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Abstract Myeloproliferative neoplasms (MPNs) are associated with immune dysregulation and increased susceptibility to infection, emphasizing the importance of vaccination for patients. This pilot study evaluated immune responses to influenza vaccination in MPN patients compared with healthy donors using mass cytometry and serology. We observed diminished CXCR5+ B‐cell, CXCR3+ T‐cell, activated CD127+ memory T‐cell subsets, and a trend toward lower hemagglutinin inhibition titer in MPN patients. These results indicate that patients with MPN exhibit distinct responses to influenza vaccination suggestive of impaired migration to lymphoid organs and T‐cell maturation which may impact the development of protective immunity.

Abstract Scenarios have emerged as valuable tools in managing complex human‐natural systems, but the traditional approach of limiting focus on a small number of predetermined scenarios can inadvertently miss consequential dynamics, extremes, and diverse stakeholder impacts. Exploratory modeling approaches have been developed to address these issues by exploring a wide range of possible futures and identifying those that yield consequential vulnerabilities. However, vulnerabilities are typically identified based on aggregate robustness measures that do not take full advantage of the richness of the underlying dynamics in the large ensembles of model simulations and can make it hard to identify key dynamics and/or storylines that can guide planning or further analyses. This study introduces the FRamework for Narrative Storylines and Impact Classification (FRNSIC; pronounced “forensic”): a scenario discovery framework that addresses these challenges by organizing and investigating consequential scenarios using hierarchical classification of diverse outcomes across actors, sectors, and scales, while also aiding in the selection of scenario storylines, based on system dynamics that drive consequential outcomes. We present an application of this framework to the Upper Colorado River Basin, focusing on decadal droughts and their water scarcity implications for the basin's diverse users and its obligations to downstream states through Lake Powell. We show how FRNSIC can explore alternative sets of impact metrics and drought dynamics and use them to identify drought scenario storylines, that can be used to inform future adaptation planning.

Abstract RNA methylation plays a central regulatory role in plant biology and is a relatively new target for plant improvement efforts. In nearly all cases, perturbation of the RNA methylation machinery results in deleterious phenotypes. However, a recent landmark paper reported that transcriptome‐wide use of the human RNA demethylase FTO substantially increased the yield of rice and potatoes. Here, we have performed the first independent replication of those results and demonstrated broader transferability of the trait, finding increased flower and fruit count in the model species Arabidopsis thaliana. We also performed RNA‐seq of our FTO‐transgenic plants, which we analyzed in conjunction with previously published datasets to detect several previously unrecognized patterns in the functional and structural classification of the upregulated and downregulated genes. From these, we present mechanistic hypotheses to explain these surprising results with the goal of spurring more widespread interest in this promising new approach to plant engineering.

Abstract Climate impacts increasingly unfold in interlinked systems of people, nature, and infrastructure. The cascading consequences are revealing sometimes surprising connections across sectors and regions, and prospects for climate responses also depend on complex, difficult‐to‐understand interactions. In this commentary, we build on the innovations of the United States Fifth National Climate Assessment to suggest a framework for understanding and responding to complex climate challenges. This approach involves: (a) integration of disciplines and expertise to understand how intersectionality shapes complex climate impacts and the wide‐ranging effects of climate responses, (b) collaborations among diverse knowledge holders to improve responses and better encompass intersectionality, and (c) sustained experimentation with and learning about governance approaches capable of handling the complexity of climate change. Together, these three pillars underscore that usability of climate‐relevant knowledge requires transdisciplinary coordination of research and practice. We outline actionable steps for climate research to incorporate intersectionality, integration, and innovative governance, as is increasingly necessary for confronting climate complexity and sustaining equitable, ideally vibrant climate futures.

Abstract A reliable and cost‐effective source of fingerlings is essential for the successful commercial aquaculture of black sea bass. This study aimed to determine the effects of nursery tank stocking densities on the growth performance, feed efficiency, survival, tolerance to shipping, and biochemical quality of juvenile black sea bass. In two experiments, different stocking densities were compared for black sea bass at different stages of development. In Experiment 1, intermediate stage juveniles (1.27 g mean wt) were stocked at densities of 4.5 and 6.5 fish per liter of tank volume. Growth performance and biochemical quality were similar between the two density treatments. In Experiment 2, early post‐metamorphic stage juveniles (mean wt. = 0.524 g) were compared using the same stocking densities. While the fish reared at 4.5 fish/L were slightly larger, there were no significant differences in growth performance or biochemical quality between the density treatments. After both experiments, the fingerlings from each density treatment showed high survival rates under acute crowding and simulated shipping conditions. The study demonstrates that high NT densities of 4.5 and 6.5 fish/L did not negatively impact the growth performance and quality of black sea bass fingerlings, providing transport‐ready fingerlings in a relatively short period.

Abstract The ability to reallocate water to higher‐value uses during drought is an increasingly important “soft‐path” tool for managing water resources in an uncertain future. In most of the Western United States, state‐level water market institutions that enable reallocation also impose substantial transaction costs on market participants related to regulatory approval and litigation. These transaction costs can be prohibitive for many participants in terms of both costs and lengthy approval periods, limiting transfers and reducing allocation efficiency, particularly during drought crises periods. This manuscript describes a mechanism to reduce transaction costs by adapting an existing form of informal leases to facilitate quicker and less expensive transfers among market participants. Instead of navigating the formal approval process to lease a water right, informal leases are financial contracts for conservation that enable more junior holders of existing rights to divert water during drought, thereby allowing the formal transfer approval process to be bypassed. The informal leasing approach is tested in the Upper Colorado River Basin, where drought and institutional barriers to transfers lead to frequent shortages for urban rights holders along Colorado's Front Range. Informal leases are facilitated via option contracts that include adaptive triggers and that define volumes of additional, compensatory, releases designed to mitigate impacts to instream flows and third parties. Results suggest that more rapid reallocation of water via informal leases could have resulted in up to $222 million in additional benefits for urban rights holders during the historical period 1950–2013.

Abstract On behalf of the journal, AGU, and the scientific community, we, the editors of Earth's Future, are delighted to publish the names of the 817 peer reviewers who provided 1,242 reviews for our journal in 2023 (italicized names have contributed three or more reviews). Your diligent efforts to provide timely comments on our submissions have significantly improved the manuscripts and elevated the scientific rigor of future research. As a unique transdisciplinary journal, Earth's Future delves into the state of the planet and its inhabitants, sustainable and resilient societies, the science of the Anthropocene, and predictions of our shared future through research articles, reviews, and commentaries. In the face of observed and anticipated global environmental and climatic changes, the need for high‐quality scientific theories, assessments, and projections about the future of our planet has never been more pressing. To safeguard research integrity in this crucial area, we rely on our reviewers' expertise and selfless cooperation. We extend our heartfelt thanks to each of the individuals listed below for their contributions to our journal and the broader scientific discourse. Your dedication is immensely appreciated.

Abstract Ascidians, known for their color variation, host species‐specific microbial symbiont communities. Some ascidians can also transition into a nonfiltering (resting) physiological state. Recent studies suggest that the microbial symbiont communities may vary across different physiological states and color morphs of the host. The colonial ascidian, Polyclinum constellatum, which exhibits several color morphs in the Caribbean Sea, periodically ceases its filtering activity. To investigate if color variation in P. constellatum is indicative of sibling speciation, we sequenced fragments of the ribosomal 18S rRNA and the mitochondrial cytochrome oxidase subunit I genes. Additionally, we sequenced a fragment of the 16S rRNA gene to characterize the microbial communities of two common color morphs (red and green) in colonies that were either actively filtering (active) or nonfiltering (resting). Phylogenetic analyses of both ascidian genes resulted in well‐supported monophyletic clades encompassing all color variants of P. constellatum. Interestingly, no significant differences were observed among the microbial communities of the green and red morphs, suggesting that color variation in this species is a result of intraspecific variation. However, the host's physiological state significantly influenced the microbial community structure. Nonfiltering (resting) colonies hosted higher relative abundances of Kiloniella (Alphaproteobacteria) and Fangia (Gammaproteobacteria), while filtering colonies hosted more Reugeria (Alphaproteobacteria) and Endozoicomonas (Gammaproteobacteria). This study demonstrates that microbial symbiont communities serve as reliable indicators of the taxonomic state of their host and are strongly influenced by the host's feeding condition.

Abstract Introduction Multiple herbicide‐resistant Avena fatua L. is common in the Northern Great Plains, USA. This prevalence and the ecological impacts of tillage in this semi‐arid agricultural region have created a need for integrated weed management, with a specific knowledge gap in using annual forage crops and targeted grazing for A. fatua suppression. Materials and Methods A 2‐year study in central Montana, USA, assessed A. fatua performance (aboveground biomass, stem density and seed production) in response to seven cropping treatments: (1–4) tall and short spring wheat cultivars crossed with high and low seeding rates, (5–6) annual forage mixture terminated using sheep grazing and simulated haying and (7) tilled fallow. Avena fatua's competitive intensity in wheat and the annual forage mixture was determined using a relative competition intensity index. Results Avena fatua performance was lowest in tilled fallow, although stem density and seed production did not differ from the grazed annual forage treatment. Response variables were lower in the forage treatments compared with the wheat treatments, and there were no differences among the four fully crossed wheat treatments. Separate analysis of the wheat treatments indicated lower A. fatua biomass and stem density when wheat was sown at a higher rate with no impact of wheat height. Avena fatua competition impacted wheat and forage crops but was more intense for wheat. Conclusion Tillage was the most effective treatment at reducing A. fatua performance, but annual forage mixtures can be used to resist A. fatua invasion (reduced A. fatua competitive intensity) and limit its performance after invasion. We conclude that crop sequences that combine higher cash crop (wheat) seeding rates and competitive annual forage mixtures may be utilized to manage A. fatua invaded systems, thereby reducing heavy reliance on tillage in the US Northern Great Plains and similar semi‐arid regions.

Abstract Interspecific foraging associations (IFAs) are biological interactions where two or more species forage in association with each other. Climate‐induced reductions in Arctic sea ice have increased polar bear (Ursus maritimus) foraging in seabird colonies, which creates foraging opportunities for avian predators. We used drone video of bears foraging within a common eider (Somateria mollissima) colony on East Bay Island (Nunavut, Canada) in 2017 to investigate herring gull (Larus argentatus) foraging in association with bears. We recorded nest visitation by gulls following n = 193 eider flushing events from nests during incubation. The probability of gulls visiting eider nests increased with higher number of gulls present (β = 0.14 ± 0.03 [SE], p

Abstract Background Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence‐free survival (RFS) following resection of Stage II–IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. Methods The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan–Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t‐tests. Results The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0–0.5 years: 0.22 ± 0.21; 0.5–1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0–0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p

Abstract Lung cancer is the leading cause of cancer‐related deaths worldwide. Surgery and chemoradiation are the standard of care in early stages of non‐small cell lung cancer (NSCLC), while immunotherapy is the standard of care in late‐stage NSCLC. The immune composition of the tumor microenvironment (TME) is recognized as an indicator for responsiveness to immunotherapy, although much remains unknown about its role in responsiveness to surgery or chemoradiation. In this pilot study, we characterized the NSCLC TME using mass cytometry (CyTOF) and bulk RNA sequencing (RNA‐Seq) with deconvolution of RNA‐Seq being performed by Kassandra, a recently published deconvolution tool. Stratification of patients based on the intratumoral abundance of B cells identified that the B‐cell rich patient group had increased expression of CXCL13 and greater abundance of PD1+ CD8 T cells. The presence of B cells and PD1+ CD8 T cells correlated positively with the presence of intratumoral tertiary lymphoid structures (TLS). We then assessed the predictive and prognostic utility of these cell types and TLS within publicly available stage 3 and 4 lung adenocarcinoma (LUAD) RNA‐Seq datasets. As previously described by others, pre‐treatment expression of intratumoral 12‐chemokine TLS gene signature is associated with progression free survival (PFS) in patients who receive treatment with immune checkpoint inhibitors (ICI). Notably and unexpectedly pre‐treatment percentages of intratumoral B cells are associated with PFS in patients who receive surgery, chemotherapy, or radiation. Further studies to confirm these findings would allow for more effective patient selection for both ICI and non‐ICI treatments.

Abstract Background Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors, CagA and VacA, to up‐regulate pro‐inflammatory cytokines and activate NF‐κB signaling. Meanwhile, the PIEZO1 upregulation and cancer‐associated fibroblast (CAF) enrichment were found in GC progression. However, the mechanisms of PIEZO1 upregulation and its involvement in GC progression have not been fully elucidated. Methods The CAF enrichment and clinical significance were investigated in animal models and primary samples. The expression of NF‐κB and PIEZO1 in GC was confirmed by immunohistochemistry staining, and expression correlation was analysed in multiple GC datasets. GSEA and Western blot analysis revealed the YAP1‐CTGF axis regulation by PIEZO1. The stimulatory effects of CTGF on CAFs were validated by the co‐culture system and animal studies. Patient‐derived organoid and peritoneal dissemination models were employed to confirm the role of the PIEZO1‐YAP1‐CTGF cascade in GC. Results Both CAF signature and PIEZO1 were positively correlated with H. pylori infection. PIEZO1, a mechanosensor, was confirmed as a direct downstream of NF‐κB to promote the transformation from intestinal metaplasia to GC. Mechanistic studies revealed that PIEZO1 transduced the oncogenic signal from NF‐κB into YAP1 signaling, a well‐documented oncogenic pathway in GC progression. PIEZO1 expression was positively correlated with the YAP1 signature (CTGF, CYR61, and c‐Myc, etc.) in primary samples. The secreted CTGF by cancer cells stimulated the CAF infiltration to form a stiffened collagen‐enrichment microenvironment, thus activating PIEZO1 to form a positive feedback loop. Both PIEZO1 depletion by shRNA and CTGF inhibition by Procyanidin C1 enhanced the efficacy of 5‐FU in suppressing the GC cell peritoneal metastasis. Conclusion This study elucidates a novel driving PIEZO1‐YAP1‐CTGF force, which opens a novel therapeutic avenue to block the transformation from precancerous lesions to GC. H. pylori‐NF‐κB activates the PIEZO1‐YAP1‐CTGF axis to remodel the GC microenvironment by promoting CAF infiltration. Targeting PIEZO1‐YAP1‐CTGF plus chemotherapy might serve as a potential therapeutic option to block GC progression and peritoneal metastasis.

Abstract To aid California's water sector to better understand and manage future climate extremes, we present a method for creating a regionally consistent ensemble of plausible daily future climate and streamflow scenarios that represent natural climate variability captured in a network of tree‐ring chronologies, and then embed anthropogenic climate change trends within those scenarios. We use 600 years of paleo‐reconstructed weather regimes to force a stochastic weather generator, which we develop for five subbasins in the San Joaquin Valley of California. To assess the compound effects of climate change, we create temperature series that reflect projected scenarios of warming and precipitation series that have been scaled to reflect thermodynamically driven shifts in the distribution of daily precipitation. We then use these weather scenarios to force hydrologic models for each of the five subbasins. The paleo‐forced streamflow scenarios highlight periods in the region's past that produce flood and drought extremes that surpass those in the modern record and exhibit large non‐stationarity through the reconstruction. Variance decomposition is employed to characterize the contribution of natural variability and climate change to variability in decision‐relevant metrics related to floods and drought. Our results show that a large portion of variability in individual subbasin and spatially compounding extreme events can be attributed to natural variability, but that anthropogenic climate changes become more influential at longer planning horizons. The joint importance of climate change and natural variability in shaping extreme floods and droughts is critical to resilient water systems planning and management in the San Joaquin.

Abstract The objective of this study was to optimize nursery diets for post‐metamorphic stage black sea bass by evaluating growth performance, whole‐body proximate and fatty acid composition, and utilization of University of North Carolina Wilmington (UNCW)‐formulated and commercial diets under laboratory conditions. A feeding trial was conducted to compare two UNCW‐formulated diets (D1 and D2) for black sea bass (54% crude protein = CP and 14% crude lipid = CL) and two premium, commercial marine finfish fry diets, Otohime (Reed Mariculture Inc., Campbell, CA, CP = 48% and CL = 14%, CD3) and Gemma Diamond (Skretting, Nutreco, Canada, CP = 57%, CL = 15%, CD4). The UNCW‐formulated diet 1 (D1) contained high fish meal (FM, 40% of diet), whereas UNCW‐formulated diet 2 (D2) replaced 50% FM protein by high‐quality poultry by‐product meal (PBM) protein. Post‐metamorphic stage black sea bass (~0.60 g, d40ph) were stocked in each of sixteen 75‐L tanks at a density of 1 fish per L (75 per tank), with four replicate aquaria per treatment. Fish were fed four times per day (0800, 1100, 1400, and 1600 h) to apparent satiation for 30 days. Final body weight (5.70–5.74), specific growth rate (7.40–7.45%/d), and percent body weight gain (834–848%) of fish fed the UNCW‐formulated D1 (FM‐based) and D2 (FM + PBM‐based) were higher (p

Objective To determine if single‐nucleotide polymorphisms (SNPs) in DNA repair genes are enriched in individuals with systemic lupus erythematosus (SLE) and if they are sufficient to confer a disease phenotype in a mouse model. Methods Human exome chip data of 2499 patients with SLE and 1230 healthy controls were analyzed to determine if variants in 10 different mismatch repair genes (MSH4, EXO1, MSH2, MSH6, MLH1, MSH3, POLH, PMS2, ML3, and APEX2) were enriched in individuals with SLE. A mouse model of the MSH6 SNP, which was found to be enriched in individuals with SLE, was created using CRISPR/Cas9 gene targeting. Wildtype mice and mice heterozygous and homozygous for the MSH6 variant were then monitored for 2 years for the development of autoimmune phenotypes, including the presence of high levels of antinuclear antibodies (ANA). Additionally, somatic hypermutation frequencies and spectra of the intronic region downstream of the VHJ558‐rearranged JH4 immunoglobulin gene was characterized from Peyer's patches. Results Based on the human exome chip data, the MSH6 variant (rs63750897, p.Ser503Cys) is enriched among patients with SLE versus controls after we corrected for ancestry (odds ratio = 8.39, P = 0.0398). Mice homozygous for the MSH6 variant (Msh6S502C/S502C) harbor significantly increased levels of ANA. Additionally, the Msh6S502C/S502C mice display a significant increase in the infiltration of CD68+ cells (a marker for monocytes and macrophages) into the lung alveolar space as well as apoptotic cells. Furthermore, characterization of somatic hypermutation in these mice reveals an increase in the DNA polymerase η mutational signature. Conclusion An MSH6 mutation that is enriched in humans diagnosed with lupus was identified. Mice harboring this Msh6 mutation develop increased autoantibodies and an inflammatory lung disease. These results suggest that the human MSH6 variant is linked to the development of SLE.

Background Postablation arrhythmia recurrence occurs in ~40% of patients with persistent atrial fibrillation. Fibrotic remodeling exacerbates arrhythmic activity in persistent atrial fibrillation and can play a key role in reentrant arrhythmia, but emergent interaction between nonconductive ablation‐induced scar and native fibrosis (ie, residual fibrosis) is poorly understood. Methods and Results We conducted computational simulations in pre‐ and postablation left atrial models reconstructed from late gadolinium enhanced magnetic resonance imaging scans to test the hypothesis that ablation in patients with persistent atrial fibrillation creates new substrate conducive to recurrent arrhythmia mediated by anchored reentry. We trained a random forest machine learning classifier to accurately pinpoint specific nonconductive tissue regions (ie, areas of ablation‐delivered scar or vein/valve boundaries) with the capacity to serve as substrate for anchored reentry‐driven recurrent arrhythmia (area under the curve: 0.91±0.03). Our analysis suggests there is a distinctive nonconductive tissue pattern prone to serving as arrhythmogenic substrate in postablation models, defined by a specific size and proximity to residual fibrosis. Conclusions Overall, this suggests persistent atrial fibrillation ablation transforms substrate that favors functional reentry (ie, rotors meandering in excitable tissue) into an arrhythmogenic milieu more conducive to anchored reentry. Our work also indicates that explainable machine learning and computational simulations can be combined to effectively probe mechanisms of recurrent arrhythmia.

Abstract Background While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non‐European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans‐ethnic PRS for body mass index (BMI) through this relatively new international effort. Methods The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta‐analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis. Results We show that in the absence of a well powered trans‐ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans‐ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans‐ethnic linkage disequilibrium reference panels. The ported trans‐ethnic scores outperform population specific‐PRS across all non‐European ancestry populations investigated including East Asians and three‐way admixed Brazilian cohort. Conclusions Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans‐ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three‐way admixed Brazilians.

Key Points Earth's Future thanks its reviewers who contributed in 2022

Abstract Sponges perform important ecosystem functions, host diverse microbial symbiont communities (microbiomes), and have been increasing in density on Caribbean coral reefs over the last decade. Sponges compete for space in coral reef communities through both morphological and allelopathic strategies, but no studies of microbiome impacts during these interactions have been conducted. Microbiome alterations mediate spatial competition in other coral reef invertebrates and may similarly impact competitive outcomes for sponges. In this study, we characterized the microbiomes of three common Caribbean sponges (Agelas tubulata, Iotrochota birotulata, and Xestospongia muta) observed to naturally interact spatially in Key Largo, Florida (USA). For each species, replicate samples were collected from sponges in contact with neighbors at the site of contact (contact) and distant from the site of contact (no contact), and from sponges spatially isolated from neighbors (control). Next‐generation amplicon sequencing (V4 region of 16S rRNA) revealed significant differences in microbial community structure and diversity among sponge species, but no significant effects were observed within sponge species across all contact states and competitor pairings, indicating no large community shifts in response to direct contact. At a finer scale, particular symbiont taxa (operational taxonomic units at 97% sequence identity, OTUs) were shown to decrease significantly in some interaction pairings, suggesting localized effects for specific sponge competitors. Overall, these results revealed that direct contact during spatial competition does not significantly alter microbial community composition or structure of interacting sponges, suggesting that allelopathic interactions and competitive outcomes are not mediated by microbiome damage or destabilization.

Abstract Objectives Existing pulmonary embolism (PE) risk scores were developed to predict death within weeks, but not more proximate adverse events. We determined the ability of 3 PE risk stratification tools (simplified pulmonary embolism severity index [sPESI], 2019 European Society of Cardiology guidelines [ESC], and PE short‐term clinical outcomes risk estimation [PE‐SCORE]) to predict 5‐day clinical deterioration after emergency department (ED) diagnosis of PE. Methods We analyzed data from six EDs on ED patients with confirmed PE. Clinical deterioration was defined as death, respiratory failure, cardiac arrest, new dysrhythmia, sustained hypotension requiring vasopressors or volume resuscitation, or escalated intervention within 5 days of PE diagnosis. We determined sensitivity and specificity of sPESI, ESC, and PE‐SCORE for predicting clinical deterioration. Results Of 1569 patients, 24.5% had clinical deterioration within 5 days. sPESI, ESC, and PE‐SCORE classifications were low‐risk in 558 (35.6%), 167 (10.6%), and 309 (19.6%), respectively. Sensitivities of sPESI, ESC, and PE‐SCORE for clinical deterioration were 81.8 (78, 85.7), 98.7 (97.6, 99.8), and 96.1 (94.2, 98), respectively. Specificities of sPESI, ESC, and PE‐SCORE for clinical deterioration were 41.2 (38.4, 44), 13.7 (11.7, 15.6), and 24.8 (22.4, 27.3). Areas under the curve were 61.5 (59.1, 63.9), 56.2 (55.1, 57.3), and 60.5 (58.9, 62.0). Negative predictive values were 87.5 (84.7, 90.2), 97 (94.4, 99.6), and 95.1 (92.7, 97.5). Conclusions ESC and PE‐SCORE were better than sPESI for detecting clinical deterioration within 5 days after PE diagnosis.

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment‐resistant disorder characterized by early‐onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a “real‐world” setting. Untreated low‐density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow‐up, despite multiple lipid‐lowering treatment, low‐density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid‐lowering treatments were prescribed for 18%; 40% were on no lipid‐lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid‐lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

Background The current standard of care for the treatment of patients with primary mitral regurgitation (MR) is surgical mitral valve repair. Transcatheter edge‐to‐edge repair with the MitraClip device provides a less invasive treatment option for patients with both primary and secondary MR. Worldwide, >150 000 patients have been treated with the MitraClip device. However, in the United States, MitraClip is approved for use only in primary patients with MR who are at high or prohibitive risk for mitral valve surgery. The REPAIR MR (Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery) trial is designed to compare early and late outcomes associated with transcatheter edge‐to‐edge repair with the MitraClip and surgical repair of primary MR in older or moderate surgical risk patients. Methods and Results The REPAIR MR trial is a prospective, randomized, parallel‐controlled, open‐label multicenter, noninferiority trial for the treatment of severe primary MR (verified by an independent echocardiographic core laboratory). Patients with severe MR and indications for surgery because of symptoms (New York Heart Association class II–IV), or without symptoms with left ventricular ejection fraction ≤60%, pulmonary artery systolic pressure >50 mm Hg, or left ventricular end‐systolic diameter ≥40 mm are eligible for the trial provided they meet the moderate surgical risk criteria as follows: (1) ≥75 years of age, or (2) if

Abstract Liposomal irinotecan is a liposomal formulation of irinotecan, which prolongs circulation of irinotecan and its active metabolite SN‐38. A population pharmacokinetic (PK) model was developed based on data from seven studies (N = 440). Adequacy of the model was assessed using multiple methods, including visual predictive check. Associations between PK exposure and the incidence of diarrhea (grade ≥3) and neutropenia adverse events (AEs) (grade ≥3) at first event in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) were investigated using logistic regression based on data from two studies (the phase III NAPOLI‐1 [N = 260] and phase I/II NCT02551991 [N = 56] trials). The PKs of total irinotecan was described by a two‐compartment model with first‐order elimination, with SN‐38 formed directly by a first‐order constant from the central compartment of irinotecan or after using a transit compartment. Clearance was 17.9 L/week (0.107 L/h) and 19,800 L/week (118 L/h) for total irinotecan and SN‐38, respectively. The UGT1A1*28 7/7 homozygous genotype had no significant impact on SN‐38 clearance. Model evaluation was satisfactory for both irinotecan and SN‐38. The incidence of diarrhea (grade ≥3) at first event was significantly higher with increasing average concentrations of total irinotecan and SN‐38; there was no significant association between an increased risk of neutropenia AEs (grade ≥3) at first event and average SN‐38 concentrations. In summary, the PKs of total irinotecan and SN‐38 after administration of liposomal irinotecan were well‐described by the model. The UGT1A1*28 status had no significant impact on the PKs of liposomal irinotecan.

Abstract Design methodologies are developed for complementary frequency modulated (FM) waveforms and for optimised complementary mismatched filtering (MMF) of arbitrary non‐repeating waveforms. The former is a sub‐class of random FM waveforms denoted as complementary FM (Comp‐FM) while the latter extends a practical instantiation of least‐squares mismatched filtering yielding the mismatched complementary‐on‐receive filtering (MiCRFt) scheme. Both of these approaches have an emphasis on the non‐ideal physical effects of the radar transmitter and receiver, thereby permitting high‐fidelity simulation analysis and subsequent experimental demonstration of their efficacy using open‐air measurements.

Abstract The role of individual and collective human action is increasingly recognized as a prominent and arguably paramount determinant in shaping the behavior, trajectory, and vulnerability of multisector systems. This human influence operates at multiple scales: from short‐term (hourly to daily) to long‐term (annually to centennial) timescales, and from the local to the global, pushing systems toward either desirable or undesirable outcomes. However, the effort to represent human systems in multisector models has been fragmented across philosophical, methodological, and disciplinary lines. To cohere insights across diverse modeling approaches, we present a new typology for classifying how human actors are represented in the broad suite of coupled human‐natural system models that are applied in MultiSector Dynamics (MSD) research. The typology conceptualizes a “sector” as a system‐of‐systems that includes a diverse group of human actors, defined across individual to collective social levels, involved in governing, provisioning, and utilizing products, goods, or services toward some human end. We trace the salient features of modeled representations of human systems by organizing the typology around two key questions: (a) Who are the actors in MSD systems and what are their actions? (b) How and for what purpose are these actors and actions operationalized in a computational model? We use this typology to critically examine existing models and chart the frontier of human systems modeling for MSD research.

Abstract Background The vast majority of chronic myeloid leukemia (CML) patients have a single translocation t(9;22)(q34;q11), BCR/ABL1 fusion genes, which is regarded as the hallmark of CML. However, around 5 to 10% of CML patients exhibit the involvement of a third chromosome. In some very rare cases a fourth or even fifth chromosome can be involved with the t(9;22). Methods This case report is based on a 40‐year‐old Saudi Arabian male patient, diagnosed with CML in lymphoid blast crisis, and observed to have a four‐way 46 XY, t(9;22;5;2)(q34;q11.2;p13;q44) translocation. The BCR/ABL1 fusion was identified by fluorescent in situ hybridization (FISH). Additionally, the BCR/ABL1 p210 mRNA fusion transcripts were identified by a molecular test. Results The clinical and prognostic impact of additional partner chromosomes to t(9;22) remains unknown. The CML patient with this novel four‐way translocation t(9;22;5;2) progressed to blast crisis and was resistant to Tyrosine Kinase Inhibitor (TKI) therapy. Therefore, this case is more in alignment with the negative impact of additional partner chromosomes to the translocation at t(9;22). Conclusion Here we report for the first time a novel four‐way translocation at t(9;22;5;2)(q34;q11.2;p13;q44).

ABSTRACT Background Pancreatic ductal adenocarcinoma (PDAC), a difficult‐to‐treat cancer, is expected to become the second‐largest cause of cancer‐related deaths by 2030, while colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer deaths. Currently, there is no effective treatment for PDAC patients. The development of novel agents to effectively treat these cancers remains an unmet clinical need. FL118, a novel anticancer small molecule, exhibits high efficacy against cancers; however, the direct biochemical target of FL118 is unknown. Methods FL118 affinity purification, mass spectrometry, Nanosep centrifugal device and isothermal titration calorimetry were used for identifying and confirming FL118 binding to DDX5/p68 and its binding affinity. Immunoprecipitation (IP), western blots, real‐time reverse transcription PCR, gene silencing, overexpression (OE) and knockout (KO) were used for analysing gene/protein function and expression. Chromatin IP was used for analysing protein‐DNA interactions. The 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromid assay and human PDAC/CRC cell/tumour models were used for determining PDAC/CRC cell/tumour in vitro and in vivo growth. Results We discovered that FL118 strongly binds to, dephosphorylates and degrades the DDX5 oncoprotein via the proteasome degradation pathway without decreasing DDX5 mRNA. Silencing and OE of DDX5 indicated that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins, including survivin, Mcl‐1, XIAP, cIAP2, c‐Myc and mutant Kras. Genetic manipulation of DDX5 in PDAC cells affects tumour growth. PDAC cells with DDX5 KO are resistant to FL118 treatment. Our human tumour animal model studies further indicated that FL118 exhibits high efficacy to eliminate human PDAC and CRC tumours that have a high expression of DDX5, while FL118 exhibits less effectiveness in PDAC and CRC tumours with low DDX5 expression. Conclusion DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumour sensitivity to FL118. This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic. FL118 may act as a ‘molecular glue degrader’ to directly glue DDX5 and ubiquitination regulators together to degrade DDX5.

Abstract Water scarcity is a growing problem around the world, and regions such as California are working to develop diversified, interconnected, flexible, and resilient water supply portfolios. To meet these goals, water utilities, irrigation districts, and other organizations will need to cooperate across scales to finance, build, and operate shared water supply infrastructure. However, planning studies to date have generally focused on partnership‐level outcomes (i.e., highly aggregated cost‐benefit analyses), while ignoring the heterogeneity of benefits, costs, and risks across the individual partners. This study contributes an exploratory modeling analysis that tests thousands of alternative infrastructure partnerships in the Central Valley of California, using a daily scale simulation model (CALFEWS) to evaluate the effects of new infrastructure on individual water providers. The viability of conveyance and groundwater banking investments are as strongly shaped by partnership design choices (i.e., which water providers are participating, and how is the project's debt distributed?) as by extreme hydrologic conditions (i.e., floods and droughts). Importantly, most of the analyzed partnerships yield highly unequal distributions of water supply and financial risks across the partners, so that only 8% of the partnerships explored are capable of providing water to each partner for under $200/ML. Partnership viability is especially rare in the absence of groundwater banking facilities (1%), or under dry hydrologic conditions (1%), even under explicitly optimistic assumptions regarding climate change. Given these results, we outline several major policy implications for institutionally complex regions such as California, which are currently investing heavily in cooperative approaches to resilient water portfolio design.

Abstract We are delighted to publish the names of the 613 peer reviewers who submitted 904 reviews in 2021. We express our deep appreciation for your thoughtful comments and suggestions on manuscripts submitted to Earth's Future.

Abstract The field of MultiSector Dynamics (MSD) explores the dynamics and co‐evolutionary pathways of human and Earth systems with a focus on critical goods, services, and amenities delivered to people through interdependent sectors. This commentary lays out core definitions and concepts, identifies MSD science questions in the context of the current state of knowledge, and describes ongoing activities to expand capacities for open science, leverage revolutions in data and computing, and grow and diversify the MSD workforce. Central to our vision is the ambition of advancing the next generation of complex adaptive human‐Earth systems science to better address interconnected risks, increase resilience, and improve sustainability. This will require convergent research and the integration of ideas and methods from multiple disciplines. Understanding the tradeoffs, synergies, and complexities that exist in coupled human‐Earth systems is particularly important in the context of energy transitions and increased future shocks.

Abstract Species distributions are governed by processes occurring at multiple spatial scales. For species with complex life cycles, the needs of all life stages must be met within the dispersal limitations of the species. Multi‐scale processes can be particularly important for these species, where small‐scale patterns in specific habitat components can affect the distribution of one life stage, whereas large‐scale patterns in land cover might better explain the distribution of other life stages. Using a conditional multi‐scale model, we evaluated which aspects of the landscape and local environment are most strongly related to occupancy patterns of western spadefoots (Spea hammondii). In northern and central California, the proportion of grassland land cover within 2 km of a site was positively related to the occurrence of the northern clade of the western spadefoot. At the pond scale, we found that western spadefoots were more likely to breed in pools with lower pH. Our results indicate that protecting remaining grasslands for adult spadefoots and ensuring multiple pools with diverse characteristics and hydroperiods so at least some pools result in successful breeding will likely be necessary to conserve western spadefoots, especially with a changing climate. Considering the processes that affect species distributions at multiple life stages and spatial scales is an essential component of effective conservation.

Abstract The endangered Silver Chub (Macrhybopsis storeriana, Kirtland 1844) is native to North America and primarily riverine, with the only known large‐lake population in Lake Erie. Once a major component of the Lake Erie fish community, it declined and became nearly extirpated in the mid‐1900s. Recent collections in western Lake Erie suggest that Silver Chub may be able to recover, but their habitat and distribution are poorly known. A recent work showed an extensive area of western Lake Erie with the potential to support large numbers of Silver Chub, but was based on a geographically limited dataset. We developed a neural network‐based species distribution model for the Silver Chub in western Lake Erie, improved by new synoptic data and using habitat variables resistant to anthropogenic activities. The Potential model predictions were compared with a model that included anthropogenic‐sensitive variables. The Potential model used 10 habitat variables and performed well, explaining > 99% of data variation and had generally low error rates. Predictions indicated that a large area of the waters approximately 2–9 m deep contained Appropriate habitat and the highest abundances should be supported by habitat in a wide arc through the western end of the basin. The model indicated that Appropriate Silver Chub habitat was associated with relatively deep water, near coastal wetlands, where effective fetch is less than average. Disturbance model predictions were similar, but predicted poorer Silver Chub habitat in more areas than that predicted by the Potential model. Our Potential model reveals Appropriate habitat conditions for Silver Chub and its spatial distribution, indicating that extensive areas of western Lake Erie could support Silver Chub. Comparisons with Disturbance model predictions demonstrate that Potential model predictions may be used in conjunction with analyses of degrading conditions in the system to better conserve and manage for this endangered species.

Abstract Evolutionary studies of insect pests improve our ability to anticipate problems in agricultural ecosystems, such as pest outbreaks, control failures, or expansions of the host range. Here, we investigated the mechanisms underlying the evolutionary processes behind the recent census size expansion and local adaptation of Chrysodeixis includens. First, we sequenced mitochondrial markers to conduct a phylogeographic investigation of C. includens historical processes. Then, we combined a de novo genotyping‐by‐sequencing approach with a study of agricultural landscapes to uncover recent processes of adaptation. Primarily, we found low genetic diversity across all markers and clear indications of a recent demographic expansion. We also found a lack of significant isolation by distance (IBD), and weak or absent genetic structure considering geographic locations. However, we did find initial signs of population differentiation that were associated with host plant types (i.e., soybean and cotton). Agricultural landscape attributes, including soybean crops, were significantly associated with putative markers under positive selection. Moreover, positive selection associated with host differentiation was putatively linked to digestive enzymes. This study showed how landscape composition and host plants can affect the evolutionary process of agricultural pest insects such as C. includens.

Abstract Cooperative management of natural resources is a key component of a transition to a sustainable society and urban water supply planning is a prime example. Regional cooperation among urban water utilities is a powerful mechanism for improving supply reliability and financial stability in urban water supply systems. Through coordinated drought mitigation and joint infrastructure investment, water utilities can efficiently exploit existing water supplies and reduce or delay the need for new supply infrastructure. However, cooperative water management brings new challenges for planning and implementation. The benefits of cooperation may not be uniformly distributed across cooperating partners, resulting in the “instability” of cooperative compromises. Further, cooperation may add new vulnerabilities for each partner by imbuing their cooperating partners with the power to impact their performance through policy actions. Power imbalances stemming from these vulnerabilities can lead to conflict between cooperating partners that destabilize otherwise robust planning alternatives. This work contributes a new exploratory modeling centered framework for assessing cooperative stability and mapping power relationships in cooperative infrastructure investment and water supply management policies. Our framework uses multi‐objective optimization as an exploratory tool to discover how cooperating partners may be incentivized to defect from robust regional water supply partnerships and identifies how the actions of each regional partner shape the vulnerability of its cooperating partners. Our methodology is demonstrated on the Sedento Valley, a highly challenging hypothetical regional urban water supply benchmarking problem. Our results reveal complex regional power relationships between the region's cooperating partners and suggest ways to improve cooperative stability.

Abstract Soil nematode community structure and composition can inform crop managers about soil quality. However, few studies have assessed the nematode community under agricultural systems in cool semi‐arid regions such as the U.S. northern Great Plains. We assessed soil nematode community structure of barley (Hordeum vulgare L.) and barley–pea (Pisum sativum L.) cropping systems from 2016 to 2018 in one tilled and two no‐till field experiments under dryland management in central and southwestern Montana. Soils were sampled prior to planting in the spring and following harvest in late summer and nematodes were classified to genus level via microscopy. Both in season moisture stress and overwinter stress explained decline in nematodes in the central Montana no‐till experiments, although consistent impacts of moisture or overwinter stress on nematodes were not detected in the tilled field experiment. Cropping system or sequence did not impact the nematode population (p > .1), but barley yield was positively correlated with larger nematode populations in both no‐till experiments (r > .60). The percentage of fungivores were negatively correlated (r = –.42) to barley yield under tillage. Plant parasitic nematodes were positively correlated (r = .43) to barley yield under tillage. These results suggest that factors which enhance cereal crop growth and productivity rather than crop diversification drive short‐term nematode community dynamics when crop rotations are established in cool semi‐arid regions. Future work is needed to determine if cropping system changes can impact nematode populations after several years in cool semi‐arid regions and, if so, what ecosystem services result from these transformations.

Abstract Spatial synchrony is a common characteristic of spatio‐temporal population dynamics across many taxa. While it is known that both dispersal and spatially autocorrelated environmental variation (i.e., the Moran effect) can synchronize populations, the relative contributions of each, and how they interact, are generally unknown. Distinguishing these mechanisms and their effects on synchrony can help us to better understand spatial population dynamics, design conservation and management strategies, and predict climate change impacts. Population genetic data can be used to tease apart these two processes as the spatio‐temporal genetic patterns they create are expected to be different. A challenge, however, is that genetic data are often collected at a single point in time, which may introduce context‐specific bias. Spatio‐temporal sampling strategies can be used to reduce bias and to improve our characterization of the drivers of spatial synchrony. Using spatio‐temporal analyses of genotypic data, our objective was to identify the relative support for these two mechanisms to the spatial synchrony in population dynamics of the irruptive forest insect pest, the spruce budworm (Choristoneura fumiferana), in Quebec (Canada). AMOVA, cluster analysis, isolation by distance, and sPCA were used to characterize spatio‐temporal genomic variation using 1,370 SBW larvae sampled over four years (2012–2015) and genotyped at 3,562 SNP loci. We found evidence of overall weak spatial genetic structure that decreased from 2012 to 2015 and a genetic diversity homogenization among the sites. We also found genetic evidence of a long‐distance dispersal event over >140 km. These results indicate that dispersal is the key mechanism involved in driving population synchrony of the outbreak. Early intervention management strategies that aim to control source populations have the potential to be effective through limiting dispersal. However, the timing of such interventions relative to outbreak progression is likely to influence their probability of success.

Summary Objective Research suggests that individuals seeking weight loss treatment do so for a variety of reasons. Limited work has explored relations of reasons for weight loss to patient characteristics or to weight loss outcomes. The current study examined these relations. Methods The sample consisted of 588 patients in a 15‐week fee‐for‐service weight loss programme. Prior to the intervention, patients completed questionnaires including items on reasons for weight loss, demographic characteristics, and a variety of weight‐based characteristics. Patients' weight change outcomes were expressed as percent weight loss and also categorized into one of three previously described weight loss trajectories. Results The results of chi‐squared and t‐test analyses suggested that endorsement of health concerns, mobility concerns, or another person's recommendation was associated with higher body mass index (BMI) and older age. These reasons were more likely to be endorsed by White patients than Black patients and by male patients than female patients. Endorsement of doctor recommendation was more likely to be seen among Black patients than White patients. There was no significant relation of any weight loss reason with weight loss outcome. Conclusions While certain reasons for weight loss were more often cited by certain patient groups, no specific reason predicted a better or worse outcome.

Background Obesity is associated with heart failure with preserved ejection fraction (HFpEF). Weight loss can improve exercise capacity in HFpEF. However, previously reported methods of weight loss are impractical for widespread clinical implementation. We tested the hypothesis that an intensive lifestyle modification program would lead to relevant weight loss and improvement in functional status in patients with HFpEF and obesity. Methods and Results Patients with ejection fraction >45%, at least 1 objective criteria for HFpEF, and body mass index ≥30 kg/m2 were offered enrollment in an established 15‐week weight management program that included weekly visits for counseling, weight checks, and provision of meal replacements. At baseline, 15 weeks, and 26 weeks, Minnesota Living With Heart Failure score, 6‐minute walk distance, echocardiography, and laboratory variables were assessed. A total of 41 patients completed the study (mean body mass index, 40.8 kg/m2), 74% of whom lost >5% of their baseline body weight following the 15‐week program. At 15 weeks, mean 6‐minute walk distance increased from 223 to 281 m (P=0.001) and then decreased to 267 m at 26 weeks. Minnesota Living With Heart Failure score improved from 59.9 to 37.3 at 15 weeks (P

Abstract Aim Amazon‐nut (Bertholletia excelsa) is a hyperdominant and protected tree species, playing a keystone role in nutrient cycling and ecosystem service provision in Amazonia. Our main goal was to develop a robust habitat suitability model of Amazon‐nut and to identify the most important predictor variables to support conservation and tree planting decisions. Localization Amazon region, South America. Methods We collected 3,325 unique Amazon‐nut records and assembled >100 spatial predictor variables organized across climatic, edaphic, and geophysical categories. We compared suitability models using variables (a) selected through statistical techniques; (b) recommended by experts; and (c) integrating both approaches (a and b). We applied different spatial filtering scenarios to reduce overfitting. We additionally fine‐tuned MAXENT settings to our data. The best model was selected through quantitative and qualitative assessments. Results Principal component analysis based on expert recommendations was the most appropriate method for predictor selection. Elevation, coarse soil fragments, clay, slope, and annual potential evapotranspiration were the most important predictors. Their relative contribution to the best model amounted to 75%. Filtering of the presences within a radius of 10 km displayed lowest overfitting, a satisfactory omission rate and the most symmetric distribution curve. Our findings suggest that under current environmental conditions, suitable habitat for Amazon‐nut is found across 2.3 million km2, that is, 32% of the Amazon Biome. Main conclusion The combination of statistical techniques with expert knowledge improved the quality of our suitability model. Topographic and soil variables were the most important predictors. The combination of predictor variable selection, fine‐tuning of model parameters and spatial filtering was critical for the construction of a reliable habitat suitability model.

Abstract Background Transient hypothalamic‐pituitary‐adrenal axis dysfunction occurs in critically ill foals with sepsis and neonatal maladjustment syndrome (NMS). Cortisol is the most commonly measured steroid. However, a complex interaction of various steroid compounds might play a role in pathophysiology of this disorder. Objective To identify steroid compounds present at high concentrations at birth that rapidly and steadily decrease within the first 7 days of life in healthy foals and that might be supportive diagnosis of NMS and other neonatal disorders. Animals Ten healthy neonatal Quarter Horse foals (5 females and 5 males). Methods Prospective study. Blood was collected in heparinized tubes within 30 minutes after birth, and at 12, 24, 48, 72, 96, 120, 144, and 168 hours of age. Plasma was separated and a panel of steroid compounds was analyzed using liquid chromatography‐mass spectrometry. A nonlinear regression model was used to determine decay concentrations over time. Confidence intervals (CIs) were calculated and significance was set a P ≤ .05. Results Five compounds were identified: pregnenolone, progesterone, deoxycorticosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Pregnenolone and progesterone concentrations rapidly decreased by 24 hours of age and remained low throughout the first 7 days of life. Their half‐life (95% CI) was short at 3.7 (3.4, 4.0) and 4.5 (2.8, 6.1) hours, respectively. No statistical differences in the concentrations of these compounds were found between males and females. Conclusions and Clinical Relevance Progesterone might be a useful marker for identifying continuous endogenous production of neuroactive steroids in foals with suspected NMS and other neonatal diseases.

Background Clinicians vary markedly in their ability to detect murmurs during cardiac auscultation and identify the underlying pathological features. Deep learning approaches have shown promise in medicine by transforming collected data into clinically significant information. The objective of this research is to assess the performance of a deep learning algorithm to detect murmurs and clinically significant valvular heart disease using recordings from a commercial digital stethoscope platform. Methods and Results Using >34 hours of previously acquired and annotated heart sound recordings, we trained a deep neural network to detect murmurs. To test the algorithm, we enrolled 962 patients in a clinical study and collected recordings at the 4 primary auscultation locations. Ground truth was established using patient echocardiograms and annotations by 3 expert cardiologists. Algorithm performance for detecting murmurs has sensitivity and specificity of 76.3% and 91.4%, respectively. By omitting softer murmurs, those with grade 1 intensity, sensitivity increased to 90.0%. Application of the algorithm at the appropriate anatomic auscultation location detected moderate‐to‐severe or greater aortic stenosis, with sensitivity of 93.2% and specificity of 86.0%, and moderate‐to‐severe or greater mitral regurgitation, with sensitivity of 66.2% and specificity of 94.6%. Conclusions The deep learning algorithm’s ability to detect murmurs and clinically significant aortic stenosis and mitral regurgitation is comparable to expert cardiologists based on the annotated subset of our database. The findings suggest that such algorithms would have utility as front‐line clinical support tools to aid clinicians in screening for cardiac murmurs caused by valvular heart disease. Registration URL: https://clinicaltrials.gov; Unique Identifier: NCT03458806.

Abstract We compared four orthogonal technologies for sizing, counting, and phenotyping of extracellular vesicles (EVs) and synthetic particles. The platforms were: single‐particle interferometric reflectance imaging sensing (SP‐IRIS) with fluorescence, nanoparticle tracking analysis (NTA) with fluorescence, microfluidic resistive pulse sensing (MRPS), and nanoflow cytometry measurement (NFCM). EVs from the human T lymphocyte line H9 (high CD81, low CD63) and the promonocytic line U937 (low CD81, high CD63) were separated from culture conditioned medium (CCM) by differential ultracentrifugation (dUC) or a combination of ultrafiltration (UF) and size exclusion chromatography (SEC) and characterized by transmission electron microscopy (TEM) and Western blot (WB). Mixtures of synthetic particles (silica and polystyrene spheres) with known sizes and/or concentrations were also tested. MRPS and NFCM returned similar particle counts, while NTA detected counts approximately one order of magnitude lower for EVs, but not for synthetic particles. SP‐IRIS events could not be used to estimate particle concentrations. For sizing, SP‐IRIS, MRPS, and NFCM returned similar size profiles, with smaller sizes predominating (per power law distribution), but with sensitivity typically dropping off below diameters of 60 nm. NTA detected a population of particles with a mode diameter greater than 100 nm. Additionally, SP‐IRIS, MRPS, and NFCM were able to identify at least three of four distinct size populations in a mixture of silica or polystyrene nanoparticles. Finally, for tetraspanin phenotyping, the SP‐IRIS platform in fluorescence mode was able to detect at least two markers on the same particle, while NFCM detected either CD81 or CD63. Based on the results of this study, we can draw conclusions about existing single‐particle analysis capabilities that may be useful for EV biomarker development and mechanistic studies.

Background Current postresuscitative care after cardiac arrest (CA) does not address the cause of CA. We previously reported that asphyxial CA (ACA) and ventricular fibrillation CA (VFCA) elicit unique injury signatures. We hypothesized that the early cytokine profiles of the serum, heart, and brain differ in response to ACA versus VFCA. Methods and Results Adult male rats were subjected to 10 minutes of either ACA or VFCA. Naives and shams (anesthesia and surgery without CA) served as controls (n=12/group). Asphyxiation produced an ≈4‐minute period of progressive hypoxemia followed by a no‐flow duration of ≈6±1 minute. Ventricular fibrillation immediately induced no flow. Return of spontaneous circulation was achieved earlier after ACA compared with VFCA (42±18 versus 105±22 seconds; P

Abstract Demographic models enhance understanding of drivers of population growth and inform conservation efforts to prevent population declines and extinction. For species with complex life histories, however, parameterizing demographic models is challenging because some life stages can be difficult to study directly. Integrated population models (IPMs) empower researchers to estimate vital rates for organisms that have cryptic or widely dispersing early life stages by integrating multiple demographic data sources. For a stream‐inhabiting frog (Rana boylii) that is declining through much of its range in Oregon and California, USA, we collected egg‐mass counts and capture–mark–recapture data on adults from two populations in California to fit IPMs that estimate adult abundance and the survival rate of both marked and unobserved life stages. Estimates of adult abundance based on long‐term monitoring of egg‐mass counts showed that study populations fluctuated greatly inter‐annually but were stable at longer timescales (i.e., decades). Adult female survival during 5–6 yr of capture–mark–recapture study periods was nearly equal in each population. Survival rate of R. boylii eggs to the subadult stage is low on average (0.002) but highly variable among years depending on post‐oviposition stream flow. Population viability analysis showed that survival of adult and subadult life stages has the greatest proportional effect on population growth; the survival of egg and tadpole life stages, however, is more malleable by management interventions. For example, simulations showed head‐starting of tadpoles, salvaging stranded egg masses, and limiting aseasonal pulsed flows could dramatically reduce the threat of extirpation. This study demonstrates the value of integrating multiple demographic data sources to construct models of population dynamics in species with complex life histories.

Background Conventional "low‐density lipoprotein cholesterol (LDL‐C)" assays measure cholesterol content in both low‐density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of “LDL‐C” and corrected LDL‐C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline‐recommended LDL‐C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from “LDL‐C” to obtain corrected LDL‐C values (LDL‐Ccorr30). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual‐patient‐data meta‐analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow‐up). When comparing top versus bottom quartiles, the multivariable‐adjusted hazard ratio for cardiovascular disease was significant for “LDL‐C” (1.17; 95% CI, 1.05–1.31; P=0.005) but not for LDL‐Ccorr30 (1.07; 95% CI, 0.93–1.22; P=0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline‐recommended LDL‐C categories when using LDL‐Ccorr30 was assessed. In “LDL‐C” categories of 70 to

Abstract A fundamental question in forest insect ecology is the role of forest landscape structure, particularly the amount and spatial configuration of host tree species, in shaping the dynamics of recurring forest insect outbreaks. For forest tent caterpillar (FTC), independent studies do not converge on a singular conclusion, although all indicate that forest structure influences outbreak dynamics. These studies also vary in how they treat climate as a covariate. We evaluated the relative importance of host forest landscape composition and configuration, as well as climate, for their influence on FTC outbreak cycling in the twentieth century. We predicted that FTC outbreaks would exhibit greater synchrony and intensity within areas associated with higher abundance of host trees. We reconstructed FTC outbreaks from 1928 to 2006 using tree‐ring analysis within a well‐structured experimental landscape located in northwestern Ontario and northern Minnesota. Time‐series clustering and spatial nonparametric covariance were used to determine whether similarities in time series and patterns in spatial synchrony corresponded with land management history. Using constrained ordination, we compared statistical properties of outbreak time series to landscape variables representing host abundance, forest configuration, and climate. We found no evidence of climatic effects at the scale of this study, but a significant albeit small influence of landscape structure on outbreak dynamics. Outbreaks were more synchronous and more cyclic within managed zones containing a greater relative abundance of aspen and other hardwood host tree species, compared with the more conifer‐dominated Wilderness area. Yet, we also observed asynchronous outbreak dynamics across the study area, such that correlations with slower‐changing forest landscape variables varied starkly among outbreak pulses. Consequently, the strength of relationship between landscape variables and FTC outbreak patterns varied strongly through time—a result that may explain why short‐term studies yield conclusions that are at odds with one another. Our results speak to the importance of long time series, contrasting landscape structure, use of multivariate methods, and controlling for climatic variation when investigating the effects of forest landscape structure on the cyclic‐eruptive spatial dynamics for forest defoliators.

Abstract Planting wheat (Triticum aestivum L.) cultivars that carry the aluminum (Al) resistance gene TaAlmt1 is a potentially lower cost alternative to lime applications in acidic agricultural soils. However, the relative importance of TaAlmt1 expression and adaptedness (to regional environmental conditions) for preserving grain yield in acidic soils is not well understood. Adaptation trials were established in low‐pH soils to compare lime‐amended (YL) and unamended grain yield (YU) among regionally adapted spring wheat cultivars with and without TaAlmt1. Averaged across YL and YU (YAVG), yield of adapted TaAlmt1 carriers was similar to adapted noncarriers (p = .939) but greater than nonadapted noncarriers (p = .024). Soil pH‐driven spatial heterogeneity appears to inflate yield coefficients of variation and the probability of committing type II errors in cultivar yield comparisons. Our results support the use of YAVG as a suitability index and decision support tool for cultivar selection in acid‐affected soils.