receive treatment, 109 received Mabs in the ED and 316 patients were treated in an outpatient setting. Composite 30-day mortality, ED visits and hospital admissions were significantly reduced in the combination therapy group (Bam/Ete or Cas/Imd) compared with monotherapy (Bam alone) or no treatment groups (aHR 0.16, 95% CI .038, .67). Significant factors associated with the composite outcome included: history of lung disease (HR 4.46, 95% CI 2.89-6.90), cardiovascular disease (HR 1.87, 95% CI 1.12-3.12), kidney disease (HR 2.04, 95% CI 1.27-3.25), and immunocompromised state (HR 3.24, 95% CI 1.02-10.26) as well as high social vulnerability index (HR 1.87, 95% CI 1.13-3.10). Over one-third of hospitalized patients who had received Mabs were confirmed to have the California variant (B.1.427/29) (Figure 1). Figure 1. Covid-19 MAB Treatment Failure Lineages Conclusion: Our data show that in a real-world setting, combination monoclonal antibody therapy, not monotherapy, significantly reduced ED visits and hospital admissions, likely due to the presence of the California variants. High socioeconomic vulnerability and certain medical conditions increased risk of treatment failure. Disclosures: Omai Garner, PhD, D(ABMM), Beckman Coulter (Scientific Research Study Investigator)

Background

While Covid-19 monoclonal antibody therapies (Mab) have been available in the outpatient setting for over a year and a half, little is known about the impact of emerging variants and vaccinations on the effectiveness of Mab therapies. We sought to determine the effectiveness of Covid-19 Mab therapies during the first two waves of the pandemic in Los Angeles County and assess the impact of vaccines, variants, and other confounding factors.

Methods and findings

We retrospectively examined records for 2209 patients of with confirmed positive molecular SARS-CoV2 test either referred for outpatient Mab therapy or receiving Mab treatment in the emergency department (ED) between December 2020 and 2021. Our primary outcome was the combined 30-day incidence of ED visit, hospitalization, or death following the date of referral. Additionally, SARS-CoV2 isolates of hospitalized patients receiving Mabs were sequenced. The primary outcome was significantly reduced with combination therapy compared to bamlanivimab or no treatment (aHR 0·60; 95% CI ·37, ·99), with greater benefit in unvaccinated, moderate-to-high-risk patients (aHR ·39; 95% CI ·20, ·77). Significant associations with the primary outcome included history of lung disease (HR 7·13; 95% CI 5·12, 9·95), immunocompromised state (HR 6·59; 95% CI 2·91-14·94), and high social vulnerability (HR 2·29, 95% CI 1·56-3·36). Two predominant variants were noted during the period of observation: the Epsilon variant and the Delta variant.

Conclusions

Only select monoclonal antibody therapies significantly reduced ED visits, hospitalizations, and death due to COVID-19 during. Vaccination diminished effectiveness of Mabs. Variant data and vaccination status should be considered when assessing the benefit of novel COVID-19 treatments.

The Majorana Demonstrator is a leading experiment searching for neutrinoless double-beta decay with high purity germanium (HPGe) detectors. Machine learning provides a new way to maximize the amount of information provided by these detectors, but the data-driven nature makes it less interpretable compared to traditional analysis. An interpretability study reveals the machine's decision-making logic, allowing us to learn from the machine to feed back to the traditional analysis. In this work, we present the first machine learning analysis of the data from the Majorana Demonstrator; this is also the first interpretable machine learning analysis of any germanium detector experiment. Two gradient boosted decision tree models are trained to learn from the data, and a game-theory-based model interpretability study is conducted to understand the origin of the classification power. By learning from data, this analysis recognizes the correlations among reconstruction parameters to further enhance the background rejection performance. By learning from the machine, this analysis reveals the importance of new background categories to reciprocally benefit the standard Majorana analysis. This model is highly compatible with next-generation germanium detector experiments like LEGEND since it can be simultaneously trained on a large number of detectors.

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

The Majorana Demonstrator was a search for neutrinoless double-beta decay (0νββ) in the 76Ge isotope. It was staged at the 4850-foot level of the Sanford Underground Research Facility (SURF) in Lead, SD. The experiment consisted of 58 germanium detectors housed in a low background shield and was calibrated once per week by deploying a 228Th line source for 1 to 2 hours. The energy scale calibration determination for the detector array was automated using custom analysis tools. We describe the offline procedure for calibration of the Demonstrator germanium detectors, including the simultaneous fitting of multiple spectral peaks, estimation of energy scale uncertainties, and the automation of the calibration procedure.

The Majorana Demonstrator searched for neutrinoless double-β decay (0νββ) of ^{76}Ge using modular arrays of high-purity Ge detectors operated in vacuum cryostats in a low-background shield. The arrays operated with up to 40.4 kg of detectors (27.2 kg enriched to ∼88% in ^{76}Ge). From these measurements, the Demonstrator has accumulated 64.5 kg yr of enriched active exposure. With a world-leading energy resolution of 2.52 keV FWHM at the 2039 keV Q_{ββ} (0.12%), we set a half-life limit of 0νββ in ^{76}Ge at T_{1/2}>8.3×10^{25}  yr (90% C.L.). This provides a range of upper limits on m_{ββ} of (113-269) meV (90% C.L.), depending on the choice of nuclear matrix elements.

This corrects the article DOI: 10.1103/PhysRevLett.129.080401.

^{180m}Ta is a rare nuclear isomer whose decay has never been observed. Its remarkably long lifetime surpasses the half-lives of all other known β and electron capture decays due to the large K-spin differences and small energy differences between the isomeric and lower-energy states. Detecting its decay presents a significant experimental challenge but could shed light on neutrino-induced nucleosynthesis mechanisms, the nature of dark matter, and K-spin violation. For this study, we repurposed the Majorana Demonstrator, an experimental search for the neutrinoless double-beta decay of ^{76}Ge using an array of high-purity germanium detectors, to search for the decay of ^{180m}Ta. More than 17 kg, the largest amount of tantalum metal ever used for such a search, was installed within the ultralow-background detector array. In this Letter, we present results from the first year of Ta data taking and provide an updated limit for the ^{180m}Ta half-life on the different decay channels. With new limits up to 1.5×10^{19}  yr, we improved existing limits by 1-2 orders of magnitude which are the most sensitive searches for a single β and electron capture decay ever achieved. Over all channels, the decay can be excluded for T_{1/2}<0.29×10^{18}  yr.