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Plants and mycorrhizal fungi form mutualistic relationships that affect how resources flow between organisms and within ecosystems. Common mycorrhizal networks (CMNs) could facilitate preferential transfer of carbon and limiting nutrients, but this remains difficult to predict. Do CMNs favour fungal resource acquisition at the expense of plant resource demands (a fungi-centric view), or are they passive channels through which plants regulate resource fluxes (a plant-centric view)? We used stable isotope tracers (13CO2 and 15NH3), plant traits, and mycorrhizal DNA to quantify above- and below-ground carbon and nitrogen transfer between 18 plant species along a 520-km latitudinal gradient in the Pacific Northwest, USA. Plant functional type and tissue stoichiometry were the most important predictors of interspecific resource transfer. Of ‘donor’ plants, 98% were 13C-enriched, but we detected transfer in only 2% of ‘receiver’ plants. However, all donors were 15N-enriched and we detected transfer in 81% of receivers. Nitrogen was preferentially transferred to annuals (0.26 ± 0.50 mg N per g leaf mass) compared with perennials (0.13 ± 0.30 mg N per g leaf mass). This corresponded with tissue stoichiometry differences. Synthesis Our findings suggest that plants and fungi that are located closer together in space and with stronger demand for resources over time are more likely to receive larger amounts of those limiting resources. Read the free Plain Language Summary for this article on the Journal blog.

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

Applied research aims to generate knowledge that can be used to improve policy and practice. In the field of visitor use management (VUM), researchers and park managers seek to generate knowledge regarding specific dimensions of visitor experiences within and across parks and other kinds of protected areas. A wide variety of management-centric questions are addressed through VUM research. In this article, we argue that to answer such questions, VUM researchers and managers can use qualitative methods (independent of or coupled with quantitative methods) to deepen our knowledge about visitor experiences while improving visitor use management policies and practices. We present current qualitative research designed to aid in the management of parks, and future directions for qualitative inquiry. Existing qualitative research and future possibilities call to expand our collective understanding of what kind of knowledge “counts” in VUM research.

PURPOSE: The purpose of this study was to assess the association between antifungal susceptibility as measured by minimum inhibitory concentration (MIC) and clinical outcomes in fungal keratitis. METHODS: This pre-specified secondary analysis of the Mycotic Ulcer Treatment Trial II (MUTT II) involved patients with filamentous fungal keratitis presenting to Aravind Eye Hospitals in South India. Antifungal susceptibility testing for natamycin and voriconazole was performed on all samples with positive fungal culture results according to Clinical and Laboratory Standards Institute Guidelines. The relationship between MIC and clinical outcomes of best-corrected visual acuity, infiltrate or scar size, corneal perforation, need for therapeutic penetrating keratoplasty, and time to re-epithelialization were assessed. RESULTS: We obtained MIC values from 141 patients with fungal keratitis. The most commonly cultured organisms were Aspergillus (46.81%, n = 66) and Fusarium (44.68%, n = 63) species. Overall, there was no association between antifungal MICs and clinical outcomes. Subgroup analysis revealed that among Fusarium-positive cases, higher voriconazole MIC was correlated with worse three-month best-corrected visual acuity (p = 0.03), increased need for therapeutic penetrating keratoplasty (p = 0.04), and time to re-epithelialization (p = 0.03). No significant correlations were found among Aspergillus-positive cases. There were no significant correlations found between natamycin MIC and clinical outcomes among organism subgroups. CONCLUSIONS: Decreased susceptibility to voriconazole was associated with increased odds of requiring a therapeutic penetrating keratoplasty in Fusarium-positive cases. Susceptibility to natamycin was not associated with any of the measured outcomes.

Contemporary research has begun to show a strong relationship between movements and the perception of time. More specifically, concurrent movements serve to both bias and enhance time estimates. To explain these effects, we recently proposed a mechanism by which movements provide a secondary channel for estimating duration that is combined optimally with sensory estimates. However, a critical test of this framework is that by introducing noise into movements, sensory estimates of time should similarly become noisier. To accomplish this, we had human participants move a robotic arm while estimating intervals of time in either auditory or visual modalities (n = 24, ea.). Crucially, we introduced an artificial tremor in the arm while subjects were moving, that varied across three levels of amplitude (1-3 N) or frequency (4-12 Hz). The results of both experiments revealed that increasing the frequency of the tremor led to noisier estimates of duration. Further, the effect of noise varied with the base precision of the interval, such that a naturally less precise timing (i.e., visual) was more influenced by the tremor than a naturally more precise modality (i.e., auditory). To explain these findings, we fit the data with a recently developed drift-diffusion model of perceptual decision-making, in which the momentary, within-trial variance was allowed to vary across conditions. Here, we found that the model could recapitulate the observed findings, further supporting the theory that movements influence perception directly. Overall, our findings support the proposed framework, and demonstrate the utility of inducing motor noise via artificial tremors.

Microbial carbon use efficiency (CUE) affects the fate and storage of carbon in terrestrial ecosystems, but its global importance remains uncertain. Accurately modeling and predicting CUE on a global scale is challenging due to inconsistencies in measurement techniques and the complex interactions of climatic, edaphic, and biological factors across scales. The link between microbial CUE and soil organic carbon relies on the stabilization of microbial necromass within soil aggregates or its association with minerals, necessitating an integration of microbial and stabilization processes in modeling approaches. In this perspective, we propose a comprehensive framework that integrates diverse data sources, ranging from genomic information to traditional soil carbon assessments, to refine carbon cycle models by incorporating variations in CUE, thereby enhancing our understanding of the microbial contribution to carbon cycling.

BackgroundRising overdose deaths globally and increased social isolation during the coronavirus disease 2019 (COVID-19) pandemic may have disproportionately impacted people with human immunodeficiency virus (PWH) with substance use disorders (SUD). We examined trends in SUD risk among PWH before and after the COVID-19 shelter-in-place (SIP) mandate.MethodsData were collected between 2018 and 2022 among PWH enrolled across 8 US sites in the Centers for AIDS Research Network of Integrated Clinical Systems cohort. We evaluated changes in moderate/high SUD risk after SIP using interrupted time series analyses.ResultsThere were 7126 participants, including 21 741 SUD assessments. The median age was 51 (interquartile range, 39-58) years; 12% identified as Hispanic or Latino/Latina, 46% Black/African American, and 46% White. Moderate/high SUD risk increased continuously after the pandemic's onset, with 43% (95% confidence interval [CI], 40%-46%) endorsing moderate/high SUD risk post-SIP, compared to 24% (95% CI, 22%-26%) pre-SIP (P < .001). There were increases in the use of heroin, methamphetamine, and fentanyl, and decreases in prescription opioids and sedatives post-SIP. Further, there was a decrease in reported substance use treatment post-SIP compared to pre-SIP (P = .025).ConclusionsThe rising prevalence of SUD through late 2022 could be related to an increase in isolation and reduced access to substance use and HIV treatment caused by disruptions due to COVID-19. A renewed investment in integrated substance use treatment is vital to address the combined epidemics of substance use and HIV following the COVID-19 pandemic and to support resilience in the face of future disruptions.

IntroductionGlobalization has increased the importance of multicultural research to address health disparities and improve healthcare outcomes for underrepresented communities. The International Nursing Network for HIV Research (The Network) serves as a platform for researchers to collaborate on cross-cultural and cross-national HIV studies. This article discusses the Network's approach to overcoming barriers in multicultural and multinational research in a qualitative context.MethodsThe network created a protocol to guide decision-making throughout the translation process of qualitative data collected from participants in their native languages. The protocol includes aspects of why, when, what, who, how, where, and by what means the translation is completed.ResultsThe protocol has allowed researchers to enhance the validity, reliability, and cultural sensitivity of translation process, ensuring the clarity and impact of their research findings.DiscussionRigorous translation practices promote cross-cultural understanding and respect for participants' perspectives, fostering global collaborations and knowledge exchange.

Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these reactive states, the cell biology underlying inflammatory reactive astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes to identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization of endolysosomal compartments, decreased autophagic flux, and increased exocytosis of certain endolysosomal cargos. Through endolysosomal proteomics, we identified and focused on one such cargo-IL-32, a disease-associated pro-inflammatory cytokine not present in rodents, whose secretion mechanism is not well understood. We found that IL-32 was partially secreted in extracellular vesicles likely to be exosomes. Furthermore, we found that IL-32 was involved in the polarization of inflammatory reactive astrocyte states and was upregulated in astrocytes in multiple sclerosis lesions. We believe that our results advance our understanding of cell biological pathways underlying inflammatory reactive astrocyte phenotypes and identify potential therapeutic targets.

An increasing amount of Californias landscape has burned in wildfires in recent decades, in conjunction with increasing temperatures and vapor pressure deficit due to climate change. As the wildland-urban interface expands, more people are exposed to and harmed by these extensive wildfires, which are also eroding the resilience of terrestrial ecosystems. With future wildfire activity expected to increase, there is an urgent demand for solutions that sustain healthy ecosystems and wildfire-resilient human communities. Those who manage disaster response, landscapes, and biodiversity rely on mapped projections of how fire activity may respond to climate change and other human factors. California wildfire is complex, however, and climate-fire relationships vary across the state. Given known geographical variability in drivers of fire activity, we asked whether the geographical extent of fire models used to create these projections may alter the interpretation of predictions. We compared models of fire occurrence spanning the entire state of California to models developed for individual ecoregions and then projected end-of-century future fire patterns under climate change scenarios. We trained a Maximum Entropy model with fire records and hydroclimatological variables from recent decades (1981 to 2010) as well as topographic and human infrastructure predictors. Results showed substantial variation in predictors of fire probability and mapped future projections of fire depending upon geographical extents of model boundaries. Only the ecoregion models, accounting for the unique patterns of vegetation, climate, and human infrastructure, projected an increase in fire in most forested regions of the state, congruent with predictions from other studies.

BACKGROUND: Low back pain (LBP) is a significant public health problem that can result in physical disability and financial burden for the individual and society. Physical therapy is effective for managing LBP and includes evaluation of posture and movement, interventions directed at modifying posture and movement, and prescription of exercises. However, physical therapists have limited tools for objective evaluation of low back posture and movement and monitoring of exercises, and this evaluation is limited to the time frame of a clinical encounter. There is a need for a valid tool that can be used to evaluate low back posture and movement and monitor exercises outside the clinic. To address this need, a fabric-based, wearable sensor, Motion Tape (MT), was developed and adapted for a low back use case. MT is a low-profile, disposable, self-adhesive, skin-strain sensor developed by spray coating piezoresistive graphene nanocomposites directly onto commercial kinesiology tape. OBJECTIVE: The objectives of this study were to (1) validate MT for measuring low back posture and movement and (2) assess the acceptability of MT for users. METHODS: A total of 10 participants without LBP were tested. A 3D optical motion capture system was used as a reference standard to measure low back kinematics. Retroreflective markers and a matrix of MTs were placed on the low back to measure kinematics (motion capture) and strain (MT) simultaneously during low back movements in the sagittal, frontal, and axial planes. Cross-correlation coefficients were calculated to evaluate the concurrent validity of MT strain in reference motion capture kinematics during each movement. The acceptability of MT was assessed using semistructured interviews conducted with each participant after laboratory testing. Interview data were analyzed using rapid qualitative analysis to identify themes and subthemes of user acceptability. RESULTS: Visual inspection of concurrent MT strain and kinematics of the low back indicated that MT can distinguish between different movement directions. Cross-correlation coefficients between MT strain and motion capture kinematics ranged from -0.915 to 0.983, and the strength of the correlations varied across MT placements and low back movement directions. Regarding user acceptability, participants expressed enthusiasm toward MT and believed that it would be helpful for remote interventions for LBP but provided suggestions for improvement. CONCLUSIONS: MT was able to distinguish between different low back movements, and most MTs demonstrated moderate to high correlation with motion capture kinematics. This preliminary laboratory validation of MT provides a basis for future device improvements, which will also involve testing in a free-living environment. Overall, users found MT acceptable for use in physical therapy for managing LBP.

ObjectivesA subset of laryngeal squamous cell carcinoma (LSCC) patients undergoing larynx preserving treatment ultimately require total laryngectomy (TL) for oncologic or functional reasons. This study aims to identify TL risk factors in these patients.MethodsRetrospective cohort study using Veterans Affairs (VA) database. T1-T4 LSCC cases treated with primary radiotherapy (XRT) or chemoradiotherapy (CRT) were assessed for TL and recurrence. Binary logistic and Cox regression and Kaplan-Meier analyses were implemented.ResultsOf 5390 cases, 863 (16.0%) underwent TL. On multivariable analysis, age (adjusted odds ratio: 0.97 [0.96-0.98]; p T1 disease (T2, 1.76 [1.44-2.17]; p

Background: Growing data indicates that thiamine deficiency occurs during acute illness in the absence of alcohol use disorder. Our primary objective was to measure clinical factors associated with thiamine deficiency in patients with sepsis, diabetic ketoacidosis, and oncologic emergencies.Methods: This was an analysis of pooled data from cross-sectional studies that enrolled adult emergency department (ED) patients at a single academic center with suspected sepsis, diabetic ketoacidosis, and oncologic emergencies. We excluded patients who had known alcohol use disorder or who had received ED thiamine treatment prior to enrollment. Investigators collected whole blood thiamine levels in addition to demographics, clinical characteristics, and available biomarkers. We defined thiamine deficiency as a whole blood thiamine level below the normal reference range and modeled the adjusted association between this outcome and age.Results: There were 269 patients, of whom the average age was 57 years; 46% were female, and 80% were Black. Fifty-five (20.5%) patients had thiamine deficiency. In univariate analysis, age >60 years (odds ratio [OR] 2.5, 95% confidence interval [CI], 1.3–4.5), female gender (OR 1.9, 95% CI 1.0–3.4), leukopenia (OR 4.9, 95% CI 2.3–10.3), moderate anemia (OR 2.8, 95% CI 1.5–5.3), and hypoalbuminemia (OR 2.2, 95% CI 1.2–4.1) were associated with thiamine deficiency. In adjusted analysis, thiamine deficiency was significantly higher in females (OR 2.1, 95% CI 1.1–4.1), patients >60 years (OR 2.0, 95% CI 1.0–3.8), and patients with leukopenia (OR 5.1, 95% CI 2.3–11.3).Conclusion: In this analysis, thiamine deficiency was common and was associated with advanced age, female gender, and leukopenia.

Media exposure to graphic images of violence has proliferated in contemporary society, particularly with the advent of social media. Extensive exposure to media coverage immediately after the 9/11 attacks and the Boston Marathon bombings (BMB) was associated with more early traumatic stress symptoms; in fact, several hours of BMB-related daily media exposure was a stronger correlate of distress than being directly exposed to the bombings themselves. Researchers have replicated these findings across different traumatic events, extending this work to document that exposure to graphic images is independently and significantly associated with stress symptoms and poorer functioning. The media exposure-distress association also appears to be cyclical over time, with increased exposure predicting greater distress and greater distress predicting more media exposure following subsequent tragedies. The war in Israel and Gaza, which began on October 7, 2023, provides a current, real-time context to further explore these issues as journalists often share graphic images of death and destruction, making media-based graphic images once again ubiquitous and potentially challenging public well-being. For individuals sharing an identity with the victims or otherwise feeling emotionally connected to the Middle East, it may be difficult to avoid viewing these images. Through a review of research on the association between exposure to graphic images and public health, we discuss differing views on the societal implications of viewing such images and advocate for media literacy campaigns to educate the public to identify mis/disinformation and understand the risks of viewing and sharing graphic images with others.

This study examines coral reef management strategies using case studies from Maui, Fiji, and Florida. Through interviews and observations, the investigation explores community-driven initiatives and scientific efforts to conserve coral reefs. In Maui, holistic projects like Pacific Whale Foundation's Mauka to Makai program respond to environmental challenges. In Fiji, organizations like Coral Gardeners and Corals for Conservation employ tailored active restoration methods. Meanwhile, ongoing efforts in Florida underscore the urgency of addressing climate change. These findings emphasize the importance of global collaboration and proactive measures to ensure the resilience of coral reef ecosystems. Digital communication through photography and videography will reveal monitoring plans to combat the local stressors to coral reefs in each region.Please see media created for this project here:   bit.ly/3VJHdMJ

Activation of PINK1 and Parkin in response to mitochondrial damage initiates a response that includes phosphorylation of RAB7A at Ser72. Rubicon is a RAB7A binding negative regulator of autophagy. The structure of the Rubicon:RAB7A complex suggests that phosphorylation of RAB7A at Ser72 would block Rubicon binding. Indeed, in vitro phosphorylation of RAB7A by TBK1 abrogates Rubicon:RAB7A binding. Pacer, a positive regulator of autophagy, has an RH domain with a basic triad predicted to bind an introduced phosphate. Consistent with this, Pacer-RH binds to phosho-RAB7A but not to unphosphorylated RAB7A. In cells, mitochondrial depolarization reduces Rubicon:RAB7A colocalization whilst recruiting Pacer to phospho-RAB7A-positive puncta. Pacer knockout reduces Parkin mitophagy with little effect on bulk autophagy or Parkin-independent mitophagy. Rescue of Parkin-dependent mitophagy requires the intact pRAB7A phosphate-binding basic triad of Pacer. Together these structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation.

The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was

INTRODUCTION: Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. METHODS: OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). RESULTS: The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279 m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). CONCLUSIONS: Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov Graphical abstract available for this article.

The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimers disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, and the potential for coupling between the entry and nucleation mechanisms has been little explored. We found that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes. This in turn leads to lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin-3, to the lysosomal membrane. These observations are consistent with nanoscale damage of the lysosomal membrane. Live cell imaging and STORM superresolution microscopy further show that the nucleation of cytosolic tau occurs primarily at the lysosome membrane under these conditions. These data suggest that tau seeds escape from lysosomes via nanoscale damage rather than wholesale rupture and that nucleation of cytosolic tau commences as soon as tau fibril ends emerge from the lysosomal membrane.

Estimates of the economic impact of widespread, long duration (WLD) power interruptions can be used to prioritize and justify significant investments in power system resilience. This report presents estimates of this type for WLDs originating within the Commonwealth Edison (ComEd) service territory. The intended audience for this research includes utility executives and technical staff, regulators, and government agencies.This project involved surveying ComEd customers to understand how they might respond when confronted with a WLD power interruption. The research team used the survey responses to calibrate a state-of-the-art regional economic model (“POET”) to estimate economic impacts to households and 38 industry sectors across 17 impacted micro-regions (individual counties or aggregations of counties) within ComEd’s service territory and beyond. We ran one-day, three-day, and 14-day interruption duration scenarios each with varying geographic extents as well as estimated the benefits of deploying additional backup generation across the service territory. The results were then compared to a “business as usual” scenario assuming that no interruption occurred. There are six key findings from this analysis:-There may be significant losses to gross output (business revenue), gross domestic product, and household consumption during WLD interruptions, especially multi-day interruptions that occur across all of ComEd, Cook county, or the suburbs of Chicago.-The wholesale trade and transportation sectors appear to be highly sensitive to power interruptions—losses to these sectors are large relative to the losses observed across the entire economy.-Several sector-region combinations—e.g., the transportation sector in Cook county—are very sensitive to interruptions.-High-income households experience proportionately larger losses to consumption during a one-day power interruption, but low-income households experience proportionately larger losses during the longest power interruptions.-Increasing the amount of backup generation deployed across ComEd’s service territory provides significant net benefits to system-wide gross domestic product, gross output, and household consumption relative to the existing amount of backup generation already being used.-Some micro-regions (e.g., Dekalb and Kendall counties), sectors (e.g., wholesale trade, transportation), and low-income households in Cook county may especially benefit from targeted resilience interventions.We recommend that decision-makers consider running cost-benefit analyses using each of the economic metrics presented in this report independent of one another to evaluate the robustness of the insights that each of these estimates may provide. In addition to this report, we developed a tool that will allow ComEd staff and other decision-makers to visualize the full suite of results using an easy-to-interpret, user interface. We hope that the findings from this research effort will provide valuable insights to ComEd, policymakers across Illinois, and other stakeholders who have an interest in the resilience of the power system.

Background/objectivesTrait mindfulness (TM) may protect against post-trauma mental health ailments and related impairment. Few studies have evaluated this association in the context of collective traumas using representative samples or longitudinal designs.Design/methodWe explored relationships between TM and collective trauma-related outcomes in a prospective, representative, probability-based sample of 1846 U.S. Gulf Coast residents repeatedly exposed to catastrophic hurricanes, assessed twice during the COVID-19 outbreak (Wave 1: 5/14/20-5/27/20; Wave 2: 12/21/21-1/11/22). Generalized estimating equations examined longitudinal relationships between TM, COVID-19-related fear/worry, hurricane-related fear/worry, global distress, and functional impairment; ordinary least squares regression analyses examined the cross-sectional association between TM and COVID-19-related posttraumatic stress symptoms (PTSS) at Wave 1. Event-related stressor exposure was explored as a moderator.ResultsIn covariate-adjusted models including pre-event mental health ailments and demographics, TM was negatively associated with COVID-19-related fear/worry, hurricane-related fear/worry, global distress, and functional impairment over time; in cross-sectional analyses, TM was negatively associated with COVID-19-related PTSS. TM moderated the relationship between COVID-19 secondary stressor exposure (e.g., lost job/wages) and both global distress and functional impairment over time.ConclusionsResults suggest TM may buffer adverse psychosocial outcomes following collective trauma, with some evidence TM may protect against negative effects of secondary stressor exposure.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the WIN site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

The direction of individual B8 solar neutrinos has been reconstructed using the SNO+ liquid scintillator detector. Prompt, directional Cherenkov light was separated from the slower, isotropic scintillation light using time information, and a maximum likelihood method was used to reconstruct the direction of individual scattered electrons. A clear directional signal was observed, correlated with the solar angle. The observation was aided by a period of low primary fluor concentration that resulted in a slower scintillator decay time. This is the first time that event-by-event direction reconstruction in high light-yield liquid scintillator has been demonstrated in a large-scale detector.

PURPOSE: This study sought to identify the sources of differential performance and misclassification error among local (Indian) and external (non-Indian) corneal specialists in identifying bacterial and fungal keratitis based on corneal photography. METHODS: This study is a secondary analysis of survey data assessing the ability of corneal specialists to identify acute bacterial versus fungal keratitis by using corneal photography. One-hundred images of 100 eyes from 100 patients with acute bacterial or fungal keratitis in South India were previously presented to an international cohort of cornea specialists for interpretation over the span of April to July 2021. Each expert provided a predicted probability that the ulcer was either bacterial or fungal. Using these data, we performed multivariable linear regression to identify factors predictive of expert performance, accounting for primary practice location and surrogate measures to infer local fungal ulcer prevalence, including locality, latitude, and dew point. In addition, Brier score decomposition was used to determine experts reliability (calibration) and resolution (boldness) and were compared between local (Indian) and external (non-Indian) experts. RESULTS: Sixty-six experts from 16 countries participated. Indian practice location was the only independently significant predictor of performance in multivariable linear regression. Resolution among Indian experts was significantly better (0.08) than among non-Indian experts (0.01; P < 0.001), indicating greater confidence in their predictions. There was no significant difference in reliability between the two groups ( P = 0.40). CONCLUSION: Local cornea experts outperformed their international counterparts independent of regional variability in tropical risk factors for fungal keratitis. This may be explained by regional characteristics of infectious ulcers with which local corneal specialists are familiar.

Introduction: Virtual interviews (VI) are now a permanent part of pediatric emergency medicine (PEM) recruitment, especially given the cost and equity advantages. Yet inability to visit programs in person can impact decision-making, leading applicants to apply to more programs. Moreover, the cost advantages of VI may encourage applicants to apply to programs farther away than they might otherwise have been willing or able to travel. This could create unnecessary strain on programs. We conducted this study to determine whether PEM fellowship applicants would apply to a larger number of programs and in different geographic patterns with VI (2020 and 2021) as compared to in-person interviews (2018 and 2019).Methods: We conducted an anonymous national survey of all PEM fellows comparing two cohorts: current fellows who interviewed in-person (applied in 2018/2019) and fellows who underwent VIs in 2020/ 2021 (current fellows and those recently matched in 2021). The study took place in March–April 2022. Questions focused on geographic considerations during interviews and the match. We used descriptive statistics, chi-square and t-tests for analysis.Results: Overall response rate was 42% (231/550); 32% (n = 74) interviewed in person and 68% (n = 157) virtually. Fellows applied to a median of 4/6 geographic regions (interquartile range 2, 5). Most applied for fellowship both in the same region as residency (216, 93%) and outside (192, 83%). Only the Pacific region saw a statistically significant increase in applicants during VI (59.9% vs 43.2%, P = 0.02). There was no statistical difference in the number of programs applied to during in-person vs VI (mean difference (95% confidence interval 0.72, −2.8 – 4.2). A majority matched in their preferred state both during VI (60.4%) and in-person interviews (65.7%). The difference was not statistically significant (P = 0.45).Conclusion: While more PEM fellowship applicants applied outside the geographic area where their residency was and to the Pacific region, there was no overall increase in the number of programs or geographic areas PEM applicants applied to during VI as compared to in-person interview seasons. As this was the first two years of VI, ongoing data collection will further identify trends and the impactof VI.

The emergence of infectious diseases presents a significant global health, economic, and security risk. Climate change can unexpectedly lead to the spread of pathogens, vectors, or hosts into new areas, contributing to the rise of infectious diseases. Surveillance plays a crucial role in monitoring disease trends and implementing control strategies. In this study, we document the first discovery of Heterobilharzia americana, a parasitic schistosome of mammals and its intermediate hosts Galba cubensis and Galba humilis along the banks of the Colorado River in California. We conducted multiple samplings of snails from various locations in the region with a previous history of canine schistosomiasis. Nucleotide sequencing of the multiple regions of the snails and parasites DNA revealed the coexistence of G. cubensis and G. humilis, both infected with H. americana. Phylogenetic analyses further validate the presence of H. americana in California, suggesting a wider distribution than previously reported. Our findings have implications for public health, veterinary medicine, and biodiversity conservation, contributing to developing effective control strategies to prevent the spread of this emerging infectious disease.

BackgroundIndividuals confronting health threats may display an optimistic bias such that judgments of their risk for illness or death are unrealistically positive given their objective circumstances.PurposeWe explored optimistic bias for health risks using k-means clustering in the context of COVID-19. We identified risk profiles using subjective and objective indicators of severity and susceptibility risk for COVID-19.MethodsBetween 3/18/2020-4/18/2020, a national probability sample of 6,514 U.S. residents reported both their subjective risk perceptions (e.g., perceived likelihood of illness or death) and objective risk indices (e.g., age, weight, pre-existing conditions) of COVID-19-related susceptibility and severity, alongside other pandemic-related experiences. Six months later, a subsample (N = 5,661) completed a follow-up survey with questions about their frequency of engagement in recommended health protective behaviors (social distancing, mask wearing, risk behaviors, vaccination intentions).ResultsThe k-means clustering procedure identified five risk profiles in the Wave 1 sample; two of these demonstrated aspects of optimistic bias, representing almost 44% of the sample. In OLS regression models predicting health protective behavior adoption at Wave 2, clusters representing individuals with high perceived severity risk were most likely to report engagement in social distancing, but many individuals who were objectively at high risk for illness and death did not report engaging in self-protective behaviors.ConclusionsObjective risk of disease severity only inconsistently predicted health protective behavior. Risk profiles may help identify groups that need more targeted interventions to increase their support for public health policy and health enhancing recommendations more broadly.

Fluorescent proteins (FPs) are ubiquitous tools in research, yet their endogenous functions in nature are poorly understood. In this work, we describe a combination of functions for FPs in a clade of intertidal sea anemones whose FPs control a genetic color polymorphism together with the ability to combat oxidative stress. Focusing on the underlying genetics of a fluorescent green "Neon" color morph, we show that allelic differences in a single FP gene generate its strong and vibrant color, by increasing both molecular brightness and FP gene expression level. Natural variation in FP sequences also produces differences in antioxidant capacity. We demonstrate that these FPs are strong antioxidants that can protect live cells against oxidative stress. Finally, based on structural modeling of the responsible amino acids, we propose a model for FP antioxidant function that is driven by molecular surface charge. Together, our findings shed light on the multifaceted functions that can co-occur within a single FP and provide a framework for studying the evolution of fluorescence as it balances spectral and physiological functions in nature.

It remains poorly understood how SARS-CoV-2 infection influences the physiological host factors important for aerosol transmission. We assessed breathing pattern, exhaled droplets, and infectious virus after infection with Alpha and Delta variants of concern (VOC) in the Syrian hamster. Both VOCs displayed a confined window of detectable airborne virus (24-48 hr), shorter than compared to oropharyngeal swabs. The loss of airborne shedding was linked to airway constriction resulting in a decrease of fine aerosols (1-10 µm) produced, which are suspected to be the major driver of airborne transmission. Male sex was associated with increased viral replication and virus shedding in the air. Next, we compared the transmission efficiency of both variants and found no significant differences. Transmission efficiency varied mostly among donors, 0-100% (including a superspreading event), and aerosol transmission over multiple chain links was representative of natural heterogeneity of exposure dose and downstream viral kinetics. Co-infection with VOCs only occurred when both viruses were shed by the same donor during an increased exposure timeframe (24-48 hr). This highlights that assessment of host and virus factors resulting in a differential exhaled particle profile is critical for understanding airborne transmission.

Poor bone quality is a major factor in skeletal fragility in elderly individuals. The molecular mechanisms that establish and maintain bone quality, independent of bone mass, are unknown but are thought to be primarily determined by osteocytes. We hypothesize that the age-related decline in bone quality results from the suppression of osteocyte perilacunar/canalicular remodeling (PLR), which maintains bone material properties. We examined bones from young and aged mice with osteocyte-intrinsic repression of TGFβ signaling (TβRIIocy-/-) that suppresses PLR. The control aged bone displayed decreased TGFβ signaling and PLR, but aging did not worsen the existing PLR suppression in male TβRIIocy-/- bone. This relationship impacted the behavior of collagen material at the nanoscale and tissue scale in macromechanical tests. The effects of age on bone mass, density, and mineral material behavior were independent of osteocytic TGFβ. We determined that the decline in bone quality with age arises from the loss of osteocyte function and the loss of TGFβ-dependent maintenance of collagen integrity.

Wildfires have become more frequent and intense due to climate change and outdoor wildfire fine particulate matter (PM2.5) concentrations differ from relatively smoothly varying total PM2.5. Thus, we introduced a conceptual model for computing long-term wildfire PM2.5 and assessed disproportionate exposures among marginalized communities. We used monitoring data and statistical techniques to characterize annual wildfire PM2.5 exposure based on intermittent and extreme daily wildfire PM2.5 concentrations in California census tracts (2006 to 2020). Metrics included: 1) weeks with wildfire PM2.5 < 5 μg/m3; 2) days with non-zero wildfire PM2.5; 3) mean wildfire PM2.5 during peak exposure week; 4) smoke waves (≥2 consecutive days with

BACKGROUND: It remains uncertain which endothelial keratoplasty (EK) technique yields the best outcomes while maintaining safety, particularly in eyes with coexisting ocular conditions. Moreover, the impact of endothelial cell loss (ECL) on long-term graft survival requires further investigation. Adjuvant ripasudil, a rho kinase inhibitor, may address the challenge of ECL in corneal transplantation. This paper presents the protocol for the Descemet Endothelial Thickness Comparison Trial 1 (DETECT 1), a multicentre, outcome-masked, randomised, placebo-controlled, four-arm clinical trial. METHODS: A total of 160 eligible patients with endothelial dysfunction will be enrolled from five participating sites in the USA. The patients will be randomly assigned in a 2×2 factorial design to one of the following treatment groups: group 1-ultrathin Descemet stripping endothelial keratoplasty (UT-DSAEK) plus topical ripasudil 0.4%; group 2-UT-DSAEK plus topical placebo; group 3-Descemet membrane endothelial keratoplasty (DMEK) plus topical ripasudil 0.4% and group 4-DMEK plus topical placebo. Primary outcomes include the best spectacle-corrected visual acuity at 12 months and ECL at 12 months. Secondary outcomes include visual acuity at different time points, vision-related quality of life, endothelial cell morphology and cost-effectiveness. RESULTS: The study outcomes will be analysed using mixed effects linear regression models, taking into account the treatment arms and relevant covariates. Adverse events, including rebubble procedures, graft failure and graft rejection, will be documented and analysed using appropriate statistical methods. CONCLUSION: DETECT I aims to provide evidence on the comparative effectiveness of UT-DSAEK and DMEK, as well as the potential benefits of adjuvant topical ripasudil in reducing ECL. The results of this trial will contribute to optimising corneal transplantation techniques and improving long-term graft survival, while also exploring the cost-effectiveness of these interventions. Dissemination of findings through peer-reviewed publications and national/international meetings will facilitate knowledge translation and guide clinical practice in the field of corneal transplantation. ETHICS AND DISSEMINATION: A data and safety monitoring committee (DSMC) has been empaneled by the NEI.All study protocols will be subject to review and approval by WCG IRB as the single IRB of record.This study will comply with the National Institute of Health (NIH) Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Data from the trial will be made available on reasonable request.

Introduction: Seizures are a common presenting complaint and account for approximately 1% of total emergency department (ED) visits. Seizures are especially common in children less than five years old as they have a lower seizure threshold as compared to adults. One potentially dangerous etiology that is far less common, especially in children, is thyroid storm, the extreme manifestationof hyperthyroidism.Case Report: We describe the case of a 3-year-old girl who presented to the ED with an afebrile seizure but was found to be in thyroid storm. This case should serve as a reminder for emergency physicians to consider thyroid disease when evaluating patients presenting with seizures.Conclusion: Although most pediatric seizures are self-limited and frequently benign, it is imperative that the emergency physician evaluate for and rule out any potentially associated dangerous conditions such as thyroid storm.

Reductions in nonresidential water demand during the COVID-19 pandemic highlighted the importance of understanding how water age impacts drinking water quality and microbiota in piped distribution systems. Using benchtop model distribution systems, we aimed to characterize the impacts of elevated water age on microbiota in bulk water and pipe wall biofilms. Five replicate constant-flow reactors were fed with municipal chloraminated tap water for 6 months prior to building closures and 7 months after. After building closures, chloramine levels entering the reactors dropped; in the reactor bulk water and biofilms the mean cell counts and ATP concentrations increased over an order of magnitude while the detection of opportunistic pathogens remained low. Water age, and the corresponding physicochemical changes, strongly influenced microbial abundance and community composition. Differential initial microbial colonization also had a lasting influence on microbial communities in each reactor (i.e., historical contingency).

Proposed large-scale electric generation and storage projects must apply for interconnection to the bulk power system via interconnection queues. While most projects that apply for interconnection are not subsequently built, data from these queues nonetheless provide a general indicator for mid-term trends in developer interest. Berkeley Lab compiled and analyzed data from all seven ISOs/RTOs in concert with 35 non-ISO utilities, representing an estimated 85% of all U.S. electricity load. We include all "active" projects in these generation interconnection queues through the end of 2022, as well as data on "operational" and "withdrawn" projects where those data are available.We find that the amount of new electric capacity in these queues is growing dramatically, with over 2,000 gigawatts (GW) of total generation and storage capacity now seeking connection to the grid (over 95% of which is for zero-carbon resources like solar, wind, and battery storage). Solar (947 GW) and battery storage (~680 GW) are – by far – the fastest growing resources in the queues; combined they accounted for over 80% of new capacity entering the queues in 2022. Substantial wind (300 GW) capacity is also seeking interconnection, 38% of which is for offshore projects (113 GW). In total, about 1,250 GW of zero-carbon generating capacity is currently seeking transmission access, as is 82 GW of natural gas capacity. Hybrids projects (co-locating multiple generation and/or storage types) comprise a large – and increasing – share of proposed projects, particularly in CAISO and the non-ISO West. 457 GW of solar hybrids (primarily solar+battery) and 24 GW of wind hybrids are currently active in the queues; over half of battery storage in the queues is paired with generation.However, much of this proposed capacity will be withdrawn from the queues and not built. Among a subset of queues for which data are available, only 21% of the projects (and 14% of capacity) seeking connection from 2000 to 2017 have been built as of the end of 2022. Additionally, interconnection wait times are on the rise: The typical duration from connection request to commercial operation increased from

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

BACKGROUND: How novel phenotypes originate from conserved genes, processes, and tissues remains a major question in biology. Research that sets out to answer this question often focuses on the conserved genes and processes involved, an approach that explicitly excludes the impact of genetic elements that may be classified as clade-specific, even though many of these genes are known to be important for many novel, or clade-restricted, phenotypes. This is especially true for understudied phyla such as mollusks, where limited genomic and functional biology resources for members of this phylum have long hindered assessments of genetic homology and function. To address this gap, we constructed a chromosome-level genome for the gastropod Berghia stephanieae (Valdés, 2005) to investigate the expression of clade-specific genes across both novel and conserved tissue types in this species. RESULTS: The final assembled and filtered Berghia genome is comparable to other high-quality mollusk genomes in terms of size (1.05 Gb) and number of predicted genes (24,960 genes) and is highly contiguous. The proportion of upregulated, clade-specific genes varied across tissues, but with no clear trend between the proportion of clade-specific genes and the novelty of the tissue. However, more complex tissue like the brain had the highest total number of upregulated, clade-specific genes, though the ratio of upregulated clade-specific genes to the total number of upregulated genes was low. CONCLUSIONS: Our results, when combined with previous research on the impact of novel genes on phenotypic evolution, highlight the fact that the complexity of the novel tissue or behavior, the type of novelty, and the developmental timing of evolutionary modifications will all influence how novel and conserved genes interact to generate diversity.

The objective of this study was to identify the prevalence and correlates of phosphatidylethanol (PEth) levels suggestive of unhealthy alcohol use among women living with and without HIV who self-reported no or low-risk drinking. We analyzed data from a cross-sectional study among women enrolled in the San Francisco Bay Area site of the Womens Interagency HIV Study (WIHS). Between October 2017 and March 2018, PEth was tested from dried blood spots in 192 women enrolled in the San Francisco site of the WIHS. Using multivariable logistic regression, we identified the correlates of PEth levels suggestive of unhealthy alcohol use (>50 ng/ml) among the 168 women who reported no or low-risk drinking ( 1 (aOR = 3.10, 95% CI = 1.18-8.13), higher high-density lipoprotein levels (aOR = 1.31 per 10 mg/dL increase, 95% CI = 1.01-1.70), and consuming a greater number of drinks per week in the past six months (aOR = 1.40, 95% CI = 1.10-1.78). Nearly a third of women in this study had PEth levels suggestive of unhealthy alcohol use and potentially under-reported their use. To optimize alcohol related health care, there is a need to consider approaches to improve ascertainment of unhealthy alcohol use, especially among Black/African American women and those living with liver disease, so that interventions can be initiated.

BACKGROUND: Almost half of all women in the US experience intimate partner violence (IPV) in their lifetime. The US Preventive Services Task Force recommends IPV screening paired with intervention for women of reproductive age. We aim to understand clinical practices and policies that are beneficial, detrimental, or insufficient to support survivors of IPV in a safety-net healthcare system. METHODS: We sampled 45 women who were 18-64 years old, had experienced IPV within the prior year and were patients in the San Francisco Health Network. We conducted in-depth, semi-structured interviews to elicit their perspectives on disclosing IPV and obtaining support within the healthcare system. We analyzed our data using thematic analysis and grounded theory practices informed by ecological systems theory. FINDINGS: We identified four themes regarding factors that impeded or facilitated discussing and addressing IPV across interpersonal and systemic levels relating to relationship-building, respect, autonomy and resources. (1) Interpersonal barriers included insufficient attention to relationship-building, lack of respect or concern for survivor circumstances, and feeling pressured to disclose IPV or to comply with clinicians recommended interventions. (2) Interpersonal facilitators consisted of patient-centered IPV inquiry, attentive listening, strength-based counseling and transparency regarding confidentiality. (3) Systemic barriers such as visit time limitations, clinician turn-over and feared loss of autonomy from involvement of governmental systems leading to separation from children or harm to partners, negatively affected interpersonal dynamics. (4) Systemic facilitators involved provision of resources through IPV universal education, on-site access to IPV services, and community partnerships. CONCLUSIONS: Women experiencing IPV in our study reported that relationship-building, respect, autonomy, and IPV-related resources were essential components to providing support, promoting safety, and enabling healing in the healthcare setting. Successful trauma-informed transformation of healthcare systems must optimize interpersonal and systemic factors that improve survivor wellbeing while eliminating barriers.

Despite decades of stress research, there still exist substantial gaps in our understanding of how social, environmental, and biological factors interact and combine with developmental stressor exposures, cognitive appraisals of stressors, and psychosocial coping processes to shape individuals stress reactivity, health, and disease risk. Relatively new biological profiling approaches, called multi-omics, are helping address these issues by enabling researchers to quantify thousands of molecules from a single blood or tissue sample, thus providing a panoramic snapshot of the molecular processes occurring in an organism from a systems perspective. In this review, we summarize two types of research designs for which multi-omics approaches are best suited, and describe how these approaches can help advance our understanding of stress processes and the development, prevention, and treatment of stress-related pathologies. We first discuss incorporating multi-omics approaches into theory-rich, intensive longitudinal study designs to characterize, in high-resolution, the transition to stress-related multisystem dysfunction and disease throughout development. Next, we discuss how multi-omics approaches should be incorporated into intervention research to better understand the transition from stress-related dysfunction back to health, which can help inform novel precision medicine approaches to managing stress and fostering biopsychosocial resilience. Throughout, we provide concrete recommendations for types of studies that will help advance stress research, and translate multi-omics data into better health and health care.

BackgroundFirearm purchasing records offer a potentially important administrative data source to identify individuals at elevated risk of perpetrating firearm violence. In this study, we describe individual, firearm, and transaction characteristics of purchasers in California who were arrested for a firearm-related violent crime (FRV) as compared to the general population of registered purchasers in the state.MethodsRelying on a dataset of all individuals with transaction records in California (1996-2021), linked to criminal records (1980-2021), we enrolled a cohort of individuals for whom we could capture the legal firearm purchase history. We identified those arrested for FRV post purchase, and using incidence density sampling, gender-matched cases to ten purchasers (controls) who remained "at risk" at the time the case was arrested. We focused on the purchase closest in time prior to the arrest ("index" purchase). We implemented conditional logistic regression and included models with controls for individual- and community-level demographics, as well as interactions between firearm and purchasing characteristics and criminal history.ResultsThe cohort included 1,212,144 individuals, of whom 6153 were arrested for FRV (0.5%). Cases were matched to 61,530 controls to form the study sample. The largest risk factor was a prior criminal history: purchasers had 5.84 times the risk of FRV if they had a prior arrest within three years of the index purchase (CI 5.44-6.27). Several transaction and firearm characteristics were also associated with FRV. For example, risk increased if the firearm was redeemed at a pawn shop (aIRR: 1.37, CI 1.05-1.77) and decreased if the transaction was a registered private party transfer (vs. retail purchase) (aIRR: 0.83, CI 0.76-0.90) or the firearm was a bolt action firearm (vs. semi-automatic) (aIRR: 0.64, CI 0.51-0.79). In the interaction models, most of the purchase and firearm features only remained significant among those with no criminal history.ConclusionsGiven limited data on firearm transactions, there has been little research on whether the type of firearm an individual purchases or the nature of the purchase might serve as indicators of risk for FRV. We found several transaction and firearm features were associated with risk of FRV. Notably, these features provided little evidence of additional risk for those with a prior criminal record.

MotivationLarge Language Models (LLMs) are being adopted at an unprecedented rate, yet still face challenges in knowledge-intensive domains like biomedicine. Solutions such as pre-training and domain-specific fine-tuning add substantial computational overhead, requiring further domain-expertise. Here, we introduce a token-optimized and robust Knowledge Graph-based Retrieval Augmented Generation (KG-RAG) framework by leveraging a massive biomedical KG (SPOKE) with LLMs such as Llama-2-13b, GPT-3.5-Turbo and GPT-4, to generate meaningful biomedical text rooted in established knowledge.ResultsCompared to the existing RAG technique for Knowledge Graphs, the proposed method utilizes minimal graph schema for context extraction and uses embedding methods for context pruning. This optimization in context extraction results in more than 50% reduction in token consumption without compromising the accuracy, making a cost-effective and robust RAG implementation on proprietary LLMs. KG-RAG consistently enhanced the performance of LLMs across diverse biomedical prompts by generating responses rooted in established knowledge, accompanied by accurate provenance and statistical evidence (if available) to substantiate the claims. Further benchmarking on human curated datasets, such as biomedical true/false and multiple-choice questions (MCQ), showed a remarkable 71% boost in the performance of the Llama-2 model on the challenging MCQ dataset, demonstrating the framework's capacity to empower open-source models with fewer parameters for domain-specific questions. Furthermore, KG-RAG enhanced the performance of proprietary GPT models, such as GPT-3.5 and GPT-4. In summary, the proposed framework combines explicit and implicit knowledge of KG and LLM in a token optimized fashion, thus enhancing the adaptability of general-purpose LLMs to tackle domain-specific questions in a cost-effective fashion.Availability and implementationSPOKE KG can be accessed at https://spoke.rbvi.ucsf.edu/neighborhood.html. It can also be accessed using REST-API (https://spoke.rbvi.ucsf.edu/swagger/). KG-RAG code is made available at https://github.com/BaranziniLab/KG_RAG. Biomedical benchmark datasets used in this study are made available to the research community in the same GitHub repository.Supplementary informationSupplementary data are available at Bioinformatics online.

Computational and data-enabled science and engineering are revolutionizing advances throughout science and society, at all scales of computing. For example, teams in the U.S. Department of Energy's Exascale Computing Project have been tackling new frontiers in modeling, simulation, and analysis by exploiting unprecedented exascale computing capabilities-building an advanced software ecosystem that supports next-generation applications and addresses disruptive changes in computer architectures. However, concerns are growing about the productivity of the developers of scientific software. Members of the Interoperable Design of Extreme-scale Application Software project serve as catalysts to address these challenges through fostering software communities, incubating and curating methodologies and resources, and disseminating knowledge to advance developer productivity and software sustainability. This article discusses how these synergistic activities are advancing scientific discovery-mitigating technical risks by building a firmer foundation for reproducible, sustainable science at all scales of computing, from laptops to clusters to exascale and beyond.

Abstract: Climate change is altering interactions among plants and pollinators. In alpine ecosystems, where snowmelt timing is a key driver of phenology, earlier snowmelt may generate shifts in plant and pollinator phenology that vary across the landscape, potentially disrupting interactions. Here we ask how experimental advancement of snowmelt timing in a topographically heterogeneous alpine-subalpine landscape impacts flowering, insect pollinator visitation, and pathways connecting key predictors of plant-pollinator interaction. Snowmelt was advanced by an average of 13.5 days in three sites via the application of black sand over snow in manipulated plots, which were paired with control plots. For each forb species, we documented flowering onset and counted flowers throughout the season. We also performed pollinator observations to measure visitation rates. The majority (79.3%) of flower visits were made by dipteran insects. We found that plants flowered earlier in advanced snowmelt plots, with the largest advances in later-flowering species, but flowering duration and visitation rate did not differ between advanced snowmelt and control plots. Using piecewise structural equation models, we assessed the interactive effects of topography on snowmelt timing, flowering phenology, floral abundance, and pollinator visitation. We found that these factors interacted to predict visitation rate in control plots. However, in plots with experimentally advanced snowmelt, none of these predictors explained a significant amount of variation in visitation rate, indicating that different predictors are needed to understand the processes that directly influence pollinator visitation to flowers under future climate conditions. Our findings demonstrate that climate change-induced early snowmelt may fundamentally disrupt the predictive relationships among abiotic and biotic drivers of plant-pollinator interactions in subalpine-alpine environments.

Translational medicine has been a buzzword for over two decades. The concept was intended to be lofty, to reflect a new bench-to-bedside approach to basic and clinical research that would bridge fields, close gaps, accelerate innovation, and shorten the time and effort it takes to bring novel technologies from basic discovery to clinical application. Has this approach been successful and lived up to its promise? Despite incredible scientific advances and innovations developed within academia, successful clinical translation into real-world solutions has been difficult. This has been particularly challenging within the pulmonary field, because there have been fewer U.S. Food and Drug Administration-approved drugs and higher failure rates for pulmonary therapies than with other common disease areas. The American Thoracic Society convened a working group with the goal of identifying major challenges related to the commercialization of technologies within the pulmonary space and opportunities to enhance this process. A survey was developed and administered to 164 participants within the pulmonary arena. This report provides a summary of these survey results. Importantly, this report identifies a number of poorly recognized challenges that exist in pulmonary academic settings, which likely contribute to diminished efficiency of commercialization efforts, ultimately hindering the rate of successful clinical translation. Because many innovations are initially developed in academic settings, this is a global public health issue that impacts the entire American Thoracic Society community. This report also summarizes key resources and opportunities and provides recommendations to enhance successful commercialization of pulmonary technologies.

IntroductionIn 2015, the National Institute of Dental and Craniofacial Research (NIDCR) launched the Multidisciplinary Collaborative Research Consortium to Reduce Oral Health Disparities in Children, supporting four randomized trials testing strategies to improve preventive care. A Coordinating Center provides scientific expertise, data acquisition and quality assurance services, safety monitoring, and final analysis-ready datasets. This paper describes the trials' economic analysis strategies, placing these strategies within the broader context of contemporary economic analysis methods.MethodsThe Coordinating Center established a Cost Collaborative Working Group to share information from the four trials about the components of their economic analyses. Study teams indicated data sources for their economic analysis using a set of structured tables. The Group meets regularly to share progress, discuss challenges, and coordinate analytic approaches.ResultsAll four trials will calculate incremental cost-effectiveness ratios; two will also conduct cost-utility analyses using proxy diseases to estimate health state utilities. Each trial will consider at least two perspectives. Key process measures include dental services provided to child participants. The non-preference-weighted Early Childhood Oral Health Impact Scale (ECOHIS) will measure oral health-related quality of life. All trials are measuring training, implementation, personnel and supervision, service, supplies, and equipment costs.ConclusionsConsistent with best practices, all four trials have integrated economic analysis during their planning stages. This effort is critical since poor quality or absence of essential data can limit retrospective analysis. Integrating economic analysis into oral health preventive intervention research can provide guidance to clinicians and practices, payers, and policymakers.