Search

Abstract Understanding the variability of extinction risk and its potential drivers across different spatial extents is crucial to revealing the underlying processes of biodiversity loss and sustainability. However, in countries with high climatic and topographic heterogeneity, studies on extinction risk are often challenged by complexities associated with extent effects. Here, using 2.02 million fine-grained distribution records and a phylogeny including 27,185 species, we find that the extinction risk of flowering plants in China is spatially concentrated in southwestern China. Our analyses suggest that spatial extinction risks of flowering plants in China may be caused by multiple drivers and are extent dependent. Vegetation structure based on proportion of growth forms is likely the dominant extinction driver at the national extent, followed by climatic and evolutionary drivers. Finer extent analyses indicate that the potential dominant extinction drivers vary across zones and vegetation regions. Despite regional heterogeneity, we detect a geographical continuity potential in extinction drivers, with variation in West China dominated by vegetation structure, South China by climate, and North China by evolution. Our findings highlight that identification of potential extent-dependent drivers of extinction risk is crucial for targeted conservation practice in countries like China.

Abstract Background SARS-CoV-2-infected patients may develop new conditions in the period after the acute infection. These conditions, the post-acute sequelae of SARS-CoV-2 infection (PASC, or Long COVID), involve a diverse set of organ systems. Limited studies have investigated the predictability of Long COVID development and its associated risk factors. Methods In this retrospective cohort study, we used electronic healthcare records from two large-scale PCORnet clinical research networks, INSIGHT (~1.4 million patients from New York) and OneFlorida+ (~0.7 million patients from Florida), to identify factors associated with having Long COVID, and to develop machine learning-based models for predicting Long COVID development. Both SARS-CoV-2-infected and non-infected adults were analysed during the period of March 2020 to November 2021. Factors associated with Long COVID risk were identified by removing background associations and correcting for multiple tests. Results We observed complex association patterns between baseline factors and a variety of Long COVID conditions, and we highlight that severe acute SARS-CoV-2 infection, being underweight, and having baseline comorbidities (e.g., cancer and cirrhosis) are likely associated with increased risk of developing Long COVID. Several Long COVID conditions, e.g., dementia, malnutrition, chronic obstructive pulmonary disease, heart failure, PASC diagnosis U099, and acute kidney failure are well predicted (C-index > 0.8). Moderately predictable conditions include atelectasis, pulmonary embolism, diabetes, pulmonary fibrosis, and thromboembolic disease (C-index 0.7–0.8). Less predictable conditions include fatigue, anxiety, sleep disorders, and depression (C-index around 0.6). Conclusions This observational study suggests that association patterns between investigated factors and Long COVID are complex, and the predictability of different Long COVID conditions varies. However, machine learning-based predictive models can help in identifying patients who are at risk of developing a variety of Long COVID conditions.

This article provides an update en events since Edward Snowden, an employee of a National Security Agency (NSA) contractor, stole and released thousands of classified documents in 2013, revealing that the U.S. government was engaged in a massive secret cybersurveilance operation that was amassing information about people all over the world, including U.S. citizens. In the U.S., Snowden’s revelations sparked a spirited debate regarding privacy rights, and in particular whether the U.S. cybersurveillance operation was appropriate in a democratic system. This article describes the scope of the cybersuveillance program, and examines how the courts and Congress responded to the Snowden revelations, and (in particular) how U.S. society evolved in the following years.

Abstract Dryland ecosystems cover 40% of our planet's land surface, support billions of people, and are responding rapidly to climate and land use change. These expansive systems also dominate core aspects of Earth's climate, storing and exchanging vast amounts of water, carbon, and energy with the atmosphere. Despite their indispensable ecosystem services and high vulnerability to change, drylands are one of the least understood ecosystem types, partly due to challenges studying their heterogeneous landscapes and misconceptions that drylands are unproductive “wastelands.” Consequently, inadequate understanding of dryland processes has resulted in poor model representation and forecasting capacity, hindering decision making for these at‐risk ecosystems. NASA satellite resources are increasingly available at the higher resolutions needed to enhance understanding of drylands' heterogeneous spatiotemporal dynamics. NASA's Terrestrial Ecology Program solicited proposals for scoping a multi‐year field campaign, of which Adaptation and Response in Drylands (ARID) was one of two scoping studies selected. A primary goal of the scoping study is to gather input from the scientific and data end‐user communities on dryland research gaps and data user needs. Here, we provide an overview of the ARID team's community engagement and how it has guided development of our framework. This includes an ARID kickoff meeting with over 300 participants held in October 2023 at the University of Arizona to gather input from data end‐users and scientists. We also summarize insights gained from hundreds of follow‐up activities, including from a tribal‐engagement focused workshop in New Mexico, conference town halls, intensive roundtables, and international engagements.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Loss of function mutations in the checkpoint kinase gene CHEK2 are associated with increased risk of breast and other cancers. Most of the 3,188 unique amino acid changes that can result from non-synonymous single nucleotide variants (SNVs) of CHEK2, however, have not been tested for their impact on the function of the CHEK2-enocded protein (CHK2). One successful approach to testing the function of variants has been to test for their ability to complement mutations in the yeast ortholog of CHEK2, RAD53. This approach has been used to provide functional information on over 100 CHEK2 SNVs and the results align with functional assays in human cells and known pathogenicity. Here we tested all but two of the 4,887 possible SNVs in the CHEK2 open reading frame for their ability to complement RAD53 mutants using a high throughput technique of deep mutational scanning (DMS). Among the non-synonymous changes, 770 were damaging to protein function while 2,417 were tolerated. The results correlate well with previous structure and function data and provide a first or additional functional assay for all the variants of uncertain significance identified in clinical databases. Combined, this approach can be used to help predict the pathogenicity of CHEK2 variants of uncertain significance that are found in susceptibility screening and could be applied to other cancer risk genes.

The space tourism industry is growing due to advances in rocket technology. Privatised space travel exposes non-professional astronauts with health profiles comprising underlying conditions to microgravity. Prior research has typically focused on the effects of microgravity on human physiology in healthy astronauts, and little is known how the effects of microgravity may play out in the pathophysiology of underlying medical conditions, such as heart failure. This study used an established, controlled lumped mathematical model of the cardiopulmonary system to simulate the effects of entry into microgravity in the setting of heart failure with both, reduced and preserved ejection fraction. We find that exposure to microgravity eventuates an increased cardiac output, and in patients with heart failure there is an unwanted increase in left atrial pressure, indicating an elevated risk for development of pulmonary oedema. This model gives insight into the risks of space flight for people with heart failure, and the impact this may have on mission success in space tourism.

Spinocerebellar ataxia type 12 (SCA12) is caused by a CAG expansion mutation in PPP2R2B, a gene encoding brain-specific regulatory units of protein phosphatase 2A (PP2A); while normal alleles carry 4 to 31 triplets, the disease alleles carry 43 to 78 triplets. Here, by CRISPR/Cas9n genome editing, we have generated a human heterozygous SCA12 iPSC line with 73 triplets for the mutant allele. The heterozygous SCA12 iPSCs have normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

IntroductionBilateral microprocessor-controlled prosthetic knee (MPK) users have unique needs in traversing environmental barriers compared to unilateral users. An enhancement to the Genium™/Genium X3™ MPK which included an updated ruleset, hydraulics, and new bilateral parameter presets was made to improve safety while stumbling and the smoothness of gait for all users while also improving the experience of bilateral users. The purpose of the study was to evaluate the effectiveness of the enhancements in a sample with unilateral and bilateral amputation.MethodsA convenience sample of MPK users was recruited from two sites in the USA in two phases. Assessments included the L-Test of Functional Mobility, Activity-specific Balance Confidence Scale, Prosthetic Limb User Survey of Mobility, a study-specific questionnaire, and the Comparative Activities of Daily Living (ADL) Questionnaire. Statistical significance of extracted data was tested with the Wilcoxon Rank-Sum Test for independent data and Wilcoxon Signed-Rank for paired data with an a priori significance level of p

Establishment of a national park protection system in China, including the latest target proposed to protect at least 30% of the land area, calls for a comprehensive exploration of conservation priorities incorporating multiple diversity facets. We herein evaluate the spatial distribution of Chinese flowering plants from the perspectives of richness, uniqueness, vulnerability, and evolutionary history, by integrating three mega-phylogenies and comprehensive distribution data. We detect significantly high consistency among hotspots of different diversity measures for Chinese flowering plants, suggesting that multiple facets of evolutionary diversity are concentrically distributed in China. Affording legal protection to these areas is expected to maximize positive conservation outcomes. We propose two integrative diversity indices by incorporating three richness-based and three phylogeny-based measures, respectively. Both methods identify areas with high species richness, but the integrative phylogeny-based index also locates key areas with ancient and unique evolutionary histories (e.g., Ailao-Wuliang Mts, Dabie Mts, Hainan rainforest, Karst area of Yunnan-Guizhou-Guangxi, Nanling Mts, and southeast coastal regions). Of all the diversity indices explored, phylogenetic endemism maximizes the incidental protection of other indices in most cases, emphasizing its significance for conservation planning. Finally, 42 priority areas are identified by combining the 5%-criterion hotspots of two integrative indices and the minimum area to protect all threatened species analyzed. These priorities cover only 13.3% of China's land area, but host 97.1% of species richness (23,394/24,095), 96.5% of endemic species (11,841/12,274), 100% of threatened species (2,613/2,613), and 99.3% of phylogenetic diversity for flowering plants involved in this study. These frameworks provide a solid scientific basis for national park planning in China.

Objectives Following up trauma patients after discharge, to evaluate their subsequent quality of life and functional outcomes, is notoriously difficult, time consuming, and expensive. Automated systems are a conceptually attractive solution. We prospectively assessed the feasibility of using a series of automated phone calls administered by Emmi Patient Engagement to survey trauma patients after discharge.Methods Recruitment into the study was incorporated into the patient discharge process by nursing staff. For this pilot, we included trauma patients discharging home and who were able to answer phone calls. A script was created to evaluate the Extended Glasgow Outcome Scale and the EuroQol EQ-5D to assess functional status and quality of life, respectively. Call attempts were made at 6 weeks, 3 months, 6 months, and 1 year after discharge.Results A total of 110 patients initially agreed to participate. 368 attempted patient encounters (calls or attempted calls) took place, with 104 (28.3%) patients answering a least one question in the study. 21 unique patients (19.1% of those enrolled) completed 27 surveys.Conclusions Automated, scripted phone calls to survey patients after discharge are not a feasible way of collecting functional and quality of life data.Level of evidence Level II/prospective.

Abstract Savannas are water‐limited ecosystems characterized by two dominant plant types: trees and an understory primarily made up grass. Different phenology and root structures of these plant types complicate how savanna primary productivity responds to changes in water availability. We tested the hypothesis that productivity in savannas is controlled by the temporal and vertical distribution of soil water content (SWC) and differences in growing season length of understory and tree plant functional types. To quantify the relationship between tree, understory, and savanna‐wide phenology and productivity, we used PhenoCam and satellite observations surrounding an eddy covariance tower at a semiarid savanna site in Arizona, USA. We distinguished between SWC across two different depth intervals (shallow, 30–100 cm). We found that tree greenness increased with SWC at both depths, while understory greenness was only sensitive to the shallower SWC measurements. Onset of ecosystem dormancy, estimated from satellite observations close to the eddy covariance tower, explained more variability in annual gross primary productivity (GPP) than in other phenometrics. Higher SWC led to an extended growing season, caused by delayed dormancy in trees, but the understory showed no evidence of delayed dormancy in wetter periods. We infer that the timing of ecosystem scale dormancy, driven by trees, is important in understanding changes in a savanna's GPP. These findings highlight the important effects of rainfall during the winter. These findings suggest that savanna GPP is conditional on different responses to moisture availability in each of the dominant vegetation components.

Background In patients with atherosclerotic cardiovascular disease, increasing age is concurrently associated with higher risks of ischemic and bleeding events. The objectives are to determine the impact of aspirin dose on clinical outcomes according to age in atherosclerotic cardiovascular disease. Methods and Results In the ADAPTABLE (Aspirin Dosing: A Patient‐Centric Trial Assessing Benefits and Long‐Term Effectiveness) trial, patients with atherosclerotic cardiovascular disease were randomized to daily aspirin doses of 81 mg or 325 mg. The primary effectiveness end point was death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. The primary safety end point was hospitalization for bleeding requiring transfusion. A total of 15 076 participants were randomized to aspirin 81 mg (n=7540) or 325 mg (n=7536) daily (median follow‐up: 26.2 months; interquartile range: 19.0–34.9 months). Median age was 67.6 years (interquartile range: 60.7–73.6 years). Among participants aged 0.05 for all). Conclusions Age does not modify the impact of aspirin dosing (81 mg or 325 mg daily) on clinical end points in secondary prevention of atherosclerotic cardiovascular disease.

Abstract Background Explaining contrasting patterns of distribution between related species is crucial for understanding the dynamics of biodiversity. Despite instances where hybridization and whole genome duplication (WGD) can yield detrimental outcomes, a role in facilitating the expansion of distribution range has been proposed. The Vitaceae genus Causonis exhibits great variations in species’ distribution ranges, with most species in the derived lineages having a much wider range than those in the early-diverged lineages. Hybridization and WGD events have been suggested to occur in Causonis based on evidence of phylogenetic discordance. The genus, therefore, provides us with an opportunity to for explore different hybridization and polyploidization modes in lineages with contrasting species’ distribution ranges. However, the evolutionary history of Causonis incorporating potential hybridization and WGD events remains to be explored. Results With plastid and nuclear data from dense sampling, this study resolved the phylogenetic relationships within Causonis and revealed significant cyto-nuclear discordance. Nuclear gene tree conflicts were detected across the genus, especially in the japonica-corniculata clade, which were mainly attributed to gene flow. This study also inferred the allopolyploid origin of the core Causonis species, which promoted the accumulation of stress-related genes. Causonis was estimated to have originated in continental Asia in the early Eocene, and experienced glaciation in the early Oligocene, shortly after the divergence of the early-divergent lineages. The japonica-corniculata clade mainly diversified in the Miocene, followed by temperature declines that may have facilitated secondary contact. Species distribution modeling based on current climate change predicted that the widespread C. japonica tends to be more invasive, while the endemic C. ciliifera may be at risk of extinction. Conclusions This study presents Causonis, a genus with complex reticulate evolutionary history, as a model of how hybridization and WGD modes differ in lineages of contrasting species’ geographic ranges. It is important to consider specific evolutionary histories and genetic properties of the focal species within conservation strategies.

Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype.

The ECMWF‘s ensemble (ECEPS) predictions are documented for the lifecycles of six tropical cyclones (TCs) that formed during a long-lasting Rossby wave breaking event in the western North Pacific. All six TC tracks started between 20° N and 25° N, and between 136° E and 160° E. All five typhoons recurved north of 30° N, and the three typhoons that did not make landfall had long tracks to 50° N and beyond. The ECEPS weighted mean vector motion track forecasts from pre-formation onward are quite accurate, with track forecast spreads that are primarily related to initial position uncertainties. The ECEPS intensity forecasts have been validated relative to the Joint Typhoon Warning Center (JTWC) Working Best Track (WBT) intensities (when available). The key results for Tokage (11 W) were the ECEPS forecasts of the intensification to a peak intensity of 100 kt, and then a rapid decay as a cold-core cyclone. For Hinnamnor (12 W), the key result was the ECEPS intensity forecasts during the post-extratropical transition period when Hinnamnor was rapidly translating poleward through the Japan Sea. For Muifa (14 W), the key advantage of the ECEPS was that intensity guidance was provided for longer periods than the JTWC 5-day forecast. The most intriguing aspect of the ECEPS forecasts for post-Merbok (15 W) was its prediction of a transition to an intense, warm-core vortex after Merbok had moved beyond 50° N and was headed toward the Aleutian Islands. The most disappointing result was that the ECEPS over-predicted the slow intensification rate of Nanmadol (16 W) until the time-to-typhoon (T2TY), but then failed to predict the large rapid intensification (RI) following the T2TY. The tentative conclusion is that the ECEPS model‘s physics are not capable of predicting the inner-core spin-up rates when a small inner-core vortex is undergoing large RI.

Cathepsin B (CtsB) is a ubiquitously expressed cysteine protease that plays important roles in health and disease. Urinary extracellular vesicles (uEVs) are released from cells associated with urinary organs. The antibiotic streptozotocin (STZ) is known to induce pancreatic islet beta cell destruction, diabetic nephropathy, and hypertension. We hypothesized that streptozotocin-induced diabetic kidney disease and hypertension result in the release of bioactive lipids from kidney cells that induce oxidative stress and renal cell death. Lipidomics was performed on uEVs isolated from CtsB knockout mice treated with or without STZ, and their kidneys were used to investigate changes in proteins associated with cell death. Lysophosphatidylethanolamine (LPE) (18:1), lysophosphatidylserine (LPS) (22:6), and lysophosphatidylglycerol (LPG) (22:5) were among the bioactive lipids enriched in uEVs from CtsB knockout mice treated with STZ compared to untreated CtsB mice (n = 3 uEV preparations per group). Anti-oxidant programming was activated in the kidneys of the CtsB knockout mice treated with STZ, as indicated by increased expression of glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter SLC7A11 (XCT) (n = 4 mice per group), which was supported by a higher reactivity to 4-hydroxy-2-nonenal (4-HNE), a marker for oxidative stress (n = 3 mice per group). Apoptosis but not ferroptosis was the ongoing form of cell death in these kidneys as cleaved caspase-3 levels were significantly elevated in the STZ-treated CtsB knockout mice (n = 4 mice per group). There were no appreciable differences in the pro-ferroptosis enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) or the inflammatory marker CD93 in the kidneys (n = 3 mice per group), which further supports apoptosis as the prevalent mechanism of pathology. These data suggest that STZ treatment leads to oxidative stress, inducing apoptotic injury in the kidneys during the development of diabetic kidney disease and hypertension.

Abstract INTRODUCTION In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS One hundred and sixty‐four participants were randomized to placebo (n = 83) or AGB101 (n = 81), an extended‐release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR‐SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS The mean change in CDR‐SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is ‐0.10 (95% CI: ‐0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was ‐0.45 (95% CI: ‐1.43, 0.53) for ApoE‐4 noncarriers and ‐0.10 (95% CI: ‐0.92, 0.72) for apolipoprotein E (ApoE)‐4 carriers. DISCUSSION The possibility that ApoE‐4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE‐4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

Abstract Background Language deficits are cardinal manifestations of some frontotemporal dementia (FTD) phenotypes and also increasingly recognized in sporadic and familial amyotrophic lateral sclerosis (ALS). They have considerable social and quality‐of‐life implications, and adaptive strategies are challenging to implement. While the neuropsychological profiles of ALS–FTD phenotypes are well characterized, the neuronal underpinnings of language deficits are less well studied. Methods A multiparametric, quantitative neuroimaging study was conducted to characterize the involvement of language‐associated networks, tracts, and cortical regions with a panel of structural, diffusivity, and functional magnetic resonance imaging (MRI) metrics. Seven study groups were evaluated along the ALS–FTD spectrum: healthy controls (HC), individuals with ALS without cognitive impairment (ALSnci), C9orf72‐negative ALS–FTD, C9orf72‐positive ALS–FTD, behavioral‐variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The integrity of the Broca's area, Wernicke's area, frontal aslant tract (FAT), arcuate fascicle (AF), inferior occipitofrontal fascicle (IFO), inferior longitudinal fascicle (ILF), superior longitudinal fascicle (SLF), and uncinate fascicle (UF) was quantitatively evaluated. The functional connectivity (FC) between Broca's and Wernicke’ areas and FC along the FAT was also specifically assessed. Results Patients with nfvPPA and svPPA exhibit distinctive patterns of gray and white matter degeneration in language‐associated brain regions. Individuals with bvFTD exhibit Broca's area, right FAT, right IFO, and UF degeneration. The ALSnci group exhibits Broca's area atrophy and decreased FC along the FAT. Both ALS–FTD cohorts, irrespective of C9orf72 status, show bilateral FAT, AF, and IFO pathology. Interestingly, only C9orf72‐negative ALS–FTD patients exhibit bilateral uncinate and right ILF involvement, while C9orf72‐positive ALS–FTD patients do not. Conclusions Language‐associated tracts and networks are not only affected in language‐variant FTD phenotypes but also in ALS and bvFTD. Language domains should be routinely assessed in ALS irrespective of the genotype.

In this study, the authors characterise post-acute sequelae of SARS-CoV-2 (PASC) in two large cohorts based on electronic health records from the USA. They identify a broad range of PASC-related conditions which were only partially replicated across the two cohorts, indicating possible heterogeneity between populations.

ABSTRACT: Objectives: To determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCWs). Methods: In a 1: 1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial at 34 US clinical centers, 1360 HCWs at risk for COVID-19 infection were enrolled between April and November 2020. Participants were randomized to HCQ or matched placebo. The HCQ dosing included a loading dose of HCQ 600 mg twice on day 1, followed by 400 mg daily for 29 days. The primary outcome was a composite of confirmed or suspected COVID-19 clinical infection by day 30, defined as new-onset fever, cough, or dyspnea and either a positive SARS-CoV-2 polymerase chain reaction test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected). Results: Study enrollment closed before full accrual due to recruitment challenges. The primary end point occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6-0.9%, P = 0.20) was identified nor any significant safety issues. Conclusion: Oral HCQ taken as prescribed appeared safe among HCWs. No significant clinical benefits were observed. The study was not powered to detect a small but potentially important reduction in infection. Trial registration: NCT04334148.

Four-dimensional COAMPS Dynamic Initialization (FCDI) analyses that include high-temporal- and high-spatial-resolution GOES-16 Atmospheric Motion Vector (AMV) datasets are utilized to understand and predict why pre-Bonnie (2022), designated as a Potential Tropical Cyclone (PTC 2), did not undergo rapid intensification (RI) while passing along the coast of Venezuela during late June 2022. A tropical cyclone lifecycle-prediction model based on the ECMWF ensemble indicated that no RI should be expected for the trifurcation southern cluster of tracks along the coast, similar to PTC 2, but would likely occur for two other track clusters farther offshore. Displaying the GOES-16 mesodomain AMVs in 50 mb layers illustrates the outflow burst domes associated with the PTC 2 circulation well. The FCDI analyses forced by thousands of AMVs every 15 min document the 13,910 m wind-mass field responses and the subsequent 540 m wind field adjustments in the PTC 2 circulation. The long-lasting outflow burst domes on both 28 June and 29 June were mainly to the north of PTC 2, and the 13,910 m FCDI analyses document conditions over the PTC 2 which were not favorable for an RI event. The 540 m FCDI analyses demonstrated that the intensity was likely less than 35 kt because of the PTC 2 interactions with land. The FCDI analyses and two model forecasts initialized from the FCDI analyses document how the PTC 2 moved offshore to become Tropical Storm Bonnie; however, they reveal another cyclonic circulation farther west along the Venezuelan coast that has some of the characteristics of a Caribbean False Alarm event.

Background The ADAPTABLE (Aspirin Dosing: A Patient‐Centric Trial Assessing Benefits and Long‐Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high‐ versus low‐dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear. Methods and Results Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non‐P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22–1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91–2.22]). We found no interaction in the relative effectiveness and safety of high‐ versus low‐dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high‐dose compared with low‐dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use. Conclusions In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high‐ versus low‐dose aspirin was not modified by baseline P2Y12 inhibitor use. Registration https://www.clinical.trials.gov. Unique identifier: NCT02697916.

Summary: Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014–2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12–26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p

Abstract Background Persons who experience paraquat poisoning rapidly develop damage to a variety of organ systems including acute kidney injury (AKI), the occurrence of which is associated with an increased risk of death. However, little is known about the effects of chronic paraquat exposure on renal function and the onset of chronic renal disease. The objective of the current study is to assess the association between paraquat exposure and the incidence of end stage renal disease (ESRD) in the United States. Methods Data on the incidence of ESRD for the period 2010 through 2017 and kilograms of paraquat use per square mile for each county in the conterminous United States was obtained from the United States Renal Data System (USRDS) and the National Water Quality Assessment (NAWQA) Program, respectively. Negative binomial regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for the association between quartiles of paraquat exposure and the incidence of ESRD. Results The incidence of ESRD increased with increasing paraquat density. Based on a 20-year exposure lag, those in the highest paraquat density quartile had a 21% higher rate of ESRD compared to the lowest quartile whereas for a 15-year lag the increase was 26%. Adjusted associations were attenuated though still followed an increasing linear trend across quintiles. Conclusions The results of this study are consistent with a large number of studies documenting a high incidence of AKI and a small number of studies chronic renal disease following acute and chronic paraquat exposure, respectively. While the pathophysiological mechanisms underlying kidney injury following paraquat poisoning are well understood, more research is necessary to understand the natural history of chronic kidney disease due to chronic paraquat exposure.

Background Internet‐based participation has the potential to enhance pragmatic and decentralized trials, where representative study populations and generalizability to clinical practice are key. We aimed to study the differences between internet and noninternet/telephone participants in a large remote, pragmatic trial. Methods and Results In a subanalysis of the ADAPTABLE (Aspirin Dosing: A Patient‐Centric Trial Assessing Benefits and Long‐Term Effectiveness) study, we compared internet participants with those who opted for noninternet participation. Study process measures examined included participant characteristics at consent, study medication adherence, and study retention. The clinical outcome examined was a composite of all‐cause mortality, hospitalization for myocardial infarction, or hospitalization for stroke. Noninternet participants were older (mean 69.4 versus 67.4 years), more likely to be female (38.9% versus 30.2%), more likely to be Black (27.3% versus 6.0%) or Hispanic (11.1% versus 2.0%), and had a higher number of comorbid conditions. The composite clinical outcome was more than twice as high in noninternet participants. The hazard of nonadherence to the assigned aspirin dosage was 46% higher in noninternet participants than internet participants. Conclusions Noninternet participants differed from internet participants in notable demographic characteristics while having poorer baseline health. Over the course of ADAPTABLE, they also had worse clinical outcomes and greater likelihood of study drug nonadherence. These results suggest that trials focused on internet participation select for younger, healthier participants with a higher proportion of traditionally overrepresented patients. Allowing noninternet participation enhances diversity; however, additional steps may be needed to promote study retention and study medication adherence. Registration Information clinicaltrials.gov. Identifier: NCT02697916.

Abstract Background Microbial etiology for community-acquired pneumonia (CAP) is evolving with pathogens known for high CAP mortality e.g., Pseudomonas species. Chronic obstructive pulmonary disease (COPD) patients are at risk for hospitalization for CAP. Understanding regional patterns and risk factors for multidrug-resistant (MDR) Pseudomonas acquisition has implications for antimicrobial stewardship. Objectives To evaluate the regional epidemiology of MDR Pseudomonas CAP and its association with COPD. Methods We queried the electronic medical records of the University of Alabama at Birmingham Healthcare System to identify patients hospitalized for CAP with Pseudomonas positive respiratory samples between 01/01/2013–12/31/2019. Log binomial regression models were used to examine associations between COPD diagnosis and risk of Pseudomonas/MDR Pseudomonas CAP. Results Cohort consisted of 913 culture positive CAP cases aged 59-year (IQR:48–68), 61% (560) male, 60% (547) white, 65% (580) current/past smokers, and 42% (384) COPD. Prevalence of Pseudomonas CAP in culture positive CAP was 18% (167), MDR Pseudomonas CAP in Pseudomonas CAP was 22% (36), and yearly incidence of MDR Pseudomonas CAP was stable (p = 0.169). COPD was associated with Pseudomonas CAP (RR 1.39; 95% CI 1.01, 1.91; p = 0.041) but not with MDR Pseudomonas CAP (0.71; 95% CI 0.35, 1.45; p = 0.349). Stroke (RR 2.64; 95% CI 1.51, 4.61; p = 0.0006) and use of supplemental oxygen (RR 2.31; 95% CI 1.30, 4.12; p = 0.005) were associated with MDR Pseudomonas CAP. Conclusion Incidence of MDR Pseudomonas CAP was stable over time. COPD was associated with Pseudomonas CAP but not with MDR Pseudomonas CAP. Larger cohort studies are needed to confirm findings.

Metabolic engineering strategies have been successfully implemented to improve the production of isobutanol, a next-generation biofuel, in Saccharomyces cerevisiae. Here, we explore how two of these strategies, pathway re-localization and redox cofactor-balancing, affect the performance and physiology of isobutanol producing strains. We equipped yeast with isobutanol cassettes which had either a mitochondrial or cytosolic localized isobutanol pathway and used either a redox-imbalanced (NADPH-dependent) or redox-balanced (NADH-dependent) ketol-acid reductoisomerase enzyme. We then conducted transcriptomic, proteomic and metabolomic analyses to elucidate molecular differences between the engineered strains. Pathway localization had a large effect on isobutanol production with the strain expressing the mitochondrial-localized enzymes producing 3.8-fold more isobutanol than strains expressing the cytosolic enzymes. Cofactor-balancing did not improve isobutanol titers and instead the strain with the redox-imbalanced pathway produced 1.5-fold more isobutanol than the balanced version, albeit at low overall pathway flux. Functional genomic analyses suggested that the poor performances of the cytosolic pathway strains were in part due to a shortage in cytosolic Fe–S clusters, which are required cofactors for the dihydroxyacid dehydratase enzyme. We then demonstrated that this cofactor limitation may be partially recovered by disrupting iron homeostasis with a fra2 mutation, thereby increasing cellular iron levels. The resulting isobutanol titer of the fra2 null strain harboring a cytosolic-localized isobutanol pathway outperformed the strain with the mitochondrial-localized pathway by 1.3-fold, demonstrating that both localizations can support flux to isobutanol.

Abstract Hemipteran insects are ubiquitous inhabitants of the phyllosphere. Changes in microbial phyllosphere communities have recently been demonstrated following infestation by Macrosteles quadrilineatus (Aster Leafhopper). Although epiphytic Salmonella enterica populations naturally decline in the phyllosphere of plants, M. quadrilineatus infestation facilitated the growth of the bacterial pathogen populations. Here, we demonstrate that cellular damage by insect stylet penetration results in a localized beneficial niche on the leaf surface, leading to enhanced S. enterica populations. We measured S. enterica populations and colonization patterns on plants infested with Hemipterans with distinct feeding behaviors. M. quadrilineatus infestation resulted in higher solute leakage and significantly greater bacterial populations than plants absent of insects. Following immigration via contaminated irrigation water, the highest populations of S. enterica are naturally found on the tips of tomato leaflets. We discovered M. quadrilineatus feeding preference altered the natural distribution of S. enterica populations, and that the presence of S. enterica altered the distribution of probing attempts. These findings elucidate how cellular damage resulting from insect feeding drives changes in bacterial colonization of the phyllosphere.

Post-acute sequelae of SARS-CoV-2 infection (PASC) affects a wide range of organ systems among a large proportion of patients with SARS-CoV-2 infection. Although studies have identified a broad set of patient-level risk factors for PASC, little is known about the association between “exposome”—the totality of environmental exposures and the risk of PASC. Using electronic health data of patients with COVID-19 from two large clinical research networks in New York City and Florida, we identified environmental risk factors for 23 PASC symptoms and conditions from nearly 200 exposome factors. The three domains of exposome include natural environment, built environment, and social environment. We conducted a two-phase environment-wide association study. In Phase 1, we ran a mixed effects logistic regression with 5-digit ZIP Code tabulation area (ZCTA5) random intercepts for each PASC outcome and each exposome factor, adjusting for a comprehensive set of patient-level confounders. In Phase 2, we ran a mixed effects logistic regression for each PASC outcome including all significant (false positive discovery adjusted p-value < 0.05) exposome characteristics identified from Phase I and adjusting for confounders. We identified air toxicants (e.g., methyl methacrylate), particulate matter (PM2.5) compositions (e.g., ammonium), neighborhood deprivation, and built environment (e.g., food access) that were associated with increased risk of PASC conditions related to nervous, blood, circulatory, endocrine, and other organ systems. Specific environmental risk factors for each PASC condition and symptom were different across the New York City area and Florida. Future research is warranted to extend the analyses to other regions and examine more granular exposome characteristics to inform public health efforts to help patients recover from SARS-CoV-2 infection.

BackgroundSoil-derived prokaryotic gut communities of the Japanese beetle Popillia japonica Newman (JB) larval gut include heterotrophic, ammonia-oxidizing, and methanogenic microbes potentially capable of promoting greenhouse gas (GHG) emissions. However, no research has directly explored GHG emissions or the eukaryotic microbiota associated with the larval gut of this invasive species. In particular, fungi are frequently associated with the insect gut where they produce digestive enzymes and aid in nutrient acquisition. Using a series of laboratory and field experiments, this study aimed to (1) assess the impact of JB larvae on soil GHG emissions; (2) characterize gut mycobiota associated with these larvae; and (3) examine how soil biological and physicochemical characteristics influence variation in both GHG emissions and the composition of larval gut mycobiota.MethodsManipulative laboratory experiments consisted of microcosms containing increasing densities of JB larvae alone or in clean (uninfested) soil. Field experiments included 10 locations across Indiana and Wisconsin where gas samples from soils, as well as JB and their associated soil were collected to analyze soil GHG emissions, and mycobiota (ITS survey), respectively.ResultsIn laboratory trials, emission rates of CO2, CH4, and N2O from infested soil were ≥ 6.3× higher per larva than emissions from JB larvae alone whereas CO2 emission rates from soils previously infested by JB larvae were 1.3× higher than emissions from JB larvae alone. In the field, JB larval density was a significant predictor of CO2 emissions from infested soils, and both CO2 and CH4 emissions were higher in previously infested soils. We found that geographic location had the greatest influence on variation in larval gut mycobiota, although the effects of compartment (i.e., soil, midgut and hindgut) were also significant. There was substantial overlap in the composition and prevalence of the core fungal mycobiota across compartments with prominent fungal taxa being associated with cellulose degradation and prokaryotic methane production/consumption. Soil physicochemical characteristics such as organic matter, cation exchange capacity, sand, and water holding capacity, were also correlated with both soil GHG emission, and fungal a-diversity within the JB larval gut. Conclusions: Results indicate JB larvae promote GHG emissions from the soil directly through metabolic activities, and indirectly by creating soil conditions that favor GHG-associated microbial activity. Fungal communities associated with the JB larval gut are primarily influenced by adaptation to local soils, with many prominent members of that consortium potentially contributing to C and N transformations capable of influencing GHG emissions from infested soil.

The purpose of this study was to evaluate the financial performances of the publicly held healthcare companies in crisis periods in Türkiye. The 2018 economic crisis and the COVID-19 pandemic crisis were included in the study as the crisis periods. We collected the financial data of the publicly held healthcare companies and calculated three liquidity, three turnover, three leverage and three profitability ratios through ratio analysis to use as financial performance indicators. We then conducted Wilcoxon signed-rank tests and we performed separate analyses for the 2018 economic crisis and the COVID-19 pandemic crisis. The results of the analyses showed that there were no statistically significant differences between the publicly held healthcare companies’ liquidity, turnover, leverage, profitability ratios and thus their financial performances before the crises and after the crises. While the results are reassuring and give valuable insights to managers and policy makers to determine the areas that needs to be strengthened to be better prepared for possible future crises, our sample was limited. Therefore, this study presents an exploratory foundation for future studies which are needed to make a case for financial stability for the publicly held healthcare companies before and after the crisis periods.

Abstract There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.

ImportanceThe COVID-19 pandemic stressed the healthcare field, resulting in a worker exodus at the onset and throughout the pandemic and straining healthcare systems. Female healthcare workers face unique challenges that may impact job satisfaction and retention. It is important to understand factors related to healthcare workers' intent to leave their current field.ObjectiveTo test the hypothesis that female healthcare workers were more likely than male counterparts to report intention to leave.DesignObservational study of healthcare workers enrolled in the Healthcare Worker Exposure Response and Outcomes (HERO) registry. After baseline enrollment, two HERO 'hot topic' survey waves, in May 2021 and December 2021, ascertained intent to leave. Unique participants were included if they responded to at least one of these survey waves.SettingHERO registry, a large national registry that captures healthcare worker and community member experiences during the COVID-19 pandemic.ParticipantsRegistry participants self-enrolled online and represent a convenience sample predominantly composed of adult healthcare workers.Exposure(s)Self-reported gender (male, female).Main outcomePrimary outcome was intention to leave (ITL), defined as having already left, actively making plans, or considering leaving healthcare or changing current healthcare field but with no active plans. Multivariable logistic regression models were performed to examine the odds of intention to leave with adjustment for key covariates.ResultsAmong 4165 responses to either May or December surveys, female gender was associated with increased odds of ITL (42.2% males versus 51.4% females reported intent to leave; aOR 1.36 [1.13, 1.63]). Nurses had 74% higher odds of ITL compared to most other health professionals. Among those who expressed ITL, three quarters reported job-related burnout as a contributor, and one third reported experience of moral injury.Conclusions and relevanceFemale healthcare workers had higher odds of intent to leave their healthcare field than males. Additional research is needed to examine the role of family-related stressors.Trial registrationClinicalTrials.gov identifier NCT04342806.

BackgroundRisk of incident cardiovascular disease (CVD) in head and neck squamous cell carcinoma (HNSCC) patients is under-reported. We assessed the association of HNSCC-related factors and traditional risk factors with 1- and 5-year CVD risk in HNSCC patients without prevalent CVD at cancer diagnosis.MethodsA clinical cohort of 1,829 HNSCC patients diagnosed between 2012 and 2018, at a National Cancer Institute (NCI)-designated cancer center was included. Information on HNSCC-related factors [HNSCC anatomical subsite, stage at diagnosis, treatment, and tumor human papillomavirus (HPV) status] were extracted from the tumor registry. Data on traditional risk factors (hypertension, dyslipidemia, diabetes, tobacco smoking status, and obesity) were extracted from the electronic health records system (EHR) at baseline (HNSCC diagnosis). A composite of ischemic heart disease, heart failure, and ischemic stroke was the outcome of interest in time to event analysis. Hazard ratio (HR) (95% CI) were reported with death as a competing risk.ResultsIn patients diagnosed with HNSCC, 10.61% developed incident CVD events by 1-year post cancer diagnosis. One-year CVD risk was lower in patients using antihypertensive medications at baseline, compared to patients without baseline hypertension [HR (95% CI): 0.41 (0.24–0.61)]. One-year CVD risk was high in patients receiving HNSCC surgery. Patients receiving radiation therapy had a higher 5-year CVD risk than surgery patients [HR (95% CI): 2.17 (1.31–3.04)]. Patients using antihypertensive medications had a lower 5-year CVD risk than patients without baseline hypertension [HR (95% CI): 0.45 (0.22–0.75)]. Older age and diabetes were associated with increased 1- and 5-year CVD risk. HPV-negative patients were older (p 0.006) and had a higher 5-year cumulative incidence of CVD (p 0.013) than HPV-positive patients.ConclusionTraditional risk factors and cancer-related factors are associated with CVD risk in HNSCC patients. Future research should investigate the role of antihypertensive medications in reducing CVD risk in HNSCC patients.

Abstract Objectives (1) To evaluate risk of hospitalization following initiation of perampanel (pre‐ and post‐analysis) and (2) to compare hospitalization rates following initiation of perampanel vs lacosamide. Methods Patients were identified from Symphony Health's Patient Integrated Database if they had a prescription for perampanel (July 1, 2014‐June 30, 2016). Patients 4‐11 years of age with any partial‐onset seizure (POS) or ≥12 years of age with any POS or primary generalized tonic‐clonic seizure (GTCS) (pre‐post); or ≥12 years of age (perampanel vs lacosamide). The first fill of perampanel (“index date”) marked the start of the analysis period. Patients had ≥1 additional fill for perampanel and ≥2 diagnoses for epilepsy or nonfebrile convulsion diagnosis during pre‐index (based on ICD‐9/ICD‐10 codes). Patients were matched using a 1:1 propensity scoring method for the perampanel vs lacosamide analysis. Primary outcome was hospitalization during the one year following medication initiation. Results Pre‐ and post‐perampanel: N = 1771 (mean age 34 years, 55% female). One‐year all‐cause hospitalization risk ratio was 0.76 (P

Upscaling in situ carbon flux measurements using remotely sensed and meteorological observations in a machine learning algorithm leads to improved estimates of average uptake, and interannual variability in global drylands.

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.MethodsSamples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.ResultsThere were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10−12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10−7). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10−4).DiscussionAlthough telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.

An in-house developed weight drop injury (WDI) device is a recently described animal model of traumatic brain injury (TBI) that was designed to produce a blunt, closed-head injury. More specifically, the apparatus was designed to reliably generate a wide range of TBI severities using precise and quantifiable biomechanical inputs in a nonsurgical user-friendly platform. The objective of this study was to define the lower limit of a single mild TBI (mTBI) impact using our WDI device by characterizing the relationship between the biomechanical input and the behavioral and histological inflammatory outcomes. Rats were subjected to a single mTBI impact using two impact energies of 0.2 and 0.5J, and post-impact outcomes were assessed over two recovery periods of 3- and 7-days. Here we report that a single, closed-head impact energy of 0.5J and below produces no significant phenotype. Despite the insignificant results of alterations in behavior and inflammatory analysis, the study revealed important aspects of lower-level impact loads. First, this work provides evidence in support of the notion that not every closed-head impact has the capacity to result in system perturbations. Although a theoretical injury threshold may not exist for rats using a WDI model, we hypothesize a biomechanical threshold of impact associated with a lack of functional impairment and neuroinflammation due to a single closed-head injury is likely around an energy level of 0.5 J.

Abstract Plasma fibrinogen is an important coagulation factor and susceptible to post-translational modification by oxidants. We have reported impairment of fibrin polymerization after exposure to hypochlorous acid (HOCl) and increased methionine oxidation of fibrinogen in severely injured trauma patients. Molecular dynamics suggests that methionine oxidation poses a mechanistic link between oxidative stress and coagulation through protofibril lateral aggregation by disruption of AαC domain structures. However, experimental evidence explaining how HOCl oxidation impairs fibrinogen structure and function has not been demonstrated. We utilized polymerization studies and two dimensional-nuclear magnetic resonance spectrometry (2D-NMR) to investigate the hypothesis that HOCl oxidation alters fibrinogen conformation and T2 relaxation time of water protons in the fibrin gels. We have demonstrated that both HOCl oxidation of purified fibrinogen and addition of HOCl-oxidized fibrinogen to plasma fibrinogen solution disrupted lateral aggregation of protofibrils similarly to competitive inhibition of fibrin polymerization using a recombinant AαC fragment (AαC 419–502). DOSY NMR measurement of fibrinogen protons demonstrated that the diffusion coefficient of fibrinogen increased by 17.4%, suggesting the oxidized fibrinogen was more compact and fast motion in the prefibrillar state. 2D-NMR analysis reflected that water protons existed as bulk water (T2) and intermediate water (T2i) in the control plasma fibrin. Bulk water T2 relaxation time was increased twofold and correlated positively with the level of HOCl oxidation. However, T2 relaxation of the oxidized plasma fibrin gels was dominated by intermediate water. Oxidation induced thinner fibers, in which less water is released into the bulk and water fraction in the hydration shell was increased. We have confirmed that T2 relaxation is affected by the self-assembly of fibers and stiffness of the plasma fibrin gel. We propose that water protons can serve as an NMR signature to probe oxidative rearrangement of the fibrin clot.

Abstract Introduction The learning health system (LHS) aligns science, informatics, incentives, stakeholders, and culture for continuous improvement and innovation. The Agency for Healthcare Research and Quality and the Patient‐Centered Outcomes Research Institute designed a K12 initiative to grow the number of LHS scientists. We describe approaches developed by 11 funded centers of excellence (COEs) to promote partnerships between scholars and health system leaders and to provide mentored research training. Methods Since 2018, the COEs have enlisted faculty, secured institutional resources, partnered with health systems, developed and implemented curricula, recruited scholars, and provided mentored training. Program directors for each COE provided descriptive data on program context, scholar characteristics, stakeholder engagement, scholar experiences with health system partnerships, roles following program completion, and key training challenges. Results To date, the 11 COEs have partnered with health systems to train 110 scholars. Nine (82%) programs partner with a Veterans Affairs health system and 9 (82%) partner with safety net providers. Clinically trained scholars (n = 87; 79%) include 70 physicians and 17 scholars in other clinical disciplines. Non‐clinicians (n = 29; 26%) represent diverse fields, dominated by population health sciences. Stakeholder engagement helps scholars understand health system and patient/family needs and priorities, enabling opportunities to conduct embedded research, improve outcomes, and grow skills in translating research methods and findings into practice. Challenges include supporting scholars through roadblocks that threaten to derail projects during their limited program time, ranging from delays in access to data to COVID‐19‐related impediments and shifts in organizational priorities. Conclusions Four years into this novel training program, there is evidence of scholars' accomplishments, both in traditional academic terms and in terms of moving along career trajectories that hold the potential to lead and accelerate transformational health system change. Future LHS training efforts should focus on sustainability, including organizational support for scholar activities.

Changing rainfall patterns will alter soil water availability to plants and microbes and likely impact soil CO2 efflux (Fs) in semiarid ecosystems. However, our understanding of the response of Fs to compound changes in rainfall event size and frequency remains relatively limited. To address this knowledge gap, we examined how compound changes in rainfall size and frequency impact Fs in a semiarid grassland by deploying automated soil chambers at a rainfall manipulation experiment. All plots within the experiment received equal total summer growing season precipitation that was temporally repackaged into regular events of inversely varied size and frequency, with event sizes ranging from 5 to 50 mm and dry intervals ranging from 3.5 to 21 days. We found that repackaging rainfall into few/large events with long dry intervals decreased seasonal cumulative Fs. Repackaging influenced key aspects of pulses including mean, maximum, and antecedent (day before irrigation) values of soil moisture and Fs and their rate of decline during drying intervals. Soil moisture explained substantial variation in Fs (R2 > 0.84) for all treatments; however, the sensitivity of Fs to soil moisture decreased in the few/large regime compared to the reference and many/small regimes. Dynamics in plant phenology (quantified by plot greenness) and soil temperature interacted with soil moisture to influence the seasonal evolution of Fs pulses and cumulative efflux. Our findings demonstrate that soil moisture and vegetation responses to changes in rainfall size and frequency impact soil CO2 efflux pulses and seasonal emissions in semiarid grasslands. These results, coupled with the knowledge that CO2 efflux pulses play an outsized role in dryland carbon exchange, indicate the possibility of future climate-mediated shifts in the carbon cycling of semiarid ecosystems.

The purpose of this study was to explore the professional impact that a youth-centered service-learning program had on college students. Participants were 34 undergraduate students (28 females, 6 males) enrolled in an academic core course that integrated Lifetime Exercise and Physical Activity Service-Learning (LE PAS), an after-school program developed to address the physical and social needs of hurricane displaced K-5 youth living in a travel trailer community. The students worked in LE PAS-related activities and completed a series of reflections. Inductive analysis revealed that a youth-centered service-learning program was effective for (a) getting college students to think seriously about working with youth professionally, and (b) discovering and adopting valuable strategies for working with youth.

ObjectiveSpine injury is highly prevalent in patients with poly-trauma, but data on the co-occurrence of spine trauma in patients with traumatic brain injury (TBI) are scarce. In this study, we used the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) database to assess the prevalence, characteristics, and outcomes of patients with TBI and a concurrent traumatic spinal injury (TSI).MethodsData from the European multi-center CENTER-TBI study were analyzed. Adult patients with TBI (≥18 years) presenting with a concomitant, isolated TSI of at least serious severity (Abbreviated Injury Scale; AIS ≥3) were included. For outcome analysis, comparison groups of TBI patients with TSI and systemic injuries (non-isolated TSI) and without TSI were created using propensity score matching. Rates of mortality, unfavorable outcomes (Glasgow Outcome Scale Extended; GOSe < 5), and full recovery (GOSe 7–8) of all patients and separately for patients with only mild TBI (mTBI) were compared between groups at 6-month follow-up.ResultsA total of 164 (4%) of the 4,254 CENTER-TBI core study patients suffered from a concomitant isolated TSI. The median age was 53 [interquartile range (IQR): 37–66] years and 71% of patients were men. mTBI was documented in 62% of cases, followed by severe TBI (26%), and spine injuries were mostly cervical (63%) or thoracic (31%). Surgical spine stabilization was performed in 19% of cases and 57% of patients were admitted to the ICU. Mortality at 6 months was 11% and only 36% of patients regained full recovery. There were no significant differences in the 6-month rates of mortality, unfavorable outcomes, or full recovery between TBI patients with and without concomitant isolated TSI. However, concomitant non-isolated TSI was associated with an unfavorable outcome and a higher mortality. In patients with mTBI, a negative association with full recovery could be observed for both concomitant isolated and non-isolated TSI.ConclusionRates of mortality, unfavorable outcomes, and full recovery in TBI patients with and without concomitant, isolated TSIs were comparable after 6 months. However, in patients with mTBI, concomitant TSI was a negative predictor for a full recovery. These findings might indicate that patients with moderate to severe TBI do not necessarily exhibit worse outcomes when having a concomitant TSI, whereas patients with mTBI might be more affected.

Abstract Cas9 nucleases permit rapid and efficient generation of gene-edited cell lines. However, in typical protocols, mutations are intentionally introduced into the donor template to avoid the cleavage of donor template or re-cleavage of the successfully edited allele, compromising the fidelity of the isogenic lines generated. In addition, the double-stranded breaks (DSBs) used for editing can introduce undesirable “on-target” indels within the second allele of successfully modified cells via non-homologous end joining (NHEJ). To address these problems, we present an optimized protocol for precise genome editing in human iPSCs that employs (1) single guided Cas9 nickase to generate single-stranded breaks (SSBs), (2) transient overexpression of BCL-XL to enhance survival post electroporation, and (3) the PiggyBac transposon system for seamless removal of dual selection markers. We have used this method to modify the length of the CAG repeat contained in exon 7 of PPP2R2B. When longer than 43 triplets, this repeat causes the neurodegenerative disorder spinocerebellar ataxia type 12 (SCA12); our goal was to seamlessly introduce the SCA12 mutation into a human control iPSC line. With our protocol, ~ 15% of iPSC clones selected had the desired gene editing without “on target” indels or off-target changes, and without the deliberate introduction of mutations via the donor template. This method will allow for the precise and efficient editing of human iPSCs for disease modeling and other purposes.

Diffu0sion-weighted magnetic resonance imaging (dMRI) is a non-invasive imaging technique that provides information about the barriers to the diffusion of water molecules in tissue. In the brain, this information can be used in several important ways, including to examine tissue abnormalities associated with brain disorders and to infer anatomical connectivity and the organization of white matter bundles through the use of tractography algorithms. However, dMRI also presents certain challenges. For example, historically, the biological validation of tractography models has shown only moderate correlations with anatomical connectivity as determined through invasive tract-tracing studies. Some of the factors contributing to such issues are low spatial resolution, low signal-to-noise ratios, and long scan times required for high-quality data, along with modeling challenges like complex fiber crossing patterns. Leveraging the capabilities provided by an ultra-high field scanner combined with denoising, we have acquired whole-brain, 0.58 mm isotropic resolution dMRI with a 2D-single shot echo planar imaging sequence on a 10.5 Tesla scanner in anesthetized macaques. These data produced high-quality tractograms and maps of scalar diffusion metrics in white matter. This work demonstrates the feasibility and motivation for in-vivo dMRI studies seeking to benefit from ultra-high fields.

Wood turtles (Glyptemys insculpta) have been suffering range-wide population declines since the 1900s. Most monitoring efforts of these turtles involve population surveys to assess population size and viability but relatively few investigate rates of reproductive success. We collected four consecutive years (2013–2016) of wood turtle nesting data at a nesting site in northwestern New Jersey; population-level hatching success was unusually low. Furthermore, annual, intra-individual hatch rates and comparisons between natural and artificial incubation revealed that approximately half of all females usually produced clutches with low (50%) or highly variable, ranging from 0 to 100%. Thus, some adult females are potentially making much larger contributions to the next generation than others. A repeatability analysis suggested that approximately 60% of the hatch rate variability observed in this population can be attributed to maternal identity. The remaining 40% may be attributed to the random environmental factors that are often theorized to be potential reasons for reduced hatch rates in turtle populations (e.g., unsuitable incubation conditions, flooding, desiccation, egg infertility, egg damage due to improper handling by researchers, root and insect predation, and microbial infection). The ultimate causes of this population’s hatching success variability are uncertain, but maternally-linked hatching failure in turtle populations could be associated with inbreeding, infertility, senescence, inadequate maternal diets, or environmental contamination. This study indicates that commonly suggested hypotheses for hatching failure, such as unsuitable incubation conditions or infertility, are unlikely to explain all of the hatch rate variability in some turtle populations. This study also reveals a cryptic conservation implication for vulnerable turtle populations: that the presence of many nesting females and nests does not necessarily assure high or even sustainable reproductive rates. When coupled with the high rates of nest predation and low juvenile survival rates that are common in most turtle populations, the exceedingly low hatch rates observed in this population suggest that recruitment in some turtle populations could be severely hindered even when nests are protected in the field or incubated in laboratory settings.

Objective:. This study employs qualitative methodology to assess surgeons’ perspective on decision making in management of recurrent diverticulitis to improve patient-centered decision making. Background:. The decision to pursue colectomy for patients with recurrent diverticulitis is nuanced. Strategies to enact broad acceptance of guidelines for surgery are hindered because of a knowledge gap in understanding surgeons’ current attitudes and opinions. Methods:. We performed semistructured interviews with board-certified North American general and colorectal surgeons who manage recurrent diverticulitis. We purposely sampled specialists by both surgeon and practice factors. An iterative inductive/deductive strategy was used to code and analyze the interviews and create a conceptual framework. Results:. Twenty-five surgeons were enrolled over a 9-month period. There was diversity in surgeons’ gender, age, experience, training, specialty (colorectal vs general surgery), and geography. Surgeons described the difficult process to determine who receives an operation. We identified 7 major themes as well as 20 subthemes of the decision-making process. These were organized into a conceptual model. Across the spectrum of interviews, it was notable that there was a move over time from decisions based on counting episodes of diverticulitis to a focus on improving quality of life. Surgeons also felt that quality of life was more dependent on psychosocial factors than the degree of physiological dysfunction. Conclusions:. Surgeons mostly have discarded older dogma in recommending colectomy for recurrent diverticulitis based on number and severity of episodes. Instead, decision making in recurrent diverticulitis is complex, involving multiple surgeon and patient factors and evolving over time. Surgeons struggle with this decision and education- or communication-based interventions that focus on shared decision-making warrant development.

BackgroundCircadian misalignment between behaviors such as feeding and endogenous circadian rhythms, particularly in the context of shiftwork, is associated with poorer cardiometabolic health. We examined whether insulin and leptin levels differ between dayshift versus nightshift nurses, as well as explored whether the timing of food intake modulates these effects in nightshift workers.MethodsFemale nurses (N=18; 8 dayshift and 10 nightshift) completed daily diet records for 8 consecutive days. The nurses then completed a 24-h inpatient stay, during which blood specimens were collected every 3 h (beginning at 09:00) and meals were consumed at regular 3-h intervals (09:00, 12:00, 15:00, and 18:00). Specimens were analyzed for insulin and leptin levels, and generalized additive models were used to examine differences in mean insulin and leptin levels.ResultsMean insulin and leptin levels were higher in nightshift nurses by 11.6 ± 3.8 mU/L (p=0.003) and 7.4 ± 3.4 ng/ml (p=0.03), respectively, compared to dayshift nurses. In an exploratory subgroup analysis of nightshift nurses, predominately eating at night (21:00 – 06:00) was associated with significantly higher insulin and leptin levels than consuming most calories during the daytime (06:00 – 21:00).ConclusionsIn our study of hospital nurses, working the nightshift was associated with higher insulin and leptin levels, and these effects were driven by eating predominately at night. We conclude that although nightshift work may raise insulin and leptin levels, eating during the daytime may attenuate some of the negative effects of nightshift work on metabolic health.