The hydrogen-bonding dynamics of water to a nitrile-functionalized electrode is modulated by voltage according to ultrafast 2D IR spectroscopy.

We report the hydrogen-bonding dynamics of water to a nitrile-functionalized and plasmonic electrode surface as a function of applied voltage. The surface-enhanced two-dimensional infrared spectra exhibit hydrogen-bonded and non-hydrogen-bonded nitrile features in similar proportions, plus cross peaks between the two. Isotopic dilution experiments show that the cross peaks arise predominantly from chemical exchange between hydrogen-bonded and non-hydrogen-bonded nitriles. The chemical exchange rate depends upon voltage, with the hydrogen bond of the water to the nitriles breaking 2 to 3 times slower (>63 vs. 25 ps) under a positive as compared to a negative potential. Spectral diffusion created by hydrogen-bond fluctuations occurs on a ~1 ps timescale and is moderately potential-dependent. Timescales from molecular dynamics simulations agree qualitatively with the experiment and show that a negative voltage causes a small net displacement of water away from the surface. These results show that the voltage applied to an electrode can alter the timescales of solvent motion at its interface, which has implications for electrochemically driven reactions.

Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction.

BACKGROUND: Whether revascularization by percutaneous coronary intervention (PCI) can improve event-free survival and left ventricular function in patients with severe ischemic left ventricular systolic dysfunction, as compared with optimal medical therapy (i.e., individually adjusted pharmacologic and device therapy for heart failure) alone, is unknown. METHODS: We randomly assigned patients with a left ventricular ejection fraction of 35% or less, extensive coronary artery disease amenable to PCI, and demonstrable myocardial viability to a strategy of either PCI plus optimal medical therapy (PCI group) or optimal medical therapy alone (optimal-medical-therapy group). The primary composite outcome was death from any cause or hospitalization for heart failure. Major secondary outcomes were left ventricular ejection fraction at 6 and 12 months and quality-of-life scores. RESULTS: A total of 700 patients underwent randomization - 347 were assigned to the PCI group and 353 to the optimal-medical-therapy group. Over a median of 41 months, a primary-outcome event occurred in 129 patients (37.2%) in the PCI group and in 134 patients (38.0%) in the optimal-medical-therapy group (hazard ratio, 0.99; 95% confidence interval [CI], 0.78 to 1.27; P = 0.96). The left ventricular ejection fraction was similar in the two groups at 6 months (mean difference, -1.6 percentage points; 95% CI, -3.7 to 0.5) and at 12 months (mean difference, 0.9 percentage points; 95% CI, -1.7 to 3.4). Quality-of-life scores at 6 and 12 months appeared to favor the PCI group, but the difference had diminished at 24 months. CONCLUSIONS: Among patients with severe ischemic left ventricular systolic dysfunction who received optimal medical therapy, revascularization by PCI did not result in a lower incidence of death from any cause or hospitalization for heart failure. (Funded by the National Institute for Health and Care Research Health Technology Assessment Program; REVIVED-BCIS2 ClinicalTrials.gov number, NCT01920048.).

Unloading the Left Ventricle in Venoarterial ECMO: In Whom, When, and How?

Venoarterial extracorporeal membrane oxygenation provides cardiorespiratory support to patients in cardiogenic shock. This comes at the cost of increased left ventricle (LV) afterload that can be partly ascribed to retrograde aortic flow, causing LV distension, and leads to complications including cardiac thrombi, arrhythmias, and pulmonary edema. LV unloading can be achieved by using an additional circulatory support device to mitigate the adverse effects of mechanical overload that may increase the likelihood of myocardial recovery. Observational data suggest that these strategies may improve outcomes, but in whom, when, and how LV unloading should be employed is unclear; all techniques require balancing presumed benefits against known risks of device-related complications. This review summarizes the current evidence related to LV unloading with venoarterial extracorporeal membrane oxygenation.

Arrhythmia and Death Following Percutaneous Revascularization in Ischemic Left Ventricular Dysfunction: Prespecified Analyses From the REVIVED-BCIS2 Trial.

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82-1.30]; P=0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01920048.

Water inside the Selectivity Filter of a K+ Ion Channel: Structural Heterogeneity, Picosecond Dynamics, and Hydrogen Bonding.

Water inside biological ion channels regulates the key properties of these proteins, such as selectivity, ion conductance, and gating. In this article, we measure the picosecond spectral diffusion of amide I vibrations of an isotope-labeled KcsA potassium channel using two-dimensional infrared (2D IR) spectroscopy. By combining waiting time (100-2000 fs) 2D IR measurements of the KcsA channel including 13C18O isotope-labeled Val76 and Gly77 residues with molecular dynamics simulations, we elucidated the site-specific dynamics of water and K+ ions inside the selectivity filter of KcsA. We observe inhomogeneous 2D line shapes with extremely slow spectral diffusion. Our simulations quantitatively reproduce the experiments and show that water is the only component with any appreciable dynamics, whereas K+ ions and the protein are essentially static on a picosecond timescale. By analyzing simulated and experimental vibrational frequencies, we find that water in the selectivity filter can be oriented to form hydrogen bonds with adjacent or nonadjacent carbonyl groups with the reorientation timescales being three times slower and comparable to that of water molecules in liquid, respectively. Water molecules can reside in the cavity sufficiently far from carbonyls and behave essentially like "free" gas-phase-like water with fast reorientation times. Remarkably, no interconversion between these configurations was observed on a picosecond timescale. These dynamics are in stark contrast with liquid water, which remains highly dynamic even in the presence of ions at high concentrations.

Endoscopic and histologic utility of transnasal endoscopy in pediatric eosinophilic esophagitis.

Unsedated transnasal endoscopy (TNE) is an alternative method of examining the esophageal mucosa in pediatric patients with eosinophilic esophagitis (EoE), reducing cost, time, and risk associated with frequent surveillance esophagogastroduodenoscopies (EGD). Adequacy of transnasal esophageal biopsies for the evaluation of eosinophilic esophagitis histologic scoring system (EoEHSS) has not yet been evaluated. We compared procedure times, endoscopic findings, and EoEHSS scoring for EoE patients undergoing TNE versus standard EGD. Sixty-six TNE patients and 132 EGD controls matched for age (mean age 14.0 years) and disease status (29.3% active) were included. Compared to patients undergoing standard EGD, patients undergoing TNE spent 1.94 h less in the GI suite (p < 0.0001), with comparable occurrence rates of all visual endoscopic findings and most EoEHSS components. TNE serves as a useful tool for long-term disease surveillance, and consideration should be given to its use in clinical trials for EoE.

Molecular dynamics simulation study of water structure and dynamics on the gold electrode surface with adsorbed 4-mercaptobenzonitrile.

Understanding water dynamics at charged interfaces is of great importance in various fields, such as catalysis, biomedical processes, and solar cell materials. In this study, we implemented molecular dynamics simulations of a system of pure water interfaced with Au electrodes, on one side of which 4-mercaptobenzonitrile (4-MBN) molecules are adsorbed. We calculated time correlation functions of various dynamic quantities, such as the hydrogen bond status of the N atom of the adsorbed 4-MBN molecules, the rotational motion of the water OH bond, hydrogen bonds between 4-MBN and water, and hydrogen bonds between water molecules in the interface region. Using the Luzar-Chandler model, we analyzed the hydrogen bond dynamics between a 4-MBN and a water molecule. The dynamic quantities we calculated can be divided into two categories: those related to the collective behavior of interfacial water molecules and the H-bond interaction between a water molecule and the CN group of 4-MBN. We found that these two categories of dynamic quantities exhibit opposite trends in response to applied potentials on the Au electrode. We anticipate that the present work will help improve our understanding of the interfacial dynamics of water in various electrolyte systems.

Left ventricular unloading in patients supported with veno-arterial extra corporeal membrane oxygenation; an international EuroELSO survey.

INTRODUCTION: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) improves end-organ perfusion in cardiogenic shock but may increase afterload, which can limit cardiac recovery. Left ventricular (LV) unloading strategies may aid cardiac recovery and prevent complications of increased afterload. However, there is no consensus on when and which unloading strategy should be used. METHODS: An online survey was distributed worldwide via the EuroELSO newsletter mailing list to describe contemporary international practice and evaluate heterogeneity in strategies for LV unloading. RESULTS: Of 192 respondents from 43 countries, 53% routinely use mechanical LV unloading, to promote ventricular recovery and/or to prevent complications. Of those that do not routinely unload, 65% cited risk of complications as the reason. The most common indications for unplanned unloading were reduced arterial line pulsatility (68%), pulmonary edema (64%) and LV dilatation (50%). An intra-aortic balloon pump was the most frequently used device for unloading followed by percutaneous left ventricular assist devices. Echocardiography was the most frequently used method to monitor the response to unloading. CONCLUSIONS: Significant variation exists with respect to international practice of ventricular unloading. Further research is required that compares the efficacy of different unloading strategies and a randomized comparison of routine mechanical unloading versus unplanned unloading.

The molecular and clinical role of Tensin 1/2/3 in cancer.

Tensin 1 was originally described as a focal adhesion adaptor protein, playing a role in extracellular matrix and cytoskeletal interactions. Three other Tensin proteins were subsequently discovered, and the family was grouped as Tensin. It is now recognized that these proteins interact with multiple cell signalling cascades that are implicated in tumorigenesis. To understand the role of Tensin 1-3 in neoplasia, current molecular evidence is categorized by the hallmarks of cancer model. Additionally, clinical data involving Tensin 1-3 are reviewed to investigate the correlation between cellular effects and clinical phenotype. Tensin proteins commonly interact with the tumour suppressor, DLC1. The ability of Tensin to promote tumour progression is directly correlated with DLC1 expression. Members of the Tensin family appear to have tumour subtype-dependent effects on oncogenesis; despite numerous data evidencing a tumour suppressor role for Tensin 2, association of Tensins 1-3 with an oncogenic role notably in colorectal carcinoma and pancreatic ductal adenocarcinoma is of potential clinical relevance. The complex interplay between these focal adhesion adaptor proteins and signalling pathways are discussed to provide an up to date review of their role in cancer biology.

Probing Ion Configurations in the KcsA Selectivity Filter with Single-Isotope Labels and 2D IR Spectroscopy.

The potassium ion (K+) configurations of the selectivity filter of the KcsA ion channel protein are investigated with two-dimensional infrared (2D IR) spectroscopy of amide I vibrations. Single 13C-18O isotope labels are used, for the first time, to selectively probe the S1/S2 or S2/S3 binding sites in the selectivity filter. These binding sites have the largest differences in ion occupancy in two competing K+ transport mechanisms: soft-knock and hard-knock. According to the former, water molecules alternate between K+ ions in the selectivity filter while the latter assumes that K+ ions occupy the adjacent sites. Molecular dynamics simulations and computational spectroscopy are employed to interpret experimental 2D IR spectra. We find that in the closed conductive state of the KcsA channel, K+ ions do not occupy adjacent binding sites. The experimental data is consistent with simulated 2D IR spectra of soft-knock ion configurations. In contrast, the simulated spectra for the hard-knock ion configurations do not reproduce the experimental results. 2D IR spectra of the hard-knock mechanism have lower frequencies, homogeneous 2D lineshapes, and multiple peaks. In contrast, ion configurations of the soft-knock model produce 2D IR spectra with a single peak at a higher frequency and inhomogeneous lineshape. We conclude that under equilibrium conditions, in the absence of transmembrane voltage, both water and K+ ions occupy the selectivity filter of the KcsA channel in the closed conductive state. The ion configuration is central to the mechanism of ion transport through potassium channels.

Agricultural soil legacy influences multitrophic interactions between crops, their pathogens and pollinators.

Soil legacy influences plant interactions with antagonists and below-ground mutualists. Plant-antagonist interactions can jeopardize plant-pollinator interactions, while soil mutualists can enhance plant-pollinator interactions. This suggests that soil legacy, either directly or mediated through plant symbionts, affects pollinators. Despite the importance of pollinators to natural and managed ecosystems, information on how soil legacy affects plant-pollinator interactions is limited. We assessed effects of soil management legacy (organic versus conventional) on floral rewards and plant interactions with wild pollinators, herbivores, beneficial fungi and pathogens. We used an observational dataset and structural equation models to evaluate hypothesized relationships between soil and pollinators, then tested observed correlations in a manipulative experiment. Organic legacy increased mycorrhizal fungal colonization and improved resistance to powdery mildew, which promoted pollinator visitation. Further, soil legacy and powdery mildew independently and interactively impacted floral traits and floral reward nutrients, which are important to pollinators. Our results indicate that pollination could be an overlooked consequence of soil legacy and suggests opportunity to develop long-term soil management plans that benefit pollinators and pollination.

Pediatric Aerodigestive Medicine: Advancing Collaborative Care for Children With Oropharyngeal Dysphagia.

OBJECTIVES: Aerodigestive disorders encompass various pathological conditions affecting the lungs, upper airway, and gastrointestinal tract in children. While advanced care has primarily occurred in specialty centers, many children first present to general pediatric gastroenterologists with aerodigestive symptoms necessitating awareness of these conditions. At the 2021 Annual North American Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting, the aerodigestive Special Interest Group held a full-day symposium entitled, Pediatric Aerodigestive Medicine: Advancing Collaborative Care of Children with Aerodigestive Disorders. The symposium aimed to underline the significance of a multidisciplinary approach to achieve better outcomes for these complex patients. METHODS: The symposium brought together leading experts to highlight the growing aerodigestive field, promote new scientific and therapeutic strategies, share the structure and benefits of a multidisciplinary approach in diagnosing common and rare aerodigestive disorders, and foster multidisciplinary discussion of complex cases while highlighting the range of therapeutic and diagnostic options. In this article, we showcase the diagnostic and therapeutic approach to oropharyngeal dysphagia (OPD), one of the most common aerodigestive conditions, emphasizing the role of a collaborative model. CONCLUSIONS: The aerodigestive field has made significant progress and continues to grow due to a unique multidisciplinary, collaborative model of care for these conditions. Despite diagnostic and therapeutic challenges, the multidisciplinary approach has enabled and greatly improved efficient, high-quality, and evidence-based care for patients, including those with OPD.

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.

Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFß-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

Myocardial viability testing: all STICHed up, or about to be REVIVED?

Patients with ischaemic left ventricular dysfunction frequently undergo myocardial viability testing. The historical model presumes that those who have extensive areas of dysfunctional-yet-viable myocardium derive particular benefit from revascularization, whilst those without extensive viability do not. These suppositions rely on the theory of hibernation and are based on data of low quality: taking a dogmatic approach may therefore lead to patients being refused appropriate, prognostically important treatment. Recent data from a sub-study of the randomized STICH trial challenges these historical concepts, as the volume of viable myocardium failed to predict the effectiveness of coronary artery bypass grafting. Should the Heart Team now abandon viability testing, or are new paradigms needed in the way we interpret viability? This state-of-the-art review critically examines the evidence base for viability testing, focusing in particular on the presumed interactions between viability, functional recovery, revascularization and prognosis which underly the traditional model. We consider whether viability should relate solely to dysfunctional myocardium or be considered more broadly and explore wider uses of viability testingoutside of revascularization decision-making. Finally, we look forward to ongoing and future randomized trials, which will shape evidence-based clinical practice in the future.

Control of sugar and amino acid feeding via pharyngeal taste neurons.

Insect gustatory systems comprise multiple taste organs for detecting chemicals that signal palatable or noxious quality. Although much is known about how taste neurons sense various chemicals, many questions remain about how individual taste neurons in each taste organ control feeding. Here, we use the Drosophila pharynx as a model to investigate how taste information is encoded at the cellular level to regulate consumption of sugars and amino acids. We first generate taste-blind animals and establish a critical role for pharyngeal input in food selection. We then investigate feeding behavior of both male and female flies in which only selected classes of pharyngeal neurons are restored via binary choice feeding preference assays as well as Fly Liquid-Food Interaction Counter (FLIC) assays. We find instances of integration as well as redundancy in how pharyngeal neurons control behavioral responses to sugars and amino acids. Additionally, we find that pharyngeal neurons drive sugar feeding preference based on sweet taste but not on nutritional value. Finally, we demonstrate functional specialization of pharyngeal and external neurons using optogenetic activation. Overall, our genetic taste neuron protection system in a taste-blind background provides a powerful approach to elucidate principles of pharyngeal taste coding and demonstrates functional overlap and subdivision among taste neurons.SIGNIFICANCE STATEMENTDietary intake of nutritious chemicals such as sugars and amino acids is essential for an animal's survival. In insects, distinct classes of taste neurons control acceptance or rejection of food sources. Here we develop a genetic system to investigate how individual taste neurons in the Drosophila pharynx encode specific tastants, focusing on sugars and amino acids. By examining flies in which only a single class of taste neurons is active, we find evidence for functional overlap as well as redundancy in responses to sugars and amino acids. We also uncover functional subdivision between pharyngeal and external neurons in driving feeding responses. Overall, we find that different pharyngeal neurons act together to control intake of the two categories of appetitive tastants.

The Impact of Centers for Medicare & Medicaid Services SEP-1 Core Measure Implementation on Antibacterial Utilization: A Retrospective Multicenter Longitudinal Cohort Study With Interrupted Time-Series Analysis.

BACKGROUND: The impact of the US Centers for Medicare & Medicaid Services (CMS) Severe Sepsis and Septic Shock: Management Bundle (SEP-1) core measure on overall antibacterial utilization is unknown. METHODS: We performed a retrospective multicenter longitudinal cohort study with interrupted time-series analysis to determine the impact of SEP-1 implementation on antibacterial utilization and patient outcomes. All adult patients admitted to 26 hospitals between 1 October 2014 and 30 September 2015 (SEP-1 preparation period) and between 1 November 2015 and 31 October 2016 (SEP-1 implementation period) were evaluated for inclusion. The primary outcome was total antibacterial utilization, measured as days of therapy (DOT) per 1000 patient-days. RESULTS: The study cohort included 701 055 eligible patient admissions and 4.2 million patient-days. Overall antibacterial utilization increased 2% each month during SEP-1 preparation (relative rate [RR], 1.02 per month [95% confidence interval {CI}, 1.00-1.04]; P = .02). Cumulatively, the mean monthly DOT per 1000 patient-days increased 24.4% (95% CI, 18.0%-38.8%) over the entire study period (October 2014-October 2016). The rate of sepsis diagnosis/1000 patients increased 2% each month during SEP-1 preparation (RR, 1.02 per month [95% CI, 1.00-1.04]; P = .04). The rate of all-cause mortality rate per 1000 patients decreased during the study period (RR for SEP-1 preparation, 0.95 [95% CI, .92-.98; P = .001]; RR for SEP-1 implementation, .98 [.97-1.00; P = .01]). Cumulatively, the monthly mean all-cause mortality rate/1000 patients declined 38.5% (95% CI, 25.9%-48.0%) over the study period. CONCLUSIONS: Announcement and implementation of the CMS SEP-1 process measure was associated with increased diagnosis of sepsis and antibacterial utilization and decreased mortality rate among hospitalized patients.

Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles.

We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.

Finding the right mix: a framework for selecting seeding rates for cover crop mixtures.

Cover crop mixtures have the potential to provide more ecosystem services than cover crop monocultures. However, seeding rates that are typically recommended (i.e. seeding rate of monoculture divided by the number of species in the mixture) are non-optimized and often result in the competitive species dominating the mixture, and therefore limiting the amount of ecosystem services that are provided. We created an analytical framework for selecting seeding rates for cover crop mixtures that maximize multifunctionality while minimizing seed costs. The framework was developed using data from a field experiment, which included six response surface designs of two-species mixtures, as well as a factorial replacement design of three-species and four-species mixtures. We quantified intraspecific and interspecific competition among two grasses and two legume cover crop species with grass and legume representing two functional groups: pearl millet [Pennisetum glaucum (L.) R.Br.], sorghum sudangrass [Sorghum bicolor (L.) Moench × Sorghum sudanense (Piper) Stapf], sunn hemp (Crotalaria juncea L.), and cowpea [Vigna unguiculata (L.) Walp]. Yield-density models were fit to estimate intraspecific and interspecific competition coefficients for each species in biculture. The hierarchy from most to least competitive was sorghum sudangrass > sunn hemp > pearl millet > cowpea. Intraspecific competition of a less competitive species was the greatest when the biculture was composed of two species in the same functional group. Competition coefficients were used to build models that estimated the biomass of each cover crop species in three-species and four-species mixtures. The competition coefficients and models were validated with an additional nine site-years testing the same cover crop mixtures. The biomass of a species in a site-year was accurately predicted 69% of the time (low root mean square error, correlation > 0.5, not biased, r2 > 0.5). Applying the framework, we designed three-species and four-species mixtures by identifying relative seeding rates that produced high biomass with high species evenness (i.e. high multifunctionality) at low seed costs based on a Pareto front analysis of 10,418 mixtures. Accounting for competition when constructing cover crop mixtures can improve the ecosystem services provided, and such an advancement is likely to lead to greater farmer adoption.

High-resolution non-contrast free-breathing coronary cardiovascular magnetic resonance angiography for detection of coronary artery disease: validation against invasive coronary angiography.

BACKGROUND: Coronary artery disease (CAD) is the single most common cause of death worldwide. Recent technological developments with coronary cardiovascular magnetic resonance angiography (CCMRA) allow high-resolution free-breathing imaging of the coronary arteries at submillimeter resolution without contrast in a predictable scan time of ~ 10 min. The objective of this study was to determine the diagnostic accuracy of high-resolution CCMRA for CAD detection against the gold standard of invasive coronary angiography (ICA). METHODS: Forty-five patients (15 female, 62 ± 10 years) with suspected CAD underwent sub-millimeter-resolution (0.6 mm3) non-contrast CCMRA at 1.5T in this prospective clinical study from 2019-2020. Prior to CCMR, patients were given an intravenous beta blockers to optimize heart rate control and sublingual glyceryl trinitrate to promote coronary vasodilation. Obstructive CAD was defined by lesions with ≥ 50% stenosis by quantitative coronary angiography on ICA. RESULTS: The mean duration of image acquisition was 10.4 ± 2.1 min. On a per patient analysis, the sensitivity, specificity, positive predictive value and negative predictive value (95% confidence intervals) were 95% (75-100), 54% (36-71), 60% (42-75) and 93% (70-100), respectively. On a per vessel analysis the sensitivity, specificity, positive predictive value and negative predictive value (95% confidence intervals) were 80% (63-91), 83% (77-88), 49% (36-63) and 95% (90-98), respectively. CONCLUSION: As an important step towards clinical translation, we demonstrated a good diagnostic accuracy for CAD detection using high-resolution CCMRA, with high sensitivity and negative predictive value. The positive predictive value is moderate, and combination with CMR stress perfusion may improve the diagnostic accuracy. Future multicenter evaluation is now required.