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Ticks are increasingly important vectors of human and agricultural diseases. While many studies have focused on tick-borne bacteria, far less is known about tick-associated viruses and their roles in public health or tick physiology. To address this, we investigated patterns of bacterial and viral communities across two field populations of western black-legged ticks (Ixodes pacificus). Through metatranscriptomic analysis of 100 individual ticks, we quantified taxon prevalence, abundance, and co-occurrence with other members of the tick microbiome. In addition to commonly found tick-associated microbes, we assembled 11 novel RNA virus genomes from Rhabdoviridae, Chuviridae, Picornaviridae, Phenuiviridae, Reoviridae, Solemovidiae, Narnaviridae and two highly divergent RNA virus genomes lacking sequence similarity to any known viral families. We experimentally verified the presence of these in I. pacificus ticks across several life stages. We also unexpectedly identified numerous virus-like transcripts that are likely encoded by tick genomic DNA, and which are distinct from known endogenous viral element-mediated immunity pathways in invertebrates. Taken together, our work reveals that I. pacificus ticks carry a greater diversity of viruses than previously appreciated, in some cases resulting in evolutionarily acquired virus-like transcripts. Our findings highlight how pervasive and intimate tick-virus interactions are, with major implications for both the fundamental biology and vectorial capacity of I. pacificus ticks.ImportanceTicks are increasingly important vectors of disease, particularly in the United States where expanding tick ranges and intrusion into previously wild areas has resulted in increasing human exposure to ticks. Emerging human pathogens have been identified in ticks at an increasing rate, and yet little is known about the full community of microbes circulating in various tick species, a crucial first step to understanding how they interact with each and their tick host, as well as their ability to cause disease in humans. We investigated the bacterial and viral communities of the Western blacklegged tick in California and found 11 previously uncharacterized viruses circulating in this population.

Electrochemical carbon dioxide reduction represents a promising path to utilize CO2 as a feedstock for generating valuable products such as fuels and chemicals. Faradaic efficiencies near 100% have been achieved for certain CO2 reduction products such as CO, but the electrolyzer outlet streams usually contain large fractions of unreacted CO2, dropping the product concentrations below 1% in many cases. The system disclosed here recycles the unreacted CO2 together with the products and flows them back into the CO2 reduction reactor, enabling much higher CO2 conversion rates without dropping the gas flow rate. However, simple recirculation is shown to accumulate significant amounts of hydrogen, impeding effective CO2 reduction. In this looped system, an electrochemical H2 pump is placed in series with the CO2 reactor, which effectively removes all the H2 from the recycled gas stream, increasing the concentrations of carbon-containing products. The system was initially tested with a CO-generating catalyst and CO concentrations above 70% were achieved in the recycled gas stream, compared to a maximum CO concentration of 8% in single-pass configuration. Results with a CO2 reactor targeting ethylene as the main product show that ethylene concentrations of at least 10% can be achieved, which is roughly 20 times higher compared to a single-pass system.

Abstract Background A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials. Methods Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 109 to 4 × 1012 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period. Results Across all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405). Conclusion TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation. Trial registrations TUNIMO—NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327 . TUNINTIL—NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473 . PROTA—NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318 .

There is abundant literature about interviewer effects on the survey process, but studies of interviewer training are quite limited. Previous research has produced mixed findings on how training affects interviewer performance. Trainings are often conducted in person despite the mixed findings. There has been no research that examines the use of videoconferencing as a medium for training field survey interviewers. We conducted an interviewer training experiment with the Medical Expenditure Panel Survey (MEPS). We randomly assigned 242 field interviewers into three training modes: in person, videoconference (i.e., WebEx), and self-administered training. Each interviewer's performance was observed before and after the training. As post-hoc analysis, we observed improvement for higher performed interviewers trained in videoconference. Interviewers trained in videoconference rated their experiences similar to their counterparts trained in person.

Ensuring a stable pool of teachers is critical to building a pipeline of future workers, especially in career and technical education (CTE), where programming can lead to immediate post-school employment or postsecondary enrollment. We use longitudinal state data with unemployment insurance records to document workforce dynamics among CTE teachers. We find that teachers in hard-to-staff CTE areas are more likely to leave teaching and are difficult to replace, creating net reductions in the number of students who can be served. We demonstrate that teachers with the greatest likelihood of leaving are also those who earn the most money in their post-teaching employment, suggesting actionable dimensions for policies to help retain or recruit teachers in these areas.

Ancestral Coast Salish societies in the Pacific Northwest kept long-haired woolly dogs that were bred and cared for over millennia. However, the dog wool-weaving tradition declined during the 19th century, and the population was lost. In this study, we analyzed genomic and isotopic data from a preserved woolly dog pelt from Mutton, collected in 1859. Mutton is the only known example of an Indigenous North American dog with dominant precolonial ancestry postdating the onset of settler colonialism. We identified candidate genetic variants potentially linked with their distinct woolly phenotype. We integrated these data with interviews from Coast Salish Elders, Knowledge Keepers, and weavers about shared traditional knowledge and memories surrounding woolly dogs, their importance within Coast Salish societies, and how colonial policies led directly to their disappearance.

While dialysis has been the prevailing treatment paradigm for patients with advanced chronic kidney disease (CKD), emphasis on conservative and preservative management in which dietary interventions are a major cornerstone have emerged. Based on high-quality evidence, international guidelines support the utilization of low-protein diets as an intervention to reduce CKD progression and mortality risk, although the precise thresholds (if any) for dietary protein intake vary across recommendations. There is also increasing evidence demonstrating that plant-dominant low-protein diets reduce the risk of developing incident CKD, CKD progression, and its related complications including cardiometabolic disease, metabolic acidosis, mineral and bone disorders, and uremic toxin generation. In this review, we discuss the premise for conservative and preservative dietary interventions, specific dietary approaches used in conservative and preservative care, potential benefits of a plant-dominant low-protein diet, and practical implementation of these nutritional strategies without dialysis.

Abstract Bats (order: Chiroptera) are known to host a diverse range of viruses, some of which present a human public health risk. Thorough viral surveillance is therefore essential to predict and potentially mitigate zoonotic spillover. Astroviruses (family: Astroviridae) are an understudied group of viruses with a growing amount of indirect evidence for zoonotic transfer. Astroviruses have been detected in bats with significant prevalence and diversity, suggesting that bats may act as important astrovirus hosts. Most astrovirus surveillance in wild bat hosts has, to date, been restricted to single-gene PCR detection and concomitant Sanger sequencing; additionally, many bat species and many geographic regions have not yet been surveyed for astroviruses at all. Here, we use metagenomic Next Generation Sequencing (mNGS) to detect astroviruses in three species of Madagascar fruit bats, Eidolon dupreanum, Pteropus rufus, and Rousettus madagascariensis. We detect numerous partial sequences from all three species and one near-full length astrovirus sequence from Rousettus madagascariensis, which we use to characterize the evolutionary history of astroviruses both within bats and the broader mammalian clade, Mamastrovirus. Taken together, applications of mNGS implicate bats as important astrovirus hosts and demonstrate novel patterns of bat astrovirus evolutionary history, particularly in the Southwest Indian Ocean region.

Abstract Introduction Arthrodesis of a (diseased) ankle joint is usually performed to achieve pain relief and stability. One basic principle of arthrodesis techniques includes rigid fixation of the surfaces until union. It seems plausible that stable anchoring and homogeneous pressure distribution should be advantageous, however, it has not been investigated yet. The aim is to achieve uniform compression, as this is expected to produce favorable results for the bony fusion of the intended arthrodesis. Numerous implants with different biomechanical concepts can be used for ankle fusion. In this study, headless compression screws (HCS, DePuy Synthes, Zuchwil, Switzerland) were compared biomechanically to an alternative fixation System, the IOFix device (Extremity Medical, Parsippany, NJ, USA) in regard to the distribution of the compression force (area of contact) and peak compression in a sawbone arthrodesis-model (Sawbones® Pacific Research Laboratories, Vashon, WA, USA). This study aims to quantify the area of contact between the bone interface that can be obtained using headless compression screws compared to the IOFix. In current literature, it is assumed, that a large contact surface with sufficient pressure between the bones brings good clinical results. However, there are no clinical or biomechanical studies, that describe the optimal compression pressure for an arthrodesis. Material and methods Two standardized sawbone blocks were placed above each other in a custom-made jig. IOFix and headless compression screws were inserted pairwise parallel to each other using a template for a uniform drilling pattern. All screws were inserted with a predefined torque of 0.5 Nm. Pressure transducers positioned between the two sawbone blocks were compressed for the measurement of peak compression force, compression distribution, and area of contact. Results With the IOFix, the compression force was distributed over significantly larger areas compared to the contact area of the HCS screws, resulting in a more homogenous contact area over the entire arthrodesis surface. Maximum compression force showed no significant difference. Conclusion The IOFix system distributes the compression pressure over a much larger area, resulting in more evenly spread compression at the surface. Clinical studies must show whether this leads to a lower pseudarthrosis rate.

OBJECTIVES:. Septic shock is a common condition necessitating timely management including hemodynamic support with vasopressors. Despite the high prevalence and mortality, there is limited data characterizing patients who require three or more vasopressors. We sought to define the demographics, outcomes, and prognostic determinants associated with septic shock requiring three or more vasopressors. DESIGN:. This is a multicenter retrospective cohort of two ICU databases, Medical Information Mart for Intensive Care IV (MIMIC-IV) and electronic ICU-Clinical Research Database, which include over 400,000 patients admitted to 342 ICUs. PATIENTS:. Inclusion criteria entailed patients who were: 1) age 18 years old and older, 2) admitted to any ICU, 3) administered at least three vasopressors for at least 2 hours at any time during their ICU stay, and 4) identified to have sepsis based on the Sepsis-3 criteria. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. A total of 3447 patients met inclusion criteria. The median age was 67 years, 60.5% were male, and 96.6% had full code orders at the time of the third vasopressor initiation. Septic shock requiring three or more vasopressors was associated with 57.6% in-hospital mortality. Code status changes occurred in 23.9% of patients following initiation of a third vasopressor. Elevated lactate upon ICU admission (odds ratio [95% CI], 2.79 [2.73–2.85]), increased duration of time between ICU admission and third vasopressor initiation (1.78 [1.69–1.87]), increased serum creatinine (1.61 [1.59–1.62]), and age above 60 years (1.47 [1.41–1.54]) were independently associated with an increased risk of mortality based on analysis of the MIMIC-IV database. Non-White race and Richmond Agitation-Sedation Scale scores were not associated with mortality. CONCLUSIONS:. Septic shock requiring three vasopressors is associated with exceptionally high mortality. Knowledge of patients at highest risk of mortality in this population may inform management and expectations conveyed in shared decision-making.

The outdoor operation of electrochemical solar fuels devices must contend with challenges presented by the cycles of solar irradiance, temperature, and other meteorological factors. Herein, we discuss challenges associated with these fluctuations presented over three timescales, including the effects of diurnal cycling over the course of many days, a single diurnal cycle over the course of hours, and meteorological phenomena that cause fluctuations on the order of seconds to minutes. We also highlight both reaction-independent and reaction-specific effects of variable conditions for the hydrogen evolution reaction and CO2 reduction reaction. We identify key areas of research for advancing the outdoor operation of solar fuels technology and highlight the need for metrics and benchmarks to enable the comparison of diurnal studies across systems and geographical locations.

The approximately 11-year solar cycle has been shown to impact the heavy ion composition of the solar wind, even when accounting for streams of differing speeds; however, the heavy ion composition observed between the same specific phases of a past solar cycle and the current cycle has rarely, if ever, been compared. Here, we compare the heavy ion composition of the solar wind, as measured in situ during the solar cycle 23 and 25 ascending phases. We examine the mean iron and oxygen charge state composition and the O7+/O6+ ratio in multiple ranges of associated bulk wind speeds. Then, we compare the iron and oxygen charge state composition and relative abundance of iron to oxygen in the traditionally defined fast and slow solar wind. Finally, to determine the impact of individual ion contributions on the solar wind iron abundance, we examine individual ratios of iron and oxygen ions. Although the charge state composition remained broadly similar between these two ascending phases, both the O7+/O6+ ratio and iron fractionation in fast-speed streams were higher in the solar cycle 25 ascending phase than they were during the solar cycle 23 ascending phase, suggesting that equatorial coronal hole fields more frequently reconnected with helmet streamers or active regions in the latter of the two ascending phases; however, more work will need to be done to connect these observations back to their coronal origins. The individual ion ratios used in this work provided a spectrum to analyze the aggregate elemental abundances, and this work, as a whole, is an important step in determining how conditions in the corona may vary between solar cycles between the same phases.

Jessica S Staempfli,1 Melanie Kistler-Fischbacher,2 Jan Gewiess,3 Johannes Dominik Bastian,3 Anna K Eggimann4 1Medical Faculty, University of Bern, Bern, Switzerland; 2Centre on Aging and Mobility, Department of Geriatrics and Aging Research, University of Zurich, Zurich, Switzerland; 3Department of Orthopaedic Surgery and Traumatology, Inselspital, Bern University Hospital, University of Bern, Bern, 3010, Switzerland; 4Department of Geriatrics, Inselspital, Bern University Hospital, and University of Bern, Bern, 3010, SwitzerlandCorrespondence: Anna K Eggimann, Department of Geriatrics, Inselspital, Bern University Hospital University of Bern, Freiburgstrasse 40, Bern, CH-3010, Switzerland, Tel +41 31 632 54 89, Email anna.eggimann@insel.chPurpose: Muscle ultrasound has emerged as a promising method in the diagnostic work-up of sarcopenia. The objective of this scoping review was to explore the validity of muscle ultrasound against the latest sarcopenia definitions among older adults.Methods: We adhered to the PRISMA guidelines for scoping reviews. A systematic search of databases was performed by two independent reviewers. All articles comparing the performance of ultrasound to an internationally acknowledged sarcopenia definition among older adults (≥ 60 years) and published between 2019/01/01 (the year updated sarcopenia definitions were introduced) and 2023/11/15 were included. Data were extracted and collated by muscle and muscle parameters.Results: Out of 2290 articles screened, six studies comprising 24 validity tests among a total of 1619 older adults (mean age 74.1 years, 52.2% female) were included. The validity tests investigated the rectus femoris (n = 7), biceps brachii (n = 5), gastrocnemius medialis (n = 4), tibialis anterior (n = 4), soleus (n = 3), and rectus abdominis (n = 1). The parameter muscle thickness (MT) (n = 14) was most commonly measured. The latest European and Asian sarcopenia definitions (EWGSOP2, AWGS2) were applied as reference standards in four validity tests each. None of the studies used the Sarcopenia Definition and Outcome Consortium (SDOC) criteria. The highest area under the curve AUC (0.92, 95% confidence interval [CI] 0.89– 0.94) was found for the muscle thickness of the rectus femoris muscle. Due to substantial heterogeneity among the studies, pooling of data using a meta-analytic approach was not feasible.Conclusion: Limited number of studies have examined the validity of muscle ultrasound for diagnosing sarcopenia based on recent definitions among older adults. Thereby, muscle thickness of the rectus femoris showed promising results regarding validity. Further studies are needed to investigate the validity of key muscles and to validate muscle ultrasound among older hospitalized patients.Keywords: geriatric assessment, muscle thickness, cross-sectional area, rectus femoris, POCUS, SARCUS, EWGSOP, AWGS, SDOC

Abstract The squash family (Cucurbitaceae) contains some of the most important crops cultivated worldwide and has played an important ecological, economic, and cultural role for millennia. In the American tropics, squashes were among the first cultivated crop species, but little is known about how their domestication unfolded. Here, we employ direct radiocarbon dating and morphological analyses of desiccated cucurbit seeds, rinds, and stems from El Gigante Rockshelter in Honduras to reconstruct human practices of selection and cultivation of Lagenaria siceraria, Cucurbita pepo, and Cucurbita moschata. Direct radiocarbon dating indicates that humans started using Lagenaria and wild Cucurbita starting ~ 10,950 calendar years before present (cal B.P.), primarily as watertight vessels and possibly as cooking and drinking containers. A rind directly dated to 11,150–10,765 cal B.P. represents the oldest known bottle gourd in the Americas. Domesticated C. moschata subsequently appeared ~ 4035 cal B.P., followed by domesticated C. pepo ~ 2190 cal B.P. associated with increasing evidence for their use as food crops. Multivariate statistical analysis of seed size and shape show that the archaeological C. pepo assemblage exhibits significant variability, representing at least three varieties: one similar to present-day zucchini, another like present-day vegetable marrow, and a native cultivar without modern analogs. Our archaeobotanical data supports the hypothesis that Indigenous cucurbit use started in the Early Holocene, and that agricultural complexity during the Late Holocene involved selective breeding that encouraged crop diversification.

Abstract Background Breeding queens may be mated with drones that are produced by a single drone-producing queen (DPQ), or a group of sister-DPQs, but often only the dam of the DPQ(s) is reported in the pedigree. Furthermore, datasets may include colony phenotypes from DPQs that were open-mated at different locations, and thus to a heterogeneous drone population. Methods Simulation was used to investigate the impact of the mating strategy and its modelling on the estimates of genetic parameters and genetic trends when the DPQs are treated in different ways in the statistical evaluation model. We quantified the bias and standard error of the estimates when breeding queens were mated to one DPQ or a group of DPQs, assuming that this information was known or not. We also investigated four alternative strategies to accommodate the phenotypes of open-mated DPQs in the genetic evaluation: excluding their phenotypes, adding a dummy pseudo-sire in the pedigree, or adding a non-genetic (fixed or random) effect to the statistical evaluation model to account for the origin of the mates. Results The most precise estimates of genetic parameters and genetic trends were obtained when breeding queens were mated with drones of single DPQs that are correctly assigned in the pedigree. However, when they were mated with drones from one or a group of DPQs, and this information was not known, erroneous assumptions led to considerable bias in these estimates. Furthermore, genetic variances were considerably overestimated when phenotypes of colonies from open-mated DPQs were adjusted for their mates by adding a dummy pseudo-sire in the pedigree for each subpopulation of open-mating drones. On the contrary, correcting for the heterogeneous drone population by adding a non-genetic effect in the evaluation model produced unbiased estimates. Conclusions Knowing only the dam of the DPQ(s) used in each mating may lead to erroneous assumptions on how DPQs were used and severely bias the estimates of genetic parameters and trends. Thus, we recommend keeping track of DPQs in the pedigree, and not only of the dams of DPQ(s). Records from DPQ colonies with queens open-mated to a heterogeneous drone population can be integrated by adding non-genetic effects to the statistical evaluation model.

Abstract Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.

The continued emergence of SARS-CoV-2 variants is one of several factors that may cause false-negative viral PCR test results. Such tests are also susceptible to false-positive results due to trace contamination from high viral titer samples. Host immune response markers provide an orthogonal indication of infection that can mitigate these concerns when combined with direct viral detection. Here, we leverage nasopharyngeal swab RNA-seq data from patients with COVID-19, other viral acute respiratory illnesses, and nonviral conditions (n = 318) to develop support vector machine classifiers that rely on a parsimonious 2-gene host signature to diagnose COVID-19. We find that optimal classifiers include an interferon-stimulated gene that is strongly induced in COVID-19 compared with nonviral conditions, such as IFI6, and a second immune-response gene that is more strongly induced in other viral infections, such as GBP5. The IFI6+GBP5 classifier achieves an area under the receiver operating characteristic curve (AUC) greater than 0.9 when evaluated on an independent RNA-seq cohort (n = 553). We further provide proof-of-concept demonstration that the classifier can be implemented in a clinically relevant RT-qPCR assay. Finally, we show that its performance is robust across common SARS-CoV-2 variants and is unaffected by cross-contamination, demonstrating its utility for improved accuracy of COVID-19 diagnostics. IMPORTANCE In this work, we study upper respiratory tract gene expression to develop and validate a 2-gene host-based COVID-19 diagnostic classifier and then demonstrate its implementation in a clinically practical qPCR assay. We find that the host classifier has utility for mitigating false-negative results, for example due to SARS-CoV-2 variants harboring mutations at primer target sites, and for mitigating false-positive viral PCR results due to laboratory cross-contamination. Both types of error carry serious consequences of either unrecognized viral transmission or unnecessary isolation and contact tracing. This work is directly relevant to the ongoing COVID-19 pandemic given the continued emergence of viral variants and the continued challenges of false-positive PCR assays. It also suggests the feasibility of pan-respiratory virus host-based diagnostics that would have value in congregate settings, such as hospitals and nursing homes, where unrecognized respiratory viral transmission is of particular concern.

El Gigante rockshelter in western Honduras provides a deeply stratified archaeological record of human-environment interaction spanning the entirety of the Holocene. Botanical materials are remarkably well preserved and include important tree (e.g., ciruela (Spondias), avocado (Persea americana)) and field (maize (Zea mays), beans (Phaseolus), and squash (Cucurbita)) crops. Here we provide a major update to the chronology of tree and field crop use evident in the sequence. We report 375 radiocarbon dates, a majority of which are for short-lived botanical macrofossils (e.g., maize cobs, avocado seeds, or rinds). Radiocarbon dates were used in combination with stratigraphic details to establish a Bayesian chronology for ~9,800 identified botanical samples spanning the last 11,000 years. We estimate that at least 16 discrete intervals of use occurred during this time, separated by gaps of ~100-2,000 years. The longest hiatus in rockshelter occupation was between ~6,400 and 4,400 years ago and the deposition of botanical remains peaked at ~2,000 calendar years before present (cal BP). Tree fruits and squash appeared early in the occupational sequence (~11,000 cal BP) with most other field crops appearing later in time (e.g., maize at ~4,400 cal BP; beans at ~2,200 cal BP). The early focus on tree fruits and squash is consistent with early coevolutionary partnering with humans as seed dispersers in the wake of megafaunal extinction in Mesoamerica. Tree crops predominated through much of the Holocene, and there was an overall shift to field crops after 4,000 cal BP that was largely driven by increased reliance on maize farming.

Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration-response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10-10 to 10-5 M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration-response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (- logEC50: - 5.73 ± 0.25 vs. - 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (- logEC50: - 6.62 ± 0.21 vs. - 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r2 = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS.

Introduction: Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis. We investigated plasma protease activity patterns in COVID-19-induced sepsis with bacterial superinfection, as well as plasma proteomics and peptidomics in order to assess the possible implications of enhanced proteolysis on major protein systems (e.g., coagulation). Methods: Patients (=4) admitted to the intensive care units (ICUs) at the University of California, San Diego (UCSD) Medical Center with confirmed positive test for COVID-19 by real-time reverse transcription polymerase chain reaction (RT-PCR) were enrolled in a study approved by the UCSD Institutional Review Board (IRB# 190699, Protocol #20-0006). Informed consent was obtained for the collection of blood samples and de-identified use of the data. Blood samples were collected at multiple time points and analyzed to quantify a) the circulating proteome and peptidome by mass spectrometry; b) the aminopeptidase activity in plasma; and c) the endopeptidase activity in plasma using fluorogenic substrates that are cleaved by trypsin-like endopeptidases, specific clotting factors and plasmin. The one patient who died was diagnosed with bacterial superinfection on day 7 after beginning of the study. Results: Spikes in protease activity (factor VII, trypsin-like activity), and corresponding increases in the intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products and downregulation of endogenous protease inhibitors were detected on day 7 for the patient who died. The activity of the analyzed proteases was stable in survivors. Discussion: The combination of multiomics and enzymatic activity quantification enabled to i) hypothesize that elevated proteolysis occurs in COVID-19-induced septic shock with bacterial superinfection, and ii) provide additional insight into malfunctioning protease-mediated systems, such as hemostasis.

Abstract Previous simulations have suggested that O+ outflow plays a role in driving the sawtooth oscillations. This study investigates the role of O+ by identifying the differences in ionospheric outflow between sawtooth and non‐sawtooth storms using 11 years of FAST/Time of flight Energy Angle Mass Spectrograph (TEAMS) ion composition data from 1996 through 2007 during storms driven by coronal mass ejections. We find that the storm's initial phase shows larger O+ outflow during non‐sawtooth storms, and the main and recovery phases revealed differences in the location of ionospheric outflow. On the pre‐midnight sector, a larger O+ outflow was observed during the main phase of sawtooth storms, while non‐sawtooth storms exhibited stronger O+ outflow during the recovery phase. On the dayside, the peak outflow shifts significantly toward dawn during sawtooth storms. This strong dawnside sector outflow during sawtooth storms warrants consideration.