Abstract: Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages.

Abstract: Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub ( https://covid19forecasthub.org/ ) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.

Abstract: CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r , in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r 〉 0.003 at greater than 5 σ , or in the absence of a detection, of reaching an upper limit of r 〈 0.001 at 95% CL.

Abstract: The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping ≈ 10% of the sky to a white noise level of 2 μK-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r , at a target level of σ( r )=0.003. The large aperture telescope will map ≈ 40% of the sky at arcminute angular resolution to an expected white noise level of 6 μK-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.

Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41597-021-00851-9.

Abstract: The FLUXNET2015 dataset provides ecosystem-scale data on CO 2 , water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.

Abstract: Introduction: Translocations involving the MLL gene on chromosome 11q23 result in fusions with ≥10 partner genes that act as drivers in relatively chemotherapy resistant MLL-rearranged (MLLr) leukemias. These chimeric proteins form part of protein complexes that aberrantly upregulate transcription of the leukemogenic HOX and MEIS1 genes. Menin is a key member of the complex and localizes the complex to chromatin. Similarly, in NPM1 mutant (mNPM1) AML, the interaction between wild-type MLL and menin leads to a HOX and MEIS1-mediated leukemogenic transcriptional program. In preclinical models of MLLr and mNPM1 leukemias, inhibition of the interaction between MLL and menin downregulates HOX and MEIS1 transcription and reverses leukemogenesis (Uckelmann 2020; Krivstov 2019). SNDX-5613 (5613) is a potent, selective protein-protein interaction inhibitor of menin being evaluated in the AUGMENT-101 study, a first-in-human (FIH), Ph 1/2 study in pts with R/R acute leukemia. Here, we report the results of the completed, Ph 1 component. Methods: The study includes 2 parallel dose-escalation cohorts: pts not taking (Arm A) or taking (Arm B) strong CYP3A4 inhibitors. An early amendment restricted enrollment to MLLr or mNPM1 leukemias. Dose escalation used a "rolling 6" design with expansion at efficacious doses. 5613 is dosed orally q12h in continuous 28-day cycles. Dose levels evaluated in Arm A were 113 (n=1), 226 (n=6), 276 (n=10), and 339 mg (n=8), and in Arm B 113 (n=16), 163 (n=6), and 226 mg (n=7). Primary objectives of Ph 1 were to determine the safety, MTD, recommended Ph 2 dose (RP2D), and PK profile of 5613. Exploratory endpoints included antileukemic activity and pharmacodynamics of 5613. Results: As of 29Jun2021, 54 pts had received at least 1 dose of 5613; 13 pts remained on treatment. Baseline characteristics are detailed in Table 1. The median age was 49 years; 82% (n=44) of pts had AML; 65% (n=35) had MLLr leukemia, and 19% (n=10) had mNPM1 leukemia. Pts had a median of 3 prior therapies (range, 1-12); 57% and 44% had prior venetoclax or transplant, respectively; 59% of pts had not responded to their most recent line of therapy. 5613 exhibited dose-proportional PK, and exposure increased ~2-3-fold when given with a strong CYP3A4 inhibitor. Measurement of target occupancy and gene expression showed that 5613 disrupted menin binding to chromatin and decreased leukemogenic gene expression consistent with the established mechanism of action. The only DLTs were Grade 3 prolonged QTc; all events were clinically asymptomatic. The MTD was 276 mg q12h in Arm A and 163 mg q12h in Arm B; 2 doses in each arm met the protocol-defined criteria (safety, percentage of planned dose intensity, and pharmacokinetic exposure) for a RP2D. The frequency of Grade 3 prolonged QTc at these doses was 8% (3/38). No ventricular arrhythmias were reported, and no pts discontinued 5613 due to a treatment-related event. Other common ( & gt;10%) treatment-related AE (TRAE) were nausea (n=12; 22%), vomiting (n=9; 17%), differentiation syndrome (n=8; 15%), and diarrhea (n=6;11%). Grade ≥3 TRAE are shown in Table 2. In the 45 pts with MLLr or mNPM1 leukemias, responses were seen in both Arms A and B and at multiple dose levels. The composite CR (CRc: CR+CRh+CRp+CRi/MLFS) rate was 44% (20/45 pts) (Table 3). Among pts with MLLr leukemia, the CRc rate was 49% (17/35 pts) and in pts with mNPM1 leukemia, the CRc rate was 30% (3/10 pts); 14/20 (70%) pts with CRc achieved MRD negativity assessed locally by flow cytometry or PCR. Of 22 pts who received prior transplant, 10 (45%) achieved CRc. The CR/CRh rate was 22% (10/45) in pts with MLLr or mNPM1 leukemia. Median time to CR/CRh was 2 months (mo). With a median follow-up of 3.2 mo, the median duration of response (DoR) for patients achieving a CR/CRh was 5.2 mo. Responding patients were censored at the time they discontinued the study to proceed to an allogeneic stem cell transplant (n=6). Consistent with the proposed preclinical mechanism of menin inhibition, the 9 patients with wild-type MLL and NPM1 did not respond to 5613. Conclusion: In this FIH Ph 1 study, SNDX-5613 demonstrates an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R MLLr and mNPM1 acute leukemia. Two dose levels in each arm met the prespecified criteria for RP2D. Ph 2 expansion includes cohorts of pts with MLLr AML, MLLr ALL, and mNPM1 AML. Figure 1 Figure 1. Disclosures Stein: Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Novartis: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Syndax Pharmaceuticals: Consultancy. Stone: Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Innate: Consultancy; Janssen: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Boston Pharmaceuticals: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Jazz: Consultancy; Onconova: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Rosen: Syndax: Current Employment. Meyers: Syndax Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Patents & Royalties; Nuvalent: Consultancy, Membership on an entity's Board of Directors or advisory committees. Huang: Syndax: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Serapta: Ended employment in the past 24 months. Smith: Syndax: Consultancy; Tempest: Current holder of stock options in a privately-held company; Athira: Current holder of stock options in a privately-held company. Bagley: Syndax: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Radius Health: Ended employment in the past 24 months. Thirman: AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pharmacyclics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Merck: Research Funding; Syndax: Research Funding; TG Therapeutics: Research Funding. Patel: Ignyta: Research Funding; Incyte: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jounce Therapeutics: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Loxo Oncology: Research Funding; LSK Biopartners: Research Funding; Lycera: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Millennium Pharmaceuticals: Research Funding; Mirati Therapeutics: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Stemline Therapeutics: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Tesaro: Research Funding; TopAlliance: Research Funding; Vedanta: Research Funding; Verastem: Research Funding; Vigeo: Research Funding; Xencor: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Hutchinson MediPharma: Research Funding; Hengrui: Research Funding; H3 Biomedicine: Research Funding; Gilead: Research Funding; GlaxoSmithKline: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Evelo Biosciences: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Effector Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Cyteir Therapeutics: Research Funding; Curis: Research Funding; Clovis: Research Funding; Ciclomed: Research Funding; Checkpoint Therapeutics: Research Funding; Calithera: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioNTech: Research Funding; Bicycle Therapeutics: Research Funding; AstraZeneca: Research Funding; Artios Pharma: Research Funding; Aileron Therapeutics: Research Funding; Agenus: Research Funding; ADC Therapeutics: Research Funding; Acerta Pharma: Research Funding; Florida Cancer Specialists: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding.