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BackgroundEsophagectomy, an esophageal cancer treatment mainstay, is a highly morbid procedure. Prolonged operative time, only partially predetermined by case complexity, may be uniquely harmful to minimally-invasive esophagectomy (MIE) patients for numerous reasons, including anastomotic leak, tenuous conduit perfusion and protracted single-lung ventilation, but the impact is unknown. This multi-center retrospective cohort study sought to characterize the relationship between MIE operative time and post-operative outcomes.MethodsWe abstracted multi-center data on esophageal cancer patients who underwent MIE from 2010 to 2021. Predictor variables included age, sex, comorbidities, body mass index, prior cardiothoracic surgery, stage, and neoadjuvant therapy. Outcomes included complications, readmissions, and mortality. Association analysis evaluated the relationship between predictor variables and operative time. Multivariate logistic regression characterized the influence of potential predictor variables and operative time on post-operative outcomes. Subgroup analysis evaluated the association between MIE >4 h vs. ≤4 h and complications, readmissions and survival.ResultsFor the 297 esophageal cancer patients who underwent MIE between 2010 and 2021, the median operative duration was 4.8 h [IQR: 3.7–6.3]. For patients with anastomotic leak (5.1%) and 1-year mortality, operative duration was elevated above the median at 6.3 h [IQR: 4.8–8.6], p = 0.008) and 5.3 h [IQR: 4.4–6.8], p = 0.04), respectively. In multivariate logistic regression, each additional hour of operative time increased the odds of anastomotic leak and 1-year mortality by 39% and 19%, respectively.ConclusionsEsophageal cancer is a poor prognosis disease, even with optimal treatment. Operative efficiency, a modifiable surgical variable, may be an important target to improve MIE patient outcomes.

Due to their short timescale, stellar flares are a challenging target for the most modern synoptic sky surveys. The upcoming Vera C. Rubin Legacy Survey of Space and Time (LSST), a project designed to collect more data than any precursor survey, is unlikely to detect flares with more than one data point in its main survey. We developed a methodology to enable LSST studies of stellar flares, with a focus on flare temperature and temperature evolution, which remain poorly constrained compared to flare morphology. By leveraging the sensitivity expected from the Rubin system, differential chromatic refraction (DCR) can be used to constrain flare temperature from a single-epoch detection, which will enable statistical studies of flare temperatures and constrain models of the physical processes behind flare emission using the unprecedentedly high volume of data produced by Rubin over the 10 yr LSST. We model the refraction effect as a function of the atmospheric column density, photometric filter, and temperature of the flare, and show that flare temperatures at or above ∼4000 K can be constrained by a single g -band observation at air mass X ≳ 1.2, given the minimum specified requirement on the single-visit relative astrometric accuracy of LSST, and that a surprisingly large number of LSST observations are in fact likely be conducted at X ≳ 1.2, in spite of image quality requirements pushing the survey to preferentially low X . Having failed to measure flare DCR in LSST precursor surveys, we make recommendations on survey design and data products that enable these studies in LSST and other future surveys.

Abstract Gene fusions are known to drive many human cancers. Therefore, the functional characterization of newly discovered fusions is critical to understanding the oncobiology of these tumors and to enable therapeutic development. NPM1–TYK2 is a novel fusion identified in CD30 + lymphoproliferative disorders, and here we present the functional evaluation of this fusion gene as an oncogene. The chimeric protein consists of the amino-terminus of nucleophosmin 1 (NPM1) and the carboxyl-terminus of tyrosine kinase 2 (TYK2), including the kinase domain. Using in vitro lymphoid cell transformation assays and in vivo tumorigenic xenograft models we present direct evidence that the fusion gene is an oncogene. NPM1 fusion partner provides the critical homodimerization needed for the fusion kinase constitutive activation and downstream signaling that are responsible for cell transformation. As a result, our studies identify NPM1–TYK2 as a novel fusion oncogene and suggest that inhibition of fusion homodimerization could be a precision therapeutic approach in cutaneous T-cell lymphoma patients expressing this chimera.

Transcription factor (TF)–promoter pairs have been repurposed from native hosts to provide tools to measure intracellular biochemical production titer and dynamically control gene expression. Most often, native TF–promoter systems require rigorous screening to obtain desirable characteristics optimized for biotechnological applications. High-throughput techniques may provide a rational and less labor-intensive strategy to engineer user-defined TF–promoter pairs using fluorescence-activated cell sorting and deep sequencing methods (sort-seq). Based on the designed promoter library’s distribution characteristics, we elucidate sequence–function interactions between the TF and DNA. In this work, we use the sort-seq method to study the sequence–function relationship of a σ54-dependent, butanol-responsive TF–promoter pair, BmoR-PBMO derived from Thauera butanivorans, at the nucleotide level to improve biosensor characteristics, specifically an improved dynamic range. Activities of promoters from a mutagenized PBMO library were sorted based on gfp expression and subsequently deep sequenced to correlate site-specific sequences with changes in dynamic range. We identified site-specific mutations that increase the sensor output. Double mutant and a single mutant, CA(129,130)TC and G(205)A, in PBMO promoter increased dynamic ranges of 4-fold and 1.65-fold compared with the native system, respectively. In addition, sort-seq identified essential sites required for the proper function of the σ54-dependent promoter biosensor in the context of the host. This work can enable high-throughput screening methods for strain development.

Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism.

Developmental Coordination Disorder (DCD) is one of the least studied and understood developmental disorders. One area that has been minimally investigated in DCD is potential issues with sensory modulation. Further, in other neurodevelopmental disorders (e.g., autism spectrum disorder (ASD)) sensory modulation is related to many other challenges (e.g., social issues, repetitive behaviors, anxiety); however, such potential relationships in children with DCD have been largely unexplored. The purpose of this study is to explore sensory modulation differences in DCD and to understand the relationships between sensory modulation and social emotional measures, behavior, and motor skills in DCD in comparison to ASD and typically developing (TD) peers. Participants (aged 8–17) and their caregivers (DCD, N = 26; ASD, N = 57; and TD, N = 53) completed behavioral and clinical measures. The results indicated that 31% of the DCD group showed sensory modulation difficulties, with the DCD group falling between the ASD and TD groups. In the DCD group, sensory modulation was significantly associated with anxiety, empathic concern, repetitive behaviors, and motor skills. Data are compared to patterns seen in ASD and TD groups and implications for interventions are discussed.

Carmen Parrotta,1 William Riley,1 Les Meredith21School of Public Health, University of Minnesota, Minneapolis, MN, 2Premier Insurance Management Services Inc, Charlotte, NC, USAAbstract: Highly reliable care requires standardization of clinical practices and is a prerequisite for patient safety. However, standardization in complex hospital settings is extremely difficult to attain and health care leaders are challenged to create care delivery processes that ensure patient safety. Moreover, once high reliability is achieved in a hospital unit, it must be maintained to avoid process deterioration. This case study examines an intervention to implement care bundles (a collection of evidence-based practices) in four hospitals to achieve standardized care in perinatal units. The results show different patterns in the rate and magnitude of change within the hospitals to achieve high reliability. The study is part of a larger nationwide study of 16 hospitals to improve perinatal safety. Based on the findings, we discuss the role of leadership for implementing and sustaining high reliability to ensure freedom from unintended injury.Keywords: care bundles, evidence-based practice, standardized care, process improvement

Methane (CH4) emissions from natural landscapes constitute roughly half of global CH4 contributions to the atmosphere, yet large uncertainties remain in the absolute magnitude and the seasonality of emission quantities and drivers. Eddy covariance (EC) measurements of CH4 flux are ideal for constraining ecosystem-scale CH4 emissions due to quasi-continuous and high-temporal-resolution CH4 flux measurements, coincident carbon dioxide, water, and energy flux measurements, lack of ecosystem disturbance, and increased availability of datasets over the last decade. Here, we (1) describe the newly published dataset, FLUXNET-CH4 Version 1.0, the first open-source global dataset of CH4 EC measurements (available at https://fluxnet.org/data/fluxnet-ch4-community-product/, last access: 7 April 2021). FLUXNET-CH4 includes half-hourly and daily gap-filled and non-gap-filled aggregated CH4 fluxes and meteorological data from 79 sites globally: 42 freshwater wetlands, 6 brackish and saline wetlands, 7 formerly drained ecosystems, 7 rice paddy sites, 2 lakes, and 15 uplands. Then, we (2) evaluate FLUXNET-CH4 representativeness for freshwater wetland coverage globally because the majority of sites in FLUXNET-CH4 Version 1.0 are freshwater wetlands which are a substantial source of total atmospheric CH4 emissions; and (3) we provide the first global estimates of the seasonal variability and seasonality predictors of freshwater wetland CH4 fluxes. Our representativeness analysis suggests that the freshwater wetland sites in the dataset cover global wetland bioclimatic attributes (encompassing energy, moisture, and vegetation-related parameters) in arctic, boreal, and temperate regions but only sparsely cover humid tropical regions. Seasonality metrics of wetland CH4 emissions vary considerably across latitudinal bands. In freshwater wetlands (except those between 20g g€¯S to 20g g€¯N) the spring onset of elevated CH4 emissions starts 3g€¯d earlier, and the CH4 emission season lasts 4g€¯d longer, for each degree Celsius increase in mean annual air temperature. On average, the spring onset of increasing CH4 emissions lags behind soil warming by 1 month, with very few sites experiencing increased CH4 emissions prior to the onset of soil warming. In contrast, roughly half of these sites experience the spring onset of rising CH4 emissions prior to the spring increase in gross primary productivity (GPP). The timing of peak summer CH4 emissions does not correlate with the timing for either peak summer temperature or peak GPP. Our results provide seasonality parameters for CH4 modeling and highlight seasonality metrics that cannot be predicted by temperature or GPP (i.e., seasonality of CH4 peak). FLUXNET-CH4 is a powerful new resource for diagnosing and understanding the role of terrestrial ecosystems and climate drivers in the global CH4 cycle, and future additions of sites in tropical ecosystems and site years of data collection will provide added value to this database. All seasonality parameters are available at 10.5281/zenodo.4672601 (Delwiche et al., 2021). Additionally, raw FLUXNET-CH4 data used to extract seasonality parameters can be downloaded from https://fluxnet.org/data/fluxnet-ch4-community-product/ (last access: 7 April 2021), and a complete list of the 79 individual site data DOIs is provided in Table 2 of this paper.

Radiocarbon (14C) is a powerful tracer of the global carbon cycle that is commonly used to assess carbon cycling rates in various Earth system reservoirs and as a benchmark to assess model performance. Therefore, it has been recommended that Earth System Models (ESMs) participating in the Coupled Model Intercomparison Project Phase 6 report predicted radiocarbon values for relevant carbon pools. However, a detailed representation of radiocarbon dynamics may be an impractical burden on model developers. Here, we present an alternative approach to compute radiocarbon values from the numerical output of an ESM that does not explicitly represent these dynamics. The approach requires computed 12C stocks and fluxes among all carbon pools for a particular simulation of the model. From this output, a time-dependent linear compartmental system is computed with its respective state-transition matrix. Using transient atmospheric 14C values as inputs, the state-transition matrix is then applied to compute radiocarbon values for each pool, the average value for the entire system, and component fluxes. We demonstrate the approach with ELMv1-ECA, the land component of an ESM model that explicitly represents 12C, and 14C in 7 soil pools and 10 vertical layers. Results from our proposed method are highly accurate (relative error

Land models, which have been developed by the modeling community in the past few decades to predict future states of ecosystems and climate, have to be critically evaluated for their performance skills of simulating ecosystem responses and feedback to climate change. Benchmarking is an emerging procedure to measure performance of models against a set of defined standards. This paper proposes a benchmarking framework for evaluation of land model performances and, meanwhile, highlights major challenges at this infant stage of benchmark analysis. The framework includes (1) targeted aspects of model performance to be evaluated, (2) a set of benchmarks as defined references to test model performance, (3) metrics to measure and compare performance skills among models so as to identify model strengths and deficiencies, and (4) model improvement. Land models are required to simulate exchange of water, energy, carbon and sometimes other trace gases between the atmosphere and land surface, and should be evaluated for their simulations of biophysical processes, biogeochemical cycles, and vegetation dynamics in response to climate change across broad temporal and spatial scales. Thus, one major challenge is to select and define a limited number of benchmarks to effectively evaluate land model performance. The second challenge is to develop metrics of measuring mismatches between models and benchmarks. The metrics may include (1) a priori thresholds of acceptable model performance and (2) a scoring system to combine data–model mismatches for various processes at different temporal and spatial scales. The benchmark analyses should identify clues of weak model performance to guide future development, thus enabling improved predictions of future states of ecosystems and climate. The near-future research effort should be on development of a set of widely acceptable benchmarks that can be used to objectively, effectively, and reliably evaluate fundamental properties of land models to improve their prediction performance skills.

This study evaluates the potential impact of clouds on ecosystem CO2 and CO2 isotope fluxes (“isofluxes”) in two contrasting ecosystems (a broadleaf deciduous forest and a C4 grassland) in a region for which cloud cover, meteorological, and isotope data are available for driving the isotope-enabled land surface model (ISOLSM). Our model results indicate a large impact of clouds on ecosystem CO2 fluxes and isofluxes. Despite lower irradiance on partly cloudy and cloudy days, predicted forest canopy photosynthesis was substantially higher than on clear, sunny days, and the highest carbon uptake was achieved on the cloudiest day. This effect was driven by a large increase in light-limited shade leaf photosynthesis following an increase in the diffuse fraction of irradiance. Photosynthetic isofluxes, by contrast, were largest on partly cloudy days, as leaf water isotopic composition was only slightly depleted and photosynthesis was enhanced, as compared to adjacent clear-sky days. On the cloudiest day, the forest exhibited intermediate isofluxes: although photosynthesis was highest on this day, leaf-to-atmosphere isofluxes were reduced from a feedback of transpiration on canopy relative humidity and leaf water. Photosynthesis and isofluxes were both reduced in the C4 grass canopy with increasing cloud cover and diffuse fraction as a result of near-constant light limitation of photosynthesis. These results suggest that some of the unexplained variation in global mean δ 18O of CO2 may be driven by large-scale changes in clouds and aerosols and their impacts on diffuse radiation, photosynthesis, and relative humidity.

Characterizing flow patterns and mixing of fossil fuel-derived CO2 is important for effectively using atmospheric measurements to constrain emissions inventories. Here we used measurements and a model of atmospheric radiocarbon (14C) to investigate the distribution and fluxes of atmospheric fossil fuel CO2 across the state of California. We sampled 14C in annual C3 grasses at 128 sites and used these measurements to test a regional model that simulated anthropogenic and ecosystem CO2 fluxes, transport in the atmosphere, and the resulting Δ14C of annual grasses (Δ g). Average measured Δ g levels in Los Angeles, San Francisco, the Central Valley, and the North Coast were 27.7 ± 20.0, 44.0 ± 10.9, 48.7 ± 1.9, and 59.9 ± 2.5‰, respectively, during the 2004–2005 growing season. Model predictions reproduced regional patterns reasonably well, with estimates of 27.6 ± 2.4, 39.4 ± 3.9, 46.8 ± 3.0, and 59.3 ± 0.2‰ for these same regions and corresponding to fossil fuel CO2 mixing ratios (C f) of 13.7, 6.1, 4.8, and 0.3 ppm. Δ g spatial heterogeneity in Los Angeles and San Francisco was higher in the measurements than in the predictions, probably from insufficient spatial resolution in the fossil fuel inventories (e.g., freeways are not explicitly included) and transport (e.g., within valleys). We used the model to predict monthly and annual transport patterns of fossil fuel-derived CO2 within and out of California. Fossil fuel CO2 emitted in Los Angeles and San Francisco was predicted to move into the Central Valley, raising C f above that expected from local emissions alone. Annually, about 21, 39, 35, and 5% of fossil fuel emissions leave the California airspace to the north, east, south, and west, respectively, with large seasonal variations in the proportions. Positive correlations between westward fluxes and Santa Ana wind conditions were observed. The southward fluxes over the Pacific Ocean were maintained in a relatively coherent flow within the marine boundary layer, while the eastward fluxes were more vertically dispersed. Our results indicate that state and continental scale atmospheric inversions need to consider areas where mixing ratio measurements are sparse (e.g., over the ocean to the south and west of California), transport within and across the marine boundary layer, and terrestrial boundary layer dynamics. Radiocarbon measurements can be very useful in constraining these estimates.

Green synthesis of lead-free Cs2AgBixSb1−xCl6 solid-solution double perovskites and their conversion into bromide and iodide derivatives is reported. Interaction of the single-phase Cs2AgBixSb1−xCl6 double perovskites with sodium iodide in 2-propanol/glycerol yields Cs3Bi2xSb2(1−x)I9 derivatives with varied Bi/Sb ratio, while the similar anion exchange with sodium bromide results in mixtures of Cs3Bi2xSb2(1−x)Cl3Br6 and Cs2AgBixSb1−xCl2Br4. A band-bowing effect is revealed for the starting chloride perovskites and the anion-exchange products, with the indirect band gap of intermediate Bi/Sb mixed compounds being significantly lower than the band gaps of corresponding Bi- and Sb-pure products. Solid-state nuclear magnetic resonance spectroscopy uncovered that the band-bowing originates from the lattice disorder of mixed Bi/Sb halide compounds, thus highlighting a new approach for the bandgap design of halide perovskites. [ABSTRACT FROM AUTHOR]

Coastal stations are critical for interpretation of continental-scale CO2 exchanges although the impacts of land and sea breezes, local topography, katabatic winds, and CO2 transport from nearby terrestrial ecosystems are not well characterized. We applied a modeling framework that couples meteorological (MM5), land-surface (LSM1), and tracer models to investigate the impact of these factors on coastal CO2 measurements. Model predictions compared well with measurements over 4 months at our case study site (Trinidad Head, California). We predicted that during midday and under strong onshore wind conditions, positive and negative CO2 anomalies from the assumed “background” marine layer air were sampled at the station. These anomalies resulted from two classes of mechanisms that couple transport and recent terrestrial ecosystem exchanges. First, and most important, are local and large-scale recirculation of nighttime positive CO2 anomalies resulting from katabatic flows off the coastal mountain range. Second, negative anomalies generated by daytime net ecosystem uptake can be transported offshore in the residual layer and then entrained in the marine boundary layer. We predicted monthly averaged CO2 anomalies associated with terrestrial exchanges of 0.53, 0.34, 3.1, and 0.05 ppm during March, June, September, and December of 2002. Positive anomalies from nighttime ecosystem respiration were more likely to be sampled than are negative anomalies associated with daytime net ecosystem uptake. Current atmospheric models used in continental-scale inverse studies do not resolve these two classes of mechanisms and therefore may infer incorrect CO2 exchange rates.

The intake fraction is defined for a specific species and emission source as the ratio of attributable population intake to total emissions. Focusing on California's South Coast Air Basin (SoCAB) as a case study, we combine ambient monitoring data with time-activity patterns to estimate the population intake of carbon monoxide and benzene emitted from motor vehicles during 1996-1999. In addition to exposures to ambient concentrations, three microenvironments are considered in which the exposure concentration of motor vehicle emissions is higher than in ambient air: in and near vehicles, inside a building that is near a freeway, and inside a residence with an attached garage. Incorporating data on motor vehicle emissions estimated by the EMFAC2000 model, we estimate that the 15 million people in the SoCAB inhale 0.003-0.009% (34 85 per million, with a best estimate of 47 per million) of primary, nonreactive compounds emitted into the basin by motor vehicles. This population intake of primary motor vehicle emissions is approximately 50% higher than the average ambient concentration times the average breathing rate, owing to higher concentrations in the three microenviromments and also to the temporal and spatial correlation among breathing rates, concentrations, and population densities. The approach demonstrated here can inform policy decisions requiring a metric of population exposure to airborne pollutants. (C) 2003 Elsevier Ltd. All rights reserved.

Mexico City is far advanced in its urban evolution, and cities in currently developing nations may soon follow a similar course. This paper investigates the strengths and weaknesses of infrastructures for the emerging megacities. The major driving force for infrastructure change in Mexico City is concern over air quality. Air chemistry data from recent field campaigns have been used to calculate fluxes in the atmosphere of the Valley of Mexico, for compounds that are important to biogeochemistry including methane (CH4), carbon monoxide (CO), nonmethane hydrocarbons (NMHCs), ammonia (NH3), sulfur dioxide (SO2), nitrogen oxides (NOx and NOy), soot, and dust. Leakage of liquified petroleum gas approached 10% during sampling periods, and automotive pollutant sources in Mexico City were found to match those in developed cities, despite a lower vehicle-to-person ratio of 0.1. Ammonia is released primarily from residential areas, at levels sufficient to titrate pollutant acids into particles across the entire basin. Enhancements of reduced nitrogen and hydrocarbons in the vapor phase skew the distribution of NOy species towards lower average deposition velocities. Partly as a result, downwind nutrient deposition occurs on a similar scale as nitrogen fixation across Central America, and augments marine nitrate upwelling. Dust suspension from unpaved roads and from the bed of Lake Texcoco was found to be comparable to that occurring on the periphery of the Sahara, Arabian, and Gobi deserts. In addition, sodium chloride (NaCl) in the dust may support heterogeneous chlorine oxide (ClOx) chemistry. The insights from our Mexico City analysis have been tentatively applied to the upcoming urbanization of Asia.