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The core G protein signaling module, which consists of Gα and extra-large Gα (XLG) subunits coupled with the Gβγ dimer, is a master regulator of various stress responses. In this study, we compared the basal and salt stress-induced transcriptomic, metabolomic and phenotypic profiles in Gα, Gβ, and XLG-null mutants of two plant species, Arabidopsis thaliana and Marchantia polymorpha, and showed that G protein mediates the shift of transcriptional and metabolic homeostasis to stress readiness status. We demonstrated that such stress readiness serves as an intrinsic protection mechanism against further stressors through enhancing the phenylpropanoid pathway and abscisic acid responses. Furthermore, WRKY transcription factors were identified as key intermediates of G protein-mediated homeostatic shifts. Statistical and mathematical model comparisons between A. thaliana and M. polymorpha revealed evolutionary conservation of transcriptional and metabolic networks over land plant evolution, whereas divergence has occurred in the function of plant-specific atypical XLG subunit. Taken together, our results indicate that the shifts in transcriptional and metabolic homeostasis at least partially act as the mechanisms of G protein-coupled stress responses that are conserved between two distantly related plants.

The aim of this study was to determine if any suspected adverse drug reactions (ADRs) observed with the use of angiotensin II receptor blockers (ARBs) could be linked to either (a) their unique respective physicochemical and pharmacological profiles and (b) the recently disclosed suspected carcinogenic manufacturing contaminants found in certain sartan drug class batches.The pharmacology profiles of ARBs were data-mined from the Chemical Database of bioactive molecules with drug-like properties, European Molecular Biology Laboratory (ChEMBL). Suspected ADR data (from 01/2016-10/2022, inclusive) and prescribing rates of ARBs over a 5-year prescribing window (from 09/2016 to 08/2021, inclusive) were obtained via analysis of the United Kingdom Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profile and Open prescribing databases, respectively.The overall suspected ADRs and fatalities per 100 000 prescriptions identified across the ARBs studied were found to be different between the sartan drug class members (chi-squared test, P .05). There is a greater relative rate of reports for valsartan across all investigated organ classes of ADRs, than other ARBs, despite valsartan's more limited pharmacological profile and similar physicochemical properties to other sartans. The disparity in ADR reporting rates with valsartan vs other ARBs could be due to the dissimilarity in formulation excipients, patient factors and publicity surrounding batch contaminations, amongst others. Cancer-related ADRs and fatalities per 100 000 prescriptions identified across the ARBs studied are not statistically significant (chi-squared test, P .05) based on the datasets used over the 5-year period.No connection between ARB pharmacology and their suspected ADRs could be found. No conclusion between sartan batch contaminations and increased suspected cancer-related ADRs was found.

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

This Personal Account describes the author's groups' research in the field of electrosynthetic anodic oxidation, beginning with initial trial and error attempts with the Shono oxidation. Early setbacks with complex rotameric amide mixtures, provided the ideal environment for the discovery of the Oxa-Shono reaction-Osp 2 -Csp 3 bond cleavage of esters-providing two useful products in one-step: aldehyde selective oxidation level products and a mild de-esterification method to afford carboxylic acids in the process. The development of the Oxa-Shono reaction provided the impetus for the discovery of other electrically propelled-Nsp 2 -Csp 2 and Nsp 2 -Csp 3 -bond breaking reactions in bioactive amide and sulfonamide systems. Understanding the voltammetric behaviour of the molecule under study, switching between controlled current- or controlled potential- electrolysis, and restricting electron flow (the reagent), affords exquisite control over the reaction outcomes in batch and flow. Importantly, this bio-inspired advance in electrosynthetic dealkylation chemistry mimics the metabolic outcomes observed in nature.

Variability in the blood-breath ratio (BBR) of alcohol is important, because it relates a measurement of the blood-alcohol concentration (BAC) with the co-existing breath-alcohol concentration (BrAC). The BBR is also used to establish the statutory BrAC limit for driving from the existing statutory BAC limits in different countries. Thein-vivoBBR depends on a host of analytical, sampling and physiological factors, including subject demographics, time after end of drinking (rising or falling BAC), the nature of the blood draw (whether venous or arterial) and the subjects breathing pattern prior to exhalation into the breath analyzer. The results from a controlled drinking study involving healthy volunteers (85 men and 15 women) from three ethnic groups (Caucasians, Hispanics and African Americans) were used to evaluate various factors influencing the BBR. Ethanol in breath was determined with a quantitative infrared analyzer (Intoxilyzer 8000) and BAC was determined by headspace gas chromatography (HS-GC). The BAC and BrAC were highly correlated (r = 0.948) and the BBR in the post-absorptive state was 2 382 +/- 119 (mean +/- SD). The BBR did not depend on gender (female: 2 396 +/- 101 and male: 2 380 +/- 123,P > 0.05) nor on racial group (Caucasians 2 398 +/- 124, African Americans 2 344 +/- 119 and Hispanics 2 364 +/- 104,P > 0.05). The BBR was lower in subjects with higher breath- and body-temperatures (P < 0.05) and it also decreased with longer exhalation times into the breath-analyzer (P < 0.001). In the post-absorptive state, none of the 100 subjects had a BBR of less than 2 100:1.

Purpose Microbial infection stimulates neutrophil/macrophage/monocyte extracellular trap formation, which leads to the release of citrullinated histone H3 (CitH3) catalyzed by peptidylarginine deiminase (PAD) 2 and 4. Understanding these molecular mechanisms in the pathogenesis of septic shock will be an important next step for developing novel diagnostic and treatment modalities. We sought to determine the expression of CitH3 in patients with septic shock, and to correlate CitH3 levels with PAD2/PAD4 and clinically relevant outcomes. Methods Levels of CitH3 were measured in serum samples of 160 critically ill patients with septic and non-septic shock, and healthy volunteers. Analyses of clinical and laboratory characteristics of patients were conducted. Results Levels of circulating CitH3 at enrollment were significantly increased in septic shock patients (n = 102) compared to patients hospitalized with non-infectious shock (NIC) (n = 32, p r = 0.36, p p p Conclusion CitH3 is increased in patients with septic shock. Its serum concentrations correlate with disease severity and prognosis, which may yield vital insights into the pathophysiology of sepsis.

Accurate determination of a person's blood alcohol concentration (BAC) is an important task in forensic toxicology laboratories because of the existence of statutory limits for driving a motor vehicle and workplace alcohol testing regulations. However, making a correct interpretation of the BAC determined in postmortem (PM) specimens is complicated, owing to the possibility that ethanol was produced in the body after death by the action of various micro-organisms (e.g., Candida species) and fermentation processes. This article reviews various ways to establish the source of ethanol in PM blood, including collection and analysis of alternative specimens (e.g., bile, vitreous humor (VH), and bladder urine), the identification of non-oxidative metabolites of ethanol, ethyl glucuronide (EtG) and ethyl sulfate (EtS), the urinary metabolites of serotonin (5-HTOL/5-HIAA), and identification of n-propanol and n-butanol in blood, which are known putrefaction products. Practical utility of the various biomarkers including specificity and stability is discussed.

Posttraumatic stress disorder (PTSD) and depression are common following orthopedic trauma. This study examined the relationship between injury- and hospital-related variables and PTSD and depression at baseline and 12 months after orthopedic trauma. This longitudinal, prospective cohort study examined adult orthopedic trauma patients admitted ≥24 hours to a level I trauma center. Non-English/Spanish-speaking and cognitively impaired patients were excluded. The Primary Care PTSD screen and PTSD Checklist-Civilian version assessed PTSD, and the Patient Health Questionnaire 8-Item assessed depression. Demographic and hospital-related variables were examined (e.g., hospital length of stay, Injury Severity Score, Glasgow Coma Scale). For 160 participants, PTSD prevalence was 23% at baseline and 21% at 12 months. Depression prevalence was 28% at baseline and 29% at 12 months. Ventilation (P = 0.023, P = 0.006) and prolonged length of stay (P = 0.008, P = 0.003) were correlated with baseline PTSD and depression. Injury etiology (P = 0.008) and Injury Severity Score (P = 0.013) were associated with baseline PTSD. Intensive care unit admission (P = 0.016, P = 0.043) was also correlated with PTSD at baseline and 12 months. Ventilation (P = 0.002, P = 0.040) and prolonged length of stay (P

In animals, several long-chain N-acylethanolamines (NAEs) have been identified as endocannabinoids and are autocrine signals that operate through cell surface G-protein-coupled cannabinoid receptors. Despite the occurrence of NAEs in land plants, including nonvascular plants, their precise signaling properties and molecular targets are not well defined. Here we show that the activity of N-linolenoylethanolamine (NAE 18:3) requires an intact G-protein complex. Specifically, genetic ablation of the Gβγ dimer or loss of the full set of atypical Gα subunits strongly attenuates an NAE-18:3-induced degreening of cotyledons in Arabidopsis (Arabidopsis thaliana) seedlings. This effect involves, at least in part, transcriptional regulation of chlorophyll biosynthesis and catabolism genes. In addition, there is feedforward transcriptional control of G-protein signaling components and G-protein interactors. These results are consistent with NAE 18:3 being a lipid signaling molecule in plants with a requirement for G-proteins to mediate signal transduction, a situation similar, but not identical, to the action of NAE endocannabinoids in animal systems.

Pelvic injuries often result from high-energy trauma and lead to significant functional impairment. While the physical outcomes of these injuries have been widely studied, the psychological consequences remain largely unexplored. The purpose of this study was to examine psychosocial and functional outcomes of patients with pelvic trauma in the year after injury. The sample (N = 32) consisted of adult patients with traumatic pelvic injures, as defined by ICD-9 codes, who were admitted to a Level I Trauma Center for at least 24 h. Participants were primarily female (53%) with a mean age of 48.7 years (SD = 17.9). Demographic, injury-related, and psychosocial data (e.g., posttraumatic stress disorder (PTSD), depression, alcohol use, quality of life, pain, return to work) were gathered at the time of hospitalization as well as at 3-, 6-, and 12 month follow-ups. Mixed regression models were used to examine the outcome variables over time. There were significant decreases in pain and alcohol use at each follow-up compared to baseline. However, despite the decrease, the levels of pain and alcohol use remained high. Physical and mental health also decreased significantly, indicating worsened functioning and lowered quality of life. Neither PTSD nor depression changed significantly over time, indicating that participants’ symptoms were not likely to improve. These data suggest that sustaining a traumatic pelvic injury increases the risk of diminished quality of life, both mentally and physically. Even one-year post-injury, participants experienced moderate physical pain and higher levels of PTSD, depression, and problematic alcohol use than would be expected in the general population. These findings highlight the need for an interdisciplinary approach to treating patients with pelvic injuries, including psychological screening and intervention in acute care and throughout recovery.

Sulfonamides are a privileged class of functional groups in medicinal chemistry and an important class of protecting groups in organic synthesis. We report the discovery and development of unexpect...

SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed.To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19.This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021.Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge.The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants.A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days).This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials.ClinicalTrials.gov Identifier: NCT04312009.

Background and aim: Wherever sunlight reaches litter there is potential for photodegradation to contribute to decomposition. Although recent studies have weighted the contribute of the short-wavelength visible spectrum and ultraviolet (UV) radiation as drivers of photodegradation, the relative importance of each spectral region across biomes and plant communities remains uncertain.Methods: We performed a systematic meta-analysis of studies that assessed photodegradation through spectrally selective attenuation of solar radiation, by synthesizing 30 published studies using field incubations of leaf litter from 110 plant species under ambient sunlight.Results: Globally, the full spectrum of sunlight significantly increased litter mass loss by 15.3% ± 1% across all studies compared to darkness. Blue light alone was responsible for most of this increase in mass loss (13.8% ± 1%), whereas neither UV radiation nor its individual constituents UV-B and UV-A radiation had significant effects at the global scale, being only important in specific environments. These waveband-dependent effects were modulated by climate and ecosystem type. Among initial litter traits, carbon content, lignin content, lignin to nitrogen ratio and SLA positively correlated with the rate of photodegradation. Global coverage of biomes and spectral regions was uneven across the meta-analysis potentially biasing the results, but also indicating where research in lacking.Conclusions: Across studies attenuating spectral regions of sunlight, our meta-analysis confirms that photodegradation is a significant driver of decomposition, but this effect is highly dependent on the spectral region considered. Blue light was the predominant driver of photodegradation across biomes rather than UV radiation.

Tranexamic acid (TXA) is a medication that is routinely used to minimize blood loss during surgery. There is minimal literature evaluating the effects of TXA in hip fractures in regards to length of stay, readmission rates, and location of discharge. This study included adult patients who were admitted for hip fracture that required surgery over a 22-month period (May 2017–February 2019). A total of 525 hip fractures were operated on during this time period. Retrospective analysis was performed on patients treated with TXA (n = 27) vs those who were not (n = 498). Primary outcomes were length of stay, disposition after discharge, need for transfusion, mobilization with therapy, and readmission rates. TXA during hip fractures reduced median length of stay in the hip fracture cohort to 3 vs 5 days (P

Refereed/Peer-reviewed The Southern African Magnetotelluric Experiment (SAMTEX) involved the collection of data at over 700 sites in Archean to Proterozoic southern Africa, spanning features including the Kalahari Craton, Bushveld Complex, and voluminous kimberlites. Here, we present the first 3D inversions of the full SAMTEX data set. In this paper, we focus on assessing the robustness of the 3D models by comparing two different inversion codes, jif3D and ModEM, and two different subsets of the data, one containing all acceptable data and the other containing a smaller selection of undistorted, high-quality data. Results show that the main conductive and resistive features are imaged by all inversions, including deep resistive features in the central Kaapvaal Craton and southern Congo Craton and a lithospheric-scale conductor beneath the Bushveld Complex. Despite this, differences exist between the jif3D and ModEM inverse models that derive mainly from the differences in regularization between the models, with jif3D producing models that are very smooth laterally and with depth, while ModEM produces models with more discrete conductive and resistive features. Analysis of the differences between these two inversions can provide a good indication of the model resolution. More minor differences are apparent between models run with different subsets of data, with the models containing all acceptable data featuring higher wavelength conductivity variations than those run with fewer stations but also demonstrating poorer data fit. Plain Language Summary: We investigate the structure of the upper 200 km of the Earth beneath southern Africa. To achieve this, we utilize an electromagnetic geophysical technique called magnetotellurics(MT) which is sensitive to variations in electrical resistivity within the Earth. To reconstruct electrical resistivity from MT measurements, we use so-called inversion algorithms. However, the results are nonunique and a variety of different parameters have to be chosen by the user during the inversion process. In order to better understand the possible variability in our Earth models, we use different inversion algorithms and compare different strategies. This allows us to assess the reliability of our results. Based on our models and their comparison, we infer that the lithosphere, the solid outer shell of the Earth, varies in thickness below our study area and is thickest below central South Africa. In addition, we can detect remnants of past continental collisions that have been preserved for hundreds of millions of years since this part of the world was assembled from the collision of various microcontinents.

Forensic science is a multidisciplinary field that involves the use of various scientific methods and techniques for the investigation of crimes. Forensic scientists are often required to testify in court as expert witnesses and explain the meaning of chemical, physical, and/or medical evidence to a judge and jury. This article took advantage of a citation database to identify the most highly cited forensic practitioners in four Nordic countries within the discipline of legal and forensic medicine. The starting point was 7 million scientists indexed in the SCOPUS database, each of whom had their name on at least five entries. Six different citation metrics were used to calculate a person’s composite citation score. Those within the top 2% of their primary research discipline were considered highly cited.

flg22 is a 22-amino peptide released from bacterial flagellin, a Microbe-Associated Molecular Pattern (MAMP) that is recognized by the plant cell as a signal indicating that bacteria are present. On its own, flg22 initiates a rapid increase in cytoplasmic calcium, extracellular reactive oxygen species, and activation of a Mitogen Activated Protein Kinase (MAPK) cascade, all of which are activated within 15 minutes after the cell perceives flg22. Here we show a massive change in protein abundance and phosphorylation state of the Arabidopsis root cell proteome within this 15-minute duration in wildtype and a mutant deficient in G-protein coupled signaling. Integration of phosphoproteome with protein-protein interactome data followed by network topology analyses discovered that many of the flg22-induced phosphoproteome changes fall on proteins that comprise the G protein interactome and on the most highly populated hubs of the immunity network. Approximately 95% of the phosphorylation changes in the G-protein interactome depend on a functional heterotrimeric G protein complex, some occur on proteins that interact directly with components of G-coupled signal transduction. One of these is ATBα, a substrate-recognition sub-unit of the PP2A Ser/Thr phosphatase and an interactor to Arabidopsis thaliana REGULATOR OF G SIGNALING 1 protein (AtRGS1), a 7-transmembrane spanning modulator of the nucleotide-binding state of the core G protein complex. AtRGS1 is phosphorylated by BAK1, a component of the flg22 receptor, to initiate AtRGS1 endocytosis. A null mutation of ATBα confers high basal endocytosis of AtRGS1, suggesting sustained phosphorylated status. Loss of ATBα confers traits associated with loss of AtRGS1. Because the basal level of AtRGS1 is lower in the atbα null mutant in a proteasome-dependent manner, we propose that phosphorylation-dependent endocytosis of AtRGS1 is part of a mechanism to degrade AtRGS1 which then sustains activation of the G protein complex. Thus, the role of ATBα is now established as a central component of phosphorylation-dependent regulation of system dynamics in innate immunity.

Sepsis-induced metabolic dysfunction is associated with mortality, but the signatures that differentiate variable clinical outcomes among survivors are unknown. Our aim was to determine the relationship between host metabolism and chronic critical illness (CCI) in patients with septic shock. We analyzed metabolomics data from mechanically ventilated patients with vasopressor-dependent septic shock from the placebo arm of a recently completed clinical trial. Baseline serum metabolites were measured by liquid chromatography-mass spectrometry and 1H-nuclear magnetic resonance. We conducted a time-to-event analysis censored at 28 days. Specifically, we determined the relationship between metabolites and time to extubation and freedom from vasopressors using a competing risk survival model, with death as a competing risk. We also compared metabolite concentrations between CCI patients, defined as intensive care unit level of care ≥ 14 days, and those with rapid recovery. Elevations in two acylcarnitines and four amino acids were related to the freedom from organ support (subdistributional hazard ratio < 1 and false discovery rate < 0.05). Proline, glycine, glutamine, and methionine were also elevated in patients who developed CCI. Our work highlights the need for further testing of metabolomics to identify patients at risk of CCI and to elucidate potential mechanisms that contribute to its etiology.

Peer-review of manuscripts submitted to scholarly journals for publication dates back ~ 350 years and this process represents the foundation of scientific publishing. After a manuscript has undergone and survived a rigorous peer-review, this conveys a stamp of approval, because it signifies the work has been checked by independent experts in the scientific discipline concerned. The publication and citation track records of people instructed to appear as expert witness in civil and criminal litigation are important considerations. Using a publically available database, the most highly cited scientists in the discipline legal and forensic medicine were identified. For each scientist, a composite score was calculated based on six different citation metrics; (i) Total number of citations, (ii) H-index, (iii) H

Procyon lotor (Raccoon) are a dominant predator on eggs of Malaclemys terrapin (Diamondback Terrapin), an estuarine specialist turtle endemic to saltmarshes of the eastern and gulf coasts of the United States. The purpose of this study was to determine if broadcast predator vocalizations could potentially deter Raccoons from foraging on Diamondback Terrapin eggs. We used artificial nests arrays to test 2 hypotheses: (1) predator vocalization playbacks (barking Canis lupus familiaris [Domestic Dog]) reduce number of artificial nests depredated by Raccoons compared to non-predator vocalization playbacks (Urocyon cinereoargenteus [Gray Fox]) or control treatments (no playbacks), and (2) predator vocalization playbacks reduce frequency of visits by Raccoons and overall foraging time compared to non-predator playbacks and control treatments. We randomly assigned sound treatments to each night of a 3-day trial, with 3 trials conducted at 4 experimental sites. We counted the number of depredated artificial nests and used trail cameras to document number of Raccoon visits and Raccoon foraging time following each sound treatment. On average, 51% of artificial nests were depredated in the predator vocalization treatments, 66% in the non-predator–vocalization treatments, and 81% of nests in the control treatments. Average number of Raccoon visits was about 3 times higher in the control treatment compared to the predator treatment but auditory treatment did not affect time spent foraging. Response to predator vocalization was attenuated by repeated exposure to recorded predator playbacks. Variation in type of predator vocalization, length, and frequency of playbacks may increase effectiveness of auditory deterrents on predators of Diamondback Terrapin nests.

Measuring the concentration of alcohol (ethanol) in exhaled breath (BrAC) provides a rapid and non-invasive way to determine the co-existing concentration in arterial blood (A-BAC). The results of breath-alcohol testing are used worldwide as evidence of excessive drinking, such as when traffic offenders are prosecuted. Two types of breath-alcohol analyzer are in common use; hand-held instruments used as preliminary screening tests of sobriety and more sophisticated evidential instruments, the results of which are accepted as evidence for prosecution of drunken drivers. Most evidential breath-alcohol analyzers are designed to capture the last portion of a prolonged exhalation, which is thought to reflect the alcohol concentration in substantially alveolar air. The basic premise of breath-alcohol analysis is that there is a physiological relationship between A-BAC and BrAC and close agreement between the two analytical methods. This article reviews the principles and practice of breath-alcohol analysis and introduces the concept of standardizing the results to a secondary physiological gas (water vapor), which therefore serves as an internal standard. The measured BrAC is thus adjusted to an alveolar air water content of 43.95 mg l−1 at 37 °C. This has several advantages, and means that a sample of breath can be captured without the person having to blow directly into the instrument. Adjusting the breath-alcohol concentration to water vapor concentration also compensates for variations in temperature of the expired air. The contact-free method of sampling breath means that a mouthpiece is unnecessary and the test subject does not need to make a continuous end exhalation.

BackgroundSARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed.MethodsMulticenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressor-free days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1–7) (Ang-(1–7)), ACE, ACE2] were measured in a subgroup of participants.FindingsFrom April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO2/FiO2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components.InterpretationInitiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury does not improve PaO2 / FiO2 ratio at 7 days. These data may have implications for ongoing clinical trials.Trial RegistrationLosartan for Patients With COVID-19 Requiring Hospitalization (NCT04312009), https://clinicaltrials.gov/ct2/show/NCT04312009

In animals, endocytosis of a 7-transmembrane GPCR is mediated by arrestins to propagate or arrest cytoplasmic G-protein-mediated signaling, depending on the bias of the receptor or ligand, which determines how much one transduction pathway is used compared to another. In Arabidopsis thaliana, GPCRs are not required for G protein-coupled signaling because the heterotrimeric G protein complex spontaneously exchanges nucleotide. Instead, the 7-transmembrane protein AtRGS1 modulates G protein signaling through ligand-dependent endocytosis, which initiates de-repression of signaling without the involvement of canonical arrestins. Here, we found that endocytosis of AtRGS1 initiated from two separate pools of plasma membrane: Sterol-dependent domains and a clathrin-accessible neighborhood, each with a select set of discriminators, activators, and candidate arrestin-like adaptors. Ligand identity (either the pathogen-associated molecular pattern flg22 or the sugar glucose) determined the origin of AtRGS1 endocytosis. Different trafficking origins and trajectories led to different cellular outcomes. Thus, in this system, compartmentation with its associated signalosome architecture drives biased signaling.

In animals, endocytosis of a seven-transmembrane GPCR is mediated by arrestins to propagate or arrest cytoplasmic G protein-mediated signaling, depending on the bias of the receptor or ligand, which determines how much one transduction pathway is used compared to another. In Arabidopsis thaliana, GPCRs are not required for G protein-coupled signaling because the heterotrimeric G protein complex spontaneously exchanges nucleotide. Instead, the seven-transmembrane protein AtRGS1 modulates G protein signaling through ligand-dependent endocytosis, which initiates derepression of signaling without the involvement of canonical arrestins. Here, we found that endocytosis of AtRGS1 initiated from two separate pools of plasma membrane: sterol-dependent domains and a clathrin-accessible neighborhood, each with a select set of discriminators, activators, and candidate arrestin-like adaptors. Ligand identity (either the pathogen-associated molecular pattern flg22 or the sugar glucose) determined the origin of AtRGS1 endocytosis. Different trafficking origins and trajectories led to different cellular outcomes. Thus, in this system, compartmentation with its associated signalosome architecture drives biased signaling.

Background Sepsis shifts cardiac metabolic fuel preference and this disruption may have implications for cardiovascular function. A greater understanding of the role of metabolism in the development and persistence of cardiovascular failure in sepsis could serve to identify novel pharmacotherapeutic approaches. Methods Secondary analysis of prospective quantitative proton nuclear magnetic resonance (1H-NMR) metabolomic data from patients enrolled in a phase II randomized control trial of L-carnitine in septic shock. Participants with a sequential organ failure assessment (SOFA) score of > = 5, lactate > = 2, and requiring vasopressor support for at least 4 h were eligible for enrollment. The independent prognostic value of metabolites to predict survival with shock resolution within 48 h and vasopressor free days were assessed. Concentrations of predictive metabolites were compared between participants with and without shock resolution at 48 h. Results Serum 1H-NMR metabolomics data from 228 patients were analyzed. Eighty-one (36%) patients met the primary outcome; 33 (14%) died prior to 48 h. The branched chain amino acids (BCAA), valine, leucine, and isoleucine were univariate predictors of the primary outcome after adjusting for multiple hypothesis testing, while valine remained significant after controlling for SOFA score. Similar results were observed when analyzed based on vasopressor free days, and persisted after controlling for confounding variables and excluding non-survivors. BCAA concentrations at 48 h significantly discriminated between those with shock resolution versus persistent shock. Conclusions Among patients with septic shock, BCAA concentrations independently predict time to shock resolution. This study provides hypothesis generating data into the potential contribution of BCAAs to the pathophysiology of cardiovascular failure in sepsis, opening areas for future investigations.

Background: The objective was to test if low-risk emergency department patients with vitamin K antagonist (venous thromboembolism [VTE]; including venous thrombosis and pulmonary embolism [PE]) can be safely and effectively treated at home with direct acting oral (monotherapy) anticoagulation in a large-scale, real-world pragmatic effectiveness trial. Methods: This was a single-arm trial, conducted from 2016 to 2019 in accordance with the Standards for Reporting Implementation Studies guideline in 33 emergency departments in the United States. Participants had newly diagnosed VTE with low risk of death based upon either the modified Hestia criteria, or physician judgment plus the simplified PE severity index score of zero, together with nonhigh bleeding risk were eligible. Patients had to be discharged within 24 hours of triage and treated with either apixaban or rivaroxaban. Effectiveness was defined by the primary efficacy and safety outcomes, image-proven recurrent VTE and bleeding requiring hospitalization >24 hours, respectively, with an upper limit of the 95% CI for the 30-day frequency of VTE recurrence below 2.0% for both outcomes. Results: We enrolled 1421 patients with complete outcomes data, including 903 with venous thrombosis and 518 with PE. The recurrent VTE requiring hospitalization occurred in 14/1421 (1.0% [95% CI, 0.5%–1.7%]), and bleeding requiring hospitalization occurred in 12/1421 (0.8% [0.4%–1.5%). The rate of severe bleeding using International Society for Thrombosis and Haemostasis criteria was 2/1421 (0.1% [0%–0.5%]). No patient died, and serious adverse events occurred in 2.5% of venous thrombosis patients and 2.3% of patients with PE. Medication nonadherence was reported by patients in 8.0% (6.6%–9.5%) and was associated with a risk ratio of 6.0 (2.3–15.2) for VTE recurrence. Among all patients diagnosed with VTE in the emergency department during the period of study, 18% of venous thrombosis patients and 10% of patients with PE were enrolled. Conclusions: Monotherapy treatment of low-risk patients with venous thrombosis or PE in the emergency department setting produced a low rate of bleeding and VTE recurrence, but may be underused. Patients with venous thrombosis and PE should undergo risk-stratification before home treatment. Improved patient adherence may reduce rate of recurrent VTE. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03404635

Subtle, and not so subtle, features in our increasingly large and complex datasets are being missed because of our reliance on a single number, typically chi-squared based, to describe the distance...

Background: Sacubitril/valsartan is a combination drug therapy for heart failure (HF) patients that has been shown to reduce mortality and hospitalisation. Aims: To explore clinically relevant real-life patient data regarding prescribing of sacubitril/valsartan for HF patients in three hospitals, in accordance with national guidelines. Methods: A retrospective multicentre study in three large UK hospital Trusts based in the West Midlands. Findings: A total of 118 symptomatic chronic HF patients with reduced ejection fraction were included in the study. A high proportion of prescribers adhered to NICE guidelines for treatment with sacubitril/valsartan; 99% of patients had a New York Heart Association functional class of at least II; 82% had a left ventricle ejection fraction of under 35%; 100% received an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker before commencing sacubitril/valsartan. The mean age of men and women at the three hospitals was 65 and 59 years, respectively. The proportion of men prescribed sacubitril/valsartan was greater than women: 80% compared to 20%, respectively. The majority of patients on the therapy were white British (65%). Total prescribing of sacubitril/valsartan at the three hospitals was 295 patients, lower than expected. Conclusion: The prescribing of sacubitril/valsartan at the Trusts generally adhered to NICE guidance; however, the prescribing rate was lower than expected compared with the NICE resource tool. Further investigations into the safety and scope of application of sacubitril/valsartan are required to match the prescribing of sacubitril/valsartan with eligible patients who could benefit from the medication.

This article is intended as a brief review or primer about cocaethylene (CE), a pharmacologically active substance formed in the body when a person co-ingests ethanol and cocaine. Reference books widely used in forensic toxicology contain scant information about CE, even though this cocaine metabolite is commonly encountered in routine casework. CE and cocaine are equi-effective at blocking the reuptake of dopamine at receptor sites, thus reinforcing the stimulant effects of the neurotransmitter. In some animal species, the LD50 of CE was lower than for cocaine. CE is also considered more toxic to the heart and liver compared with the parent drug cocaine. The plasma elimination half-life of CE is ~2 h compared with ~1 h for cocaine. The concentrations of CE in blood after drinking alcohol and taking cocaine are difficult to predict and will depend on the timing of administration and the amounts of the two precursor drugs ingested. After an acute single dose of cocaine and ethanol, the concentration–time profile of CE runs on a lower level to that of cocaine, although CE is detectable in blood for several hours longer. A strong case can be made for adding together the concentrations of cocaine and CE in forensic blood samples when toxicological results are interpreted in relation to acute intoxication and the risk of an overdose death.