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Tall fescue ( Lolium arundinaceum (Schreb.) S.J. Darbyshire) often forms a symbiotic relationship with fungal endophytes ( Epichloë coenophiala ), which provides increased plant performance and greater tolerance to environmental stress compared to endophyte-free tall fescue. Whether this enhanced performance of tall fescue exclusively results from the grass-fungus symbiosis, or this symbiosis additionally results in the recruitment of soil microbes in the rhizosphere that in turn promote plant growth, remain a question. We investigated the soil bacterial and fungal community composition in iron-rich soil in the southeastern USA, and possible community shifts in soil microbial populations based on endophyte infection in tall fescue by analyzing the 16s rRNA gene and ITS specific region. Our data revealed that plant-available phosphorus (P) was significantly ( p < 0.05) influenced by endophyte infection in tall fescue. While the prominent soil bacterial phyla were similar, a clear fungal community shift was observed between endophyte-infected (E+) and endophyte-free (E-) tall fescue soil at the phylum level. Moreover, compared to E- soil, E+ soil showed a greater fungal diversity at the genus level. Our results, thus, indicate a possible three-way interaction between tall fescue, fungal endophyte, and soil fungal communities resulting in improved tall fescue performance.

The COVID-19 pandemic has had devastating medical and economic consequences globally. The severity of COVID-19 is related, in a large measure, to the extent of pulmonary involvement. The role of chest CT imaging in the management of patients with COVID-19 has evolved since the onset of the pandemic. Specifically, the description of CT scan findings, use of chest CT imaging in various acute and subacute settings, and its usefulness in predicting chronic disease have been defined better. We performed a review of published data on CT scans in patients with COVID-19. A summary of the range of imaging findings, from typical to less common abnormalities, is provided. Familiarity with these findings may facilitate the diagnosis and management of this disease. A comparison of sensitivity and specificity of chest CT imaging with reverse-transcriptase polymerase chain reaction testing highlights the potential role of CT imaging in difficult-to-diagnose cases of COVID-19. The usefulness of CT imaging to assess prognosis, to guide management, and to identify acute pulmonary complications associated with SARS-CoV-2 infection is highlighted. Beyond the acute stage, it is important for clinicians to recognize pulmonary parenchymal abnormalities, progressive fibrotic lung disease, and vascular changes that may be responsible for persistent respiratory symptoms. A large collection of multi-institutional images were included to elucidate the CT scan findings described., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Abnormalities that characterize pulmonary arterial hypertension include impairment in the structure and function of pulmonary vascular endothelial and smooth muscle cells. Aldosterone levels are elevated in human pulmonary arterial hypertension and in experimental pulmonary hypertension, while inhibition of the aldosterone-binding mineralocorticoid receptor attenuates pulmonary hypertension in multiple animal models. We explored the role of mineralocorticoid receptor in endothelial and smooth muscle cells in using cell-specific mineralocorticoid receptor knockout mice exposed to sugen/hypoxia-induced pulmonary hypertension. Treatment with the mineralocorticoid receptor inhibitor spironolactone significantly reduced right ventricular systolic pressure. However, this is not reproduced by selective mineralocorticoid receptor deletion in smooth muscle cells or endothelial cells. Similarly, spironolactone attenuated the increase in right ventricular cardiomyocyte area independent of vascular mineralocorticoid receptor with no effect on right ventricular weight or interstitial fibrosis. Right ventricular perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of mineralocorticoid receptor from endothelial cells. Endothelial cell-mineralocorticoid receptor deletion attenuated the sugen/hypoxia-induced increase in the leukocyte-adhesion molecule, E-selectin, and collagen IIIA1 in the right ventricle. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of endothelial cell-mineralocorticoid receptor or smooth muscle cell-mineralocorticoid receptor. Finally, the degree of pulmonary perivascular inflammation was attenuated by mineralocorticoid receptor antagonism and was fully reproduced by smooth muscle cell-specific mineralocorticoid receptor deletion. These studies demonstrate that in the sugen/hypoxia pulmonary hypertension model, systemic-mineralocorticoid receptor blockade significantly attenuates the disease and that mineralocorticoid receptor has cell-specific effects, with endothelial cell-mineralocorticoid receptor contributing to right ventricular perivascular fibrosis and smooth muscle cell-mineralocorticoid receptor participating in pulmonary vascular inflammation. As mineralocorticoid receptor antagonists are being investigated to treat pulmonary arterial hypertension, these findings support novel mechanisms and potential mineralocorticoid receptor targets that mediate therapeutic benefits in patients., (© The Author(s) 2021.)

The low-lying electronic states of Irgacure 2959, a Norrish-type I photoinitiator, complexed with a single metal cation are investigated in the gas phase by photodissociation action spectroscopy. Analysis of the band shifts using quantum chemical calculations (TD-DFT and SCS-CC2) reveals the underlying influence of the charge on the key electronic energy levels. Since the cations (H + , Li + , Na + , K + , Zn 2+ , Ca 2+ , and Mg 2+ ) bind at varying distances, the magnitude of the electric field at the center of the chromophore due to the cation is altered, and this shifts the electronic states by different amounts. Photodissociation action spectra of cation-Irg complexes show that absorption transitions to the first 1 ππ* state are red-shifted with a magnitude proportional to the electric field strength (with red shifts >1 eV), and in most cases, the cation is essentially acting as a point charge. Calculations show that a neighboring 3 nπ* state, a key state for the α-cleavage pathway, is destabilized (blue-shifted) by the orientated electric field. As such, if the 1 ππ*- 3 nπ* energy gap is reduced, increased intersystem crossing rates are expected, resulting in higher yields of the desired radical photoproducts, and this is controlled by the orientated electric field arising from the cation.

Objective: To develop and validate a clinical risk prediction score for noninvasive ventilation (NIV) failure defined as intubation after a trial of NIV in non-surgical patients., Design: Retrospective cohort study of a multihospital electronic health record database., Patients: Non-surgical adult patients receiving NIV as the first method of ventilation within two days of hospitalization., Measurement: Primary outcome was intubation after a trial of NIV. We used a non-random split of the cohort based on year of admission for model development and validation. We included subjects admitted in years 2010-2014 to develop a risk prediction model and built a parsimonious risk scoring model using multivariable logistic regression. We validated the model in the cohort of subjects hospitalized in 2015 and 2016., Main Results: Of all the 47,749 patients started on NIV, 11.7% were intubated. Compared with NIV success, those who were intubated had worse mortality (25.2% vs. 8.9%). Strongest independent predictors for intubation were organ failure, principal diagnosis group (substance abuse/psychosis, neurological conditions, pneumonia, and sepsis), use of invasive ventilation in the prior year, low body mass index, and tachypnea. The c-statistic was 0.81, 0.80 and 0.81 respectively, in the derivation, validation and full cohorts. We constructed three risk categories of the scoring system built on the full cohort; the median and interquartile range of risk of intubation was: 2.3% [1.9%-2.8%] for low risk group; 9.3% [6.3%-13.5%] for intermediate risk category; and 35.7% [31.0%-45.8%] for high risk category., Conclusions: In patients started on NIV, we found that in addition to factors known to be associated with intubation, neurological, substance abuse, or psychiatric diagnoses were highly predictive for intubation. The prognostic score that we have developed may provide quantitative guidance for decision-making in patients who are started on NIV.

The evolution of gaseous products is a feature common to several electrochemical processes, often resulting in bubbles adhering to the electrode's surface. Adherent bubbles reduce the electrode active area, and are therefore generally treated as electrochemically inert entities. Here, we show that this general assumption does not hold for gas bubbles masking anodes operating in water. By means of imaging electrochemiluminescent systems, and by studying the anisotropy of polymer growth around bubbles, we demonstrate that gas cavities adhering to an electrode surface initiate the oxidation of water-soluble species more effectively than electrode areas free of bubbles. The corona of a bubble accumulates hydroxide anions, unbalanced by cations, a phenomenon which causes the oxidation of hydroxide ions to hydroxyl radicals to occur at potentials at least 0.7 V below redox tabled values. The downhill shift of the hydroxide oxidation at the corona of the bubble is likely to be a general mechanism involved in the initiation of heterogeneous electrochemical reactions in water, and could be harnessed in chemical synthesis.

A dry-powder inhaled formulation of treprostinil (LIQ861) produced using PRINT® technology offers a substantial advantage over current nebulized therapy. Treprostinil is a synthetic prostacyclin analogue that is currently approved for inhalation administration to patients with pulmonary arterial hypertension via nebulized Tyvaso® inhalation solution. LTI-101 was a phase 1, placebo-controlled, double-blind, randomized, single-center study that evaluated the ascending single-dose pharmacokinetics of LIQ861 in healthy subjects. Six sequential, escalating doses (25, 50, 75, 100, 125, and 150 mcg) were studied to investigate treprostinil exposure from LIQ861 inhalation. Subjects ( n  = 57) were randomly assigned in a 3:1 ratio to receive a single dose of either LIQ861 ( n  = 43) or placebo ( n  = 14); 56 subjects completed all protocol-defined assessments. Following single-dose administration, treprostinil exposure from LIQ861 increased proportionally across the dose range studied, and the pharmacokinetics profile of treprostinil administered as LIQ861 was similar to prior reports of inhaled treprostinil. All doses of LIQ861 were generally well-tolerated with no deaths, serious adverse events, or dose-limiting toxicities. The most frequently reported treatment-emergent adverse events related to study drug administration were coughing and throat irritation, which are common to dry-powder formulations. Treatment-related treatment-emergent adverse events were reported more frequently at higher dose levels; however, all were assessed as mild in severity. We conclude that the pharmacokinetics profile of treprostinil using a dry-powder inhaled formulation increased in proportion to dose as anticipated and was similar to earlier reports of inhaled, nebulized treprostinil (Tyvaso®). Based on these results, a phase 3 study (INSPIRE; Clinicaltrials.gov Identifier NCT03399604) evaluating the long-term safety and tolerability of LIQ861 in patients with pulmonary arterial hypertension was initiated., (© The Author(s) 2020.)

The coronavirus disease 2019 pandemic will be remembered for the rapidity with which it spread, the morbidity and mortality associated with it, and the paucity of evidence-based management guidelines. One of the major concerns of hospitals was to limit spread of infection to health-care workers. Because the virus is spread mainly by respiratory droplets and aerosolized particles, procedures that may potentially disperse viral particles, the so-called "aerosol-generating procedures" were avoided whenever possible. Included in this category were noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), and awake (nonintubated) proning. Accordingly, at many health-care facilities, patients who had increasing oxygen requirements were emergently intubated and mechanically ventilated to avoid exposure to aerosol-generating procedures. With experience, physicians realized that mortality of invasively ventilated patients was high and it was not easy to extubate many of these patients. This raised the concern that HFNC and NIV were being underutilized to avoid intubation and to facilitate extubation. In this article, we attempt to separate fact from fiction and perception from reality pertaining to the aerosol dispersion with NIV, HFNC, and awake proning. We describe precautions that hospitals and health-care providers must take to mitigate risks with these devices. Finally, we take a practical approach in describing how we use the three techniques, including the common indications, contraindications, and practical aspects of application., (Copyright © 2020. Published by Elsevier Inc.)

Theoretical calculations have been performed in order to investigate the impact of different substitution patterns on predicted photoreactivity of alkoxyamines fused to an anthraquinone chromophore. Amino and hydroxy groups (similar to those which have been previously synthesized) are introduced and their effect on excited state energies and charge transfer is assessed. Analogous to formally oxidized alkoxyamines, the charge-separated nNπ* state can undergo mesolytic cleavage or bimolecular or SN2 reactions with nucleophiles, according to the substitution patterns and other reagents present. While homolytic cleavage is in principle promoted by triplet ππ* states, the accessible ππ* triplet states in this system are centered on the chromophore and unreactive. We show that the reactive nNπ* state, which bears a negative charge, is stabilized by hydroxy substitution while amino substitution will destabilize it. After mesolysis to a carbon centred radical, the nitroxide radical re-forms; however, when carbocations are produced the remaining open-shell singlet is stable and unable to undergo coupling with the carbocation.

Background: Very low-birth-weight (VLBW; birth weight < 1500 g) infants are often dependent on intravenous nutrition after birth. Conventional soy-based intravenous lipid emulsions (Soy LE) are associated with inflammatory and metabolic complications that may be harmful to preterm infants. Evidence to support any clinical benefit associated with newer multicomponent emulsions (Mixed LE), remains inconsistent and unsubstantiated in appropriate studies. This retrospective study aimed to determine whether growth and clinical outcomes differed between VLBW infants given Mixed LE vs Soy LE at Auckland City Hospital., Methods: Data were collected on nutrition, growth, and neonatal morbidities for the first 4 weeks after birth. Outcomes were compared between 2 lipid cohorts, Soy LE (February 2013 - August 2014) and Mixed LE (August 2014 - December 2015), using univariate and multivariate analysis., Results: 207 infants (Soy LE, 105 vs Mixed LE, 102) were included in the study. Significantly fewer infants in the Mixed LE cohort developed any stage retinopathy of prematurity (Soy LE 59% vs Mixed LE 39%, P = .005) or intraventricular hemorrhage (Soy LE 27% vs Mixed LE 15%, P = .03) during their admission. Mixed LE was also associated with significantly lower mean (P = .01), minimum (P = .03), and maximum (P = .04) total bilirubin concentrations across the first 4 weeks after birth. There was no difference in growth velocity or weight, length, and head circumference z-score change., Conclusion: SMOFlipid may represent a favorable alternative to conventional lipid emulsions in neonatal parenteral nutrition regimens; however, long-term effects should be further evaluated., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Three monoamino-substituted anthraquinone derivatives (AAQs), that is, 1-aminoanthraquinone (AAQ), 1-(methylamino)anthraquinone (MAAQ), and 1-(benzamido)anthraquinone (BAAQ), incorporated with various additives [e.g., triethanolamine (TEAOH) and phenacyl bromide (PhC(═O)CH 2 Br)] are investigated for their roles as photoinitiating systems of free radical photopolymerization of (meth)acrylate monomers upon the exposure to UV to green LEDs. The AAQs-based photoinitiating systems, AAQ/TEAOH/PhC(═O)CH 2 Br and BAAQ/TEAOH/PhC(═O)CH 2 Br photoinitiators exhibit the highest efficiency for the free radical photopolymerization of DPGDA under the irradiation of blue LED and UV LED, respectively, which is consistent with the extent of overlap between their absorption spectra and the emission spectra of the LEDs. AAQ/TEAOH/PhC(═O)CH 2 Br photoinitiator can also initiate the free radical photopolymerization of different (meth)acrylate monomers, with an efficiency dependent on the chemical structures of these monomers., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Ambrisentan has shown effectiveness in the treatment of Group 1 pulmonary arterial hypertension (PAH). Although portopulmonary hypertension (PoPH) is a subset of Group 1 PAH, few clinical trials have been testing PAH therapies in patients with PoPH. The objective of this study is to evaluate the efficacy and safety of ambrisentan in PoPH., Methods: This study is a prospective, multicenter, open-label trial in which treatment-naive patients with PoPH with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks). The primary end-points were change in pulmonary vascular resistance (PVR) and 6-minutes walk distance (6MWD) at 24 weeks, whereas secondary end-points included safety, World Health Organization (WHO) functional class (FC) and echocardiographic assessments., Results: Of the 31 patients, 23 finished 24 weeks of ambrisentan therapy and 19 finished the extension. PVR decreased significantly (mean ± SD) (7.1 ± 5 vs 3.8 ± 1.8 Wood units, p < 0.001), whereas 6MWD remained unchanged (314 ± 94 vs 336 ± 108 m). Other hemodynamic parameters such as right atrial pressure (13 ± 8 vs 9 ± 4 mm Hg, p < 0.05), mean pulmonary arterial pressure (46 ± 13 vs. 38 ± 8 mm Hg, p < 0.01), cardiac index (2.6 ± 0.6 vs. 3.5 ± 0.7 liter/min/m 2 , p < 0.001) showed improvement, whereas pulmonary capillary wedge pressure remained unchanged. Of the 22 patients with WHO FC assessments at baseline and 24 weeks, WHO FC improved significantly (p = 0.005). Most frequent drug-related adverse events were edema (38.7%) and headache (22.5%). One episode of leg edema resulted into the permanent discontinuation of ambrisentan., Conclusions: Ambrisentan monotherapy in PoPH improves hemodynamics and FC at 24 weeks; however, it did not show any improvement in 6MWD. These preliminary outcomes should be interpreted with caution (Clinicaltrials.Gov:NCT01224210)., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The remarkable power of enzymes to undertake catalysis frequently stems from their grouping of multiple, complementary chemical units within close proximity around the enzyme active site. Motivated by this, we report here a bioinspired surfactant catalyst that incorporates a variety of chemical functionalities common to hydrolytic enzymes. The textbook hydrolase active site, the catalytic triad, is modeled by positioning the three groups of the triad (-OH, -imidazole, and -CO 2 H) on a single, trifunctional surfactant molecule. To support this, we recreate the hydrogen bond donating arrangement of the oxyanion hole by imparting surfactant functionality to a guanidinium headgroup. Self-assembly of these amphiphiles in solution drives the collection of functional headgroups into close proximity around a hydrophobic nano-environment, affording hydrolysis of a model ester at rates that challenge α-chymotrypsin. Structural assessment via NMR and XRD, paired with MD simulation and QM calculation, reveals marked similarities of the co-micelle catalyst to native enzymes., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension., Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise., Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02980887.

Impaired thermoregulation and lowered average daily gains (ADG) result when livestock graze toxic endophyte (Epichloë coenophialum)-infected tall fescue (E+) and are hallmark signs of fescue toxicosis (FT), a disease exacerbated by increased temperature and humidity (+temperature-humidity index; +THI). We previously reported FT is associated with metabolic and microbiota perturbations under thermoneutral conditions; here, we assessed the influence of E+ grazing and +THI on the microbiota:metabolome interactions. Using high-resolution metabolomics and 16S rRNA gene sequencing, plasma/urine metabolomes and the fecal microbiota of Angus steers grazing non-toxic or E+ tall fescue were evaluated in the context of +THI. E+ grazing affected the fecal microbiota profile; +THI conditions modulated the microbiota only in E+ steers. E+ also perturbed many metabolic pathways, namely amino acid and inflammation-related metabolism; +THI affected these pathways only in E+ steers. Integrative analyses revealed the E+ microbiota correlated and co-varied with the metabolomes in a THI-dependent manner. Operational taxonomic units in the families Peptococcaceae, Clostridiaceae, and Ruminococcaceae correlated with production parameters (e.g., ADG) and with multiple plasma/urine metabolic features, providing putative FT biomarkers and/or targets for the development of FT therapeutics. Overall, this study suggests that E+ grazing increases Angus steer susceptibility to +THI, and offers possible targets for FT interventions.

Background: COPD is the fourth leading cause of death in the US, and COPD exacerbations result in approximately 700,000 hospitalizations annually. Patients with acute respiratory failure due to severe COPD exacerbation are treated with invasive (IMV) or noninvasive mechanical ventilation (NIV). Although IMV reverses hypercapnia/hypoxia, it causes significant morbidity and mortality. There is strong evidence that patients treated with NIV have better outcomes, and NIV is recommended as first line therapy in these patients. Yet, several studies have demonstrated substantial variation in the use of NIV across hospitals, leading to preventable morbidity and mortality. Through a series of mixed-methods studies, we have found that successful implementation of NIV requires physicians, respiratory therapists (RTs), and nurses to communicate and collaborate effectively, suggesting that efforts to increase the use of NIV in COPD need to account for the complex and interdisciplinary nature of NIV delivery and the need for team coordination. Therefore, we propose to compare two educational strategies: online education (OLE) and interprofessional education (IPE) which targets complex team-based care in NIV delivery., Methods and Design: Twenty hospitals with low baseline rates of NIV use will be randomized to either the OLE or IPE study arm. The primary outcome of the trial is change in the hospital rate of NIV use among patients with COPD requiring ventilatory support. In aim 1, we will compare the uptake change over time of NIV use among patients with COPD in hospitals enrolled in the two arms. In aim 2, we will explore mediators' role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and implementation effectiveness. Finally, in aim 3, through interviews with providers, we will assess acceptability and feasibility of the educational training., Discussions: This study will be among the first to carefully test the impact of IPE in the inpatient setting. This work promises to change practice by offering approaches to facilitate greater uptake of NIV and may generalize to other interventions directed to seriously-ill patients., Trial Registration: Name of registry: ClinicalTrials.govTrial registration number: NCT04206735Date of Registration: December 20, 2019., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

The pathophysiology of pulmonary hypertension (PH) and heart failure (HF) includes fibrogenic remodeling associated with the loss of pulmonary arterial (PA) and cardiac compliance. We and others have previously identified transglutaminase 2 (TG2) as a participant in adverse fibrogenic remodeling. However, little is known about the biologic mechanisms that regulate TG2 function. We examined physiological mouse models of experimental PH, HF, and type 1 diabetes that are associated with altered glucose metabolism/glycolysis and report here that TG2 expression and activity are elevated in pulmonary and cardiac tissues under all these conditions. We additionally used PA adventitial fibroblasts to test the hypothesis that TG2 is an intermediary between enhanced tissue glycolysis and fibrogenesis. Our in vitro results show that glycolytic enzymes and TG2 are upregulated in fibroblasts exposed to high glucose, which stimulates cellular glycolysis as measured by Seahorse analysis. We examined the relationship of TG2 to a terminal glycolytic enzyme, pyruvate kinase M2 (PKM2), and found that PKM2 regulates glucose-induced TG2 expression and activity as well as fibrogenesis. Our studies further show that TG2 inhibition blocks glucose-induced fibrogenesis and cell proliferation. Our findings support a novel role for glycolysis-mediated TG2 induction and tissue fibrosis associated with experimental PH, HF, and hyperglycemia., (© 2019 Federation of American Societies for Experimental Biology.)

Rationale: In critically ill patients receiving invasive mechanical ventilation (MV), research supports the use of daily screening to identify patients who are ready to undergo a spontaneous breathing trial (SBT) followed by conduct of an SBT. However, once daily (OD) screening is poorly aligned with the continuous care provided in most intensive care units (ICUs) and the best SBT technique for clinicians to use remains controversial., Objectives: To identify the optimal screening frequency and SBT technique to wean critically ill adults in the ICU., Methods: We aim to conduct a multicenter, factorial design randomized controlled trial with concealed allocation, comparing the effect of both screening frequency (once versus at least twice daily [ALTD]) and SBT technique (Pressure Support [PS] + Positive End-Expiratory Pressure [PEEP] vs T-piece) on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American ICUs. In the OD arm, respiratory therapists (RTs) will screen study patients between 06:00 and 08:00 h. In the ALTD arm, patients will be screened at least twice daily between 06:00 and 08:00 h and between 13:00 and 15:00 h with additional screens permitted at the clinician's discretion. When the SBT screen is passed, an SBT will be conducted using the assigned technique (PS + PEEP or T-piece). We will follow patients until successful extubation, death, ICU discharge, or until day 60 after randomization. We will contact patients or their surrogates six months after randomization to assess health-related quality of life and functional status., Relevance: The around-the-clock availability of RTs in North American ICUs presents an important opportunity to identify the optimal SBT screening frequency and SBT technique to minimize patients' exposure to invasive ventilation and ventilator-related complications., Trial Registration: Clinical Trials.gov, NCT02399267 . Registered on Nov 21, 2016 first registered.

Vascular smooth muscle cells from the pulmonary arteries (HPASMC) of subjects with pulmonary arterial hypertension (PAH) exhibit hyperplastic growth. The PAH HPASMC display an increased sensitivity to fetal bovine serum (FBS) and undergo growth at a very low, 0.2%, FBS concentration. On the other hand, normal HPASMC (obtained from non-PAH donors) do not proliferate at low FBS (0.2%). A previous genomic study suggested that the nuclear factor, FOXM1 and the polo like kinase 1 (PLK1) are involved in promoting this hyperplastic growth of the PAH HPASMC. Here we find that limiting the action of FOXM1 or PLK1 not only restricts the hyperplastic proliferation of the PAH HPASMC but also modulates the FBS stimulated growth of normal HPASMC. The PAH HPASMC exhibit significantly elevated PLK1 and FOXM1 expression and decreased p27 (quiescence protein) levels compared to normal HPASMC. Regulation of the expression of FOXM1 and PLK1 is accompanied by the regulation of downstream expression of cell cycle components, Aurora B, cyclin B1 and cyclin D1. Expression of these cell cycle components is reversed by the knockdown of FOXM1 or PLK1 expression/activity. Furthermore, the knockdown of PLK1 expression lowers the protein level of FOXM1. On the other hand, inhibiting the action of FOXO1, a growth inhibitor, further increases the expression of FOXM1 in PAH HPASMC. Although PLK1 and FOXM1 clearly participate in PAH HPASMC hyperplasia, at this time it is not clear whether their increased activity is the primary driver of the hyperplastic behavior of the PAH HPASMC or merely a component of the pathway(s) leading to this response., Competing Interests: Dr. Hill has served on Scientific Advisory Boards for and received research grants paid to Tufts Medical Center from Actelion. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The design and development of photoinitiating systems applicable to UV or even visible light delivered from light-emitting diodes (LEDs) has been attracting increasing attention due to their great potential applications in various fields. Compared to the strategy of synthesizing novel compounds, the exploration of existing chemicals with interesting photochemical/photophysical properties for their usage as photoinitiators is more appealing and easily commercialized. Nevertheless, a number of compounds such as monoamino-substituted anthraquinone derivatives, which are intensively investigated for their photophysical and photochemical properties, have seldom been studied for their roles as photoinitiators under LED irradiation. Herein, three monoamino-substituted anthraquinone derivatives, that is, 1-aminoanthraquinone, 1-(methylamino)anthraquinone and 1-(benzamido)anthraquinone, are studied for their potential as photoinitiators. The photoinitiation mechanism of these monoamino-substituted anthraquinone derivatives, when combined with iodonium salt, is first clarified using computational quantum chemistry, fluorescence, steady-state photolysis, and electron spin resonance spin-trapping techniques. Then, their photoinitiation ability for the cationic photopolymerization of epoxide and divinyl ether monomers is also investigated., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Tall fescue, the predominant southeastern United States cool-season forage grass, frequently becomes infected with an ergot alkaloid-producing toxic endophyte, Epichloë coenophialum Consumption of endophyte-infected fescue results in fescue toxicosis (FT), a condition that lowers beef cow productivity. Limited data on the influence of ergot alkaloids on rumen fermentation profiles or ruminal bacteria that could degrade the ergot alkaloids are available, but how FT influences the grazing bovine fecal microbiota or what role fecal microbiota might play in FT etiology and associated production losses has yet to be investigated. Here, we used 16S rRNA gene sequencing of fecal samples from weaned Angus steers grazing toxic endophyte-infected (E+; n  = 6) or nontoxic (Max-Q; n  = 6) tall fescue before and 1, 2, 14, and 28 days after pasture assignment. Bacteria in the Firmicutes and Bacteroidetes phyla comprised 90% of the Max-Q and E+ steer fecal microbiota throughout the trial. Early decreases in the Erysipelotrichaceae family and delayed increases of the Ruminococcaceae and Lachnospiraceae families were among the major effects of E+ grazing. E+ also increased abundances within the Planctomycetes , Chloroflexi , and Proteobacteria phyla and the Clostridiaceae family. Multiple operational taxonomic units classified as Ruminococcaceae and Lachnospiraceae were correlated negatively with weight gains (lower in E+) and positively with respiration rates (increased by E+). These data provide insights into how E+ grazing alters the Angus steer microbiota and the relationship of fecal microbiota dynamics with FT. IMPORTANCE Consumption of E+ tall fescue has an estimated annual $1 billion negative impact on the U.S. beef industry, with one driver of these costs being lowered weight gains. As global agricultural demand continues to grow, mitigating production losses resulting from grazing the predominant southeastern United States forage grass is of great value. Our investigation of the effects of E+ grazing on the fecal microbiota furthers our understanding of bovine fescue toxicosis in a real-world grazing production setting and provides a starting point for identifying easy-to-access fecal bacteria that could serve as potential biomarkers of animal productivity and/or FT severity for tall fescue-grazing livestock., (Copyright © 2019 American Society for Microbiology.)

Noninvasive ventilation is well established as the ventilatory modality of first choice to treat acute or acute-on-chronic hypercapnic respiratory failure in patients with COPD by improving dyspnea and gas exchange, avoiding the need for intubation, and reducing morbidity and mortality rates. Noninvasive ventilation also offers benefit for patients with COPD and with accompanying pneumonia or with hypercapnic respiratory failure in postextubation, postoperative, and do not intubate settings. Noninvasive ventilation, in addition, offers benefit in other forms of acute hypercapnic respiratory failure, including those caused by asthma, cystic fibrosis, and obesity hypoventilation. A newer form of noninvasive ventilatory assistance, high-flow nasal cannula, has emerged in recent years as a technique to not only oxygenate effectively but also to improve ventilatory efficiency and reduce the work of breathing in patients with severe COPD. Results of recent studies indicate that high-flow nasal cannula therapy can benefit some patients with acute hypercapnic respiratory failure, either instead of or in combination with noninvasive ventilation, but more study is needed., Competing Interests: The remaining authors have disclosed no conflicts of interest., (Copyright © 2019 by Daedalus Enterprises.)

Background: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes., Methods: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses., Findings: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10 -15 ) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10 -20 ) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10 -12 ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity., Interpretation: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials., Funding: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Time-dependent density functional theory calculations have been performed on acetophenone derivatives to explore the possibility of using charged functional groups as internal electric fields, the orientation of which can be altered to change photochemical behavior at will. Results demonstrate that nonconjugated charged groups can significantly alter, by up to -1.44 eV, the stabilities of excited states. Specifically, a nonconjugated negatively charged group in the para position will destabilize the nπ* and stabilize the ππ* transitions, while a positively charged group will do the opposite. These electrostatic effects can be tuned by moving these substituents into the meta and ortho positions. Through use of acids and bases, these charged groups can be switched on or off with pH, allowing for selective alteration of the energy levels and photochemical reactivity. Solvent effects are shown to attenuate the electric field effect with increasing dielectric permittivity; however electrostatic effects are shown to remain significant even in quite polar solvents. Using charged functional groups to deliver the position-dependent electrostatic (de)stabilization effects is therefore a potential route to improving the efficiency of desirable photochemical processes.

Purpose: To assess the role of high-flow nasal therapy (HFNT) compared to standard oxygen (SO) as complementary therapy to non-invasive ventilation (NIV)., Methods: Multicenter trial including patients (n = 54) anticipated to receive NIV for ≥24 h due to acute or acute-on-chronic respiratory failure. Subjects were randomized (1:1) to SO or HFNT during breaks off NIV. Primary outcome was total time on and off NIV. Secondary outcomes were comfort and dyspnea, respiratory rate (RR), oxygen saturation (S p O 2 ), tolerance and side effects., Results: Total time per patient on NIV (1315 vs 1441 min) and breaks (1362 vs 1196 min), and mean duration of each break (520 vs 370 min) were similar in the HFNT and SO arms (p > .05). Comfort score was higher on HFNT than on SO (8.3 ± 2.7 vs 6.9 ± 2.3, p = .001). Dyspnea, RR and S p O 2 were similar in the two arms, but the increase in RR and dyspnea seen with SO during breaks did not occur with HFNT., Conclusion: Compared to SO, HFNT did not reduce time on NIV. However, it was more comfortable and the increase in RR and dyspnea seen with SO did not occur with HFNT. Therefore, HFNT could be a suitable alternative to SO during breaks off NIV., (Copyright © 2018. Published by Elsevier Inc.)

The genesis of dyspnea involves the activation of several mechanisms that are mediated and perceived depending on previous experiences, values, emotions, and beliefs. Breathlessness may become unbearable, especially in patients who are terminally ill, whether afflicted by respiratory-, cardiac-, or cancer-related disorders, because of a final stage of a chronic process, an acute event, or both. Compared with pain, palliation of dyspnea has received relatively little attention in clinical practice and the medical literature. This is particularly true when the breathlessness is associated with acute respiratory failure because most of the studies on pharmacologic and nonpharmacologic treatments of respiratory distress have excluded such patients. Assessments of the quality of dying for patients in an ICU consistently show that few patients are considered by family members to breathe comfortably at the end of their life. This review focuses on the management of dyspnea in patients with advanced terminal illness, summarizing clinical trial evidence on pharmacologic and nonpharmacologic interventions available for these patients., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown.Post-menopausal women aged ≥55 years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay.Lower levels of DHEA-S (p<0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p<0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1 µg·dL -1 ) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01).High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH., Competing Interests: Conflict of interest: S.M. Kawut reports grants (for research and CME) from Actelion, United Therapeutics, Gilead, Lung Biotech, Bayer and the Cardiovascular Medical Research and Education Fund, and personal fees (for travel) from the American Thoracic Society, outside the submitted work. Conflict of interest: J.R. Klinger reports grants from Actelion, United Therapeutics, Gilead, Eiger and Bayer, outside the submitted work. Conflict of interest: H.I. Palevsky reports personal fees from Actelion, Janssen, Bayer, GSK and United Therapeutics, outside the submitted work. Conflict of interest: I.R. Preston reports grants and personal fees from Actelion, grants from Bayer and Gilead, and personal fees from Arena, United Therapeutics and Pfizer, outside the submitted work. Conflict of interest: A. Smith reports grants from Actelion, Gilead and United Therapeutics, outside the submitted work. Conflict of interest: M. Whittenhall reports personal fees from Actelion, Bayer, Gilead and United Therapeutics, outside the submitted work. Conflict of interest: C.E. Ventetuolo reports personal fees from Bayer, Acceleron and United Therapeutics and grants from the CHEST Foundation (Actelion sponsored) and Eiger paid to her institution, outside the submitted work. Conflict of interest: C. Archer-Chicko reports personal fees from Actelion, outside the submitted work., (Copyright ©ERS 2018.)

Rationale: Dexmedetomidine is associated with less delirium than benzodiazepines and better sleep architecture than either benzodiazepines or propofol; its effect on delirium and sleep when administered at night to patients requiring sedation remains unclear., Objectives: To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill adults., Methods: This two-center, double-blind, placebo-controlled trial randomized 100 delirium-free critically ill adults receiving sedatives to receive nocturnal (9:30 p.m. to 6:15 a.m.) intravenous dexmedetomidine (0.2 μg/kg/h, titrated by 0.1 μg /kg/h every 15 min until a goal Richmond Agitation and Sedation Scale score of -1 or maximum rate of 0.7 μg/kg/h was reached) or placebo until ICU discharge. During study infusions, all sedatives were halved; opioids were unchanged. Delirium was assessed using the Intensive Care Delirium Screening Checklist every 12 hours throughout the ICU admission. Sleep was evaluated each morning by the Leeds Sleep Evaluation Questionnaire., Measurements and Main Results: Nocturnal dexmedetomidine (vs. placebo) was associated with a greater proportion of patients who remained delirium-free during the ICU stay (dexmedetomidine [40 (80%) of 50 patients] vs. placebo [27 (54%) of 50 patients]; relative risk, 0.44; 95% confidence interval, 0.23-0.82; P = 0.006). The average Leeds Sleep Evaluation Questionnaire score was similar (mean difference, 0.02; 95% confidence interval, 0.42-1.92) between the 34 dexmedetomidine (average seven assessments per patient) and 30 placebo (six per patient) group patients able to provide one or more assessments. Incidence of hypotension, bradycardia, or both did not differ significantly between groups., Conclusions: Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay; patient-reported sleep quality appears unchanged. Clinical trial registered with www.clinicaltrials.gov (NCT01791296).

Background: Changes in nutrient availability have dramatic and well-defined impacts on both transcription and translation in bacterial cells. At the same time, the role of post-translational control in adaptation to nutrient-poor environments is poorly understood. Previous studies demonstrate the ability of the glucosyltransferase UgtP to influence cell size in response to nutrient availability. Under nutrient-rich medium, interactions with its substrate UDP-glucose promote interactions between UgtP and the tubulin-like cell division protein FtsZ in Bacillus subtilis, inhibiting maturation of the cytokinetic ring and increasing cell size. In nutrient-poor medium, reductions in UDP-glucose availability favor UgtP oligomerization, sequestering it from FtsZ and allowing division to occur at a smaller cell mass., Results: Intriguingly, in nutrient-poor conditions UgtP levels are reduced ~ 3-fold independent of UDP-glucose. B. subtilis cells cultured under different nutrient conditions indicate that UgtP accumulation is controlled through a nutrient-dependent post-translational mechanism dependent on the Clp proteases. Notably, all three B. subtilis Clp chaperones appeared able to target UgtP for degradation during growth in nutrient-poor conditions., Conclusions: Together these findings highlight conditional proteolysis as a mechanism for bacterial adaptation to a rapidly changing nutritional landscape.

Introduction: Mechanical ventilatory support is life-saving therapy for patients with respiratory failure in intensive care units (ICU) but is linked to ventilator-associated pneumonia and other nosocomial infections. Interventions that improve the efficiency of weaning from mechanical ventilation may improve patient outcomes., Objective: To determine whether inhaled budesonide decreases time-to-weaning in COPD stage 4 difficult-to-wean patients and reduces the release of pro-inflammatory cytokines in ICU patients., Materials and Methods: We recruited 55 difficult-to-wean COPD patients (Stage 4) within the ICU of the Masih Daneshvari Hospital. Subjects were randomly assigned to receive inhaled budesonide (0.5mg/day) or placebo (normal saline). Dynamic compliance and BAL cytokines were measured., Results: Budesonide significantly reduced the number of days on MV (days-to-weaning=4.6±1.6days) compared to that seen in the control group (7.2±2.7days, p=0.014). Dynamic compliance was significantly improved in the budesonide group on days 3 (p=0.018) and 5 (p=0.011) The levels of CXCL-8 and IL-6 diminished on days 3-5 after start of budesonide (p<0.05)., Conclusion: In COPD patients on MV, nebulized budesonide was associated with reduced BAL CXCL8 and IL-6 levels and neutrophil numbers as well as an improvement in ventilatory mechanics and facilitated weaning., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To compare the outcomes of patients hospitalized with pneumonia treated with noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV)., Materials and Methods: Using the HealthFacts multihospital electronic medical record database, we included patients hospitalized with a diagnosis of pneumonia and treated with NIV or IMV. We developed a propensity model for receipt of initial NIV and assessed the outcomes in a propensity-matched cohort, and in a covariate adjusted and propensity score weighted models., Results: Among 3971 ventilated patients, 1109 (27.9%) were initially treated with NIV. Patients treated with NIV were older, had lower acuity of illness score, and were more likely to have congestive heart failure and chronic pulmonary disease. Mortality was 15.8%, 29.8% and 25.9.0% among patients treated with initial NIV, initial IMV and among those with NIV failure. In the propensity matched analysis, the risk of death was lower in patients treated with NIV (relative risk: 0.71, 95% CI: 0.59-0.85). Subgroup analysis showed that NIV was beneficial among patients with cardiopulmonary comorbidities (relative risk 0.59, 95% CI: 0.47-0.75) but not in those without (relative risk 0.96, 95% CI: 0.74-0.1.25)NIV failure was significantly (p=0.002) more common in patients without cardiopulmonary conditions (21.3%) compared to those with these conditions (13.8%)., Conclusions: Initial NIV was associated with better survival among the subgroup of patients hospitalized with pneumonia who had COPD or heart failure. Patients who failed NIV had high in-hospital mortality, emphasizing the importance of careful patient selection monitoring when managing severe pneumonia with NIV., (Copyright © 2017 Elsevier Inc. All rights reserved.)

One of the major contributors to sickle cell disease (SCD) pathobiology is the hemolysis of sickle red blood cells (RBCs), which release free hemoglobin and platelet agonists including adenosine 5'-diphosphate (ADP) into the plasma. While platelet activation/aggregation may promote tissue ischemia and pulmonary hypertension in SCD, modulation of sickle platelet dysfunction remains poorly understood. Calpain-1, a ubiquitous calcium-activated cysteine protease expressed in hematopoietic cells, mediates aggregation of platelets in healthy mice. We generated calpain-1 knockout Townes sickle (SSCKO) mice to investigate the role of calpain-1 in steady state and hypoxia/reoxygenation (H/R)-induced sickle platelet activation and aggregation, clot retraction, and pulmonary arterial hypertension. Using multi-electrode aggregometry, which measures platelet adhesion and aggregation in whole blood, we determined that steady state SSCKO mice exhibit significantly impaired PAR4-TRAP-stimulated platelet aggregation as compared to Townes sickle (SS) and humanized control (AA) mice. Interestingly, the H/R injury induced platelet hyperactivity in SS and SSCKO, but not AA mice, and partially rescued the aggregation defect in SSCKO mice. The PAR4-TRAP-stimulated GPIIb-IIIa (α IIb β 3 ) integrin activation was normal in SSCKO platelets suggesting that an alternate mechanism mediates the impaired platelet aggregation in steady state SSCKO mice. Taken together, we provide the first evidence that calpain-1 regulates platelet hyperactivity in sickle mice, and may offer a viable pharmacological target to reduce platelet hyperactivity in SCD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rationale: Noninvasive ventilation (NIV) is a cornerstone of treatment for patients with severe exacerbations of chronic obstructive pulmonary disease (COPD), where it has been shown to reduce the need for intubation, hospital length of stay, and mortality. Despite high-quality evidence and strong recommendations in clinical guidelines, use of NIV varies widely across hospitals., Objectives: To identify approaches used by hospitals that have been successful in implementing NIV to treat patients with severe exacerbations of COPD., Methods: Adopting a positive deviance approach, in-depth interviews were conducted with key stakeholders from a sample of high-performing hospitals selected from a large and representative network of 386 U.S. hospitals. High performers were defined as hospitals in which a high proportion of patients with COPD requiring mechanical ventilation were treated with NIV, and that also achieved low risk-adjusted mortality for all patients with COPD. Interviews were audio-recorded and transcribed verbatim. Themes and subthemes were identified through iterative readings of the transcripts and discussion until the team agreed that all important themes and subthemes had been identified. All transcripts were coded by three or four researchers. Differences in coding were discussed to negotiate consensus, resulting in a single agreed-on set of coded transcripts., Results: Interviews were conducted with 32 participants from seven hospitals. Hospitals were diverse regarding size, teaching status, and geographic location. Participants included respiratory therapists (n = 15), physicians (n = 10), and nurses (n = 7). The qualitative analyses revealed three interrelated domains that characterized effective NIV use: processes, structural elements, and contextual factors. Several themes comprised each domain. Key processes included timely identification of appropriate patients, early initiation of NIV, frequent reassessment of patients, and attention to patient comfort. Necessary structural elements included adequate equipment, sufficient numbers of qualified respiratory therapists, and flexibility in staffing. Important contextual factors included provider buy-in, respiratory therapist autonomy, interdisciplinary teamwork, and staff education. Hospital leaders, policies, and protocols were identified as playing a supporting role in promoting essential elements., Conclusions: We identified factors, such as respiratory therapist autonomy, that facilitated essential processes (e.g., timely initiation) of NIV use at high-performing hospitals. These findings may be useful to hospitals seeking to optimize their use of NIV among patients with COPD.