Crystal Structure of Caryolan-1-ol Synthase, a Sesquiterpene Synthase Catalyzing an Initial Anti-Markovnikov Cyclization Reaction.

In a continuing effort to understand reaction mechanisms of terpene synthases catalyzing initial anti-Markovnikov cyclization reactions, we solved the X-ray crystal structure of (+)-caryolan-1-ol synthase (CS) from Streptomyces griseus , with and without an inactive analog of the FPP substrate, 2-fluorofarnesyl diphosphate (2FFPP), bound in the active site of the enzyme. The CS-2FFPP complex was solved to 2.65 Å resolution and showed the ligand in a linear, elongated orientation, incapable of undergoing the initial cyclization event to form a bond between carbons C1 and C11. Intriguingly, the apo CS structure (2.2 Å) also had electron density in the active site, in this case density that was well fit with a curled-up tetraethylene glycol molecule presumably recruited from the crystallization medium. The density was also well fit by a molecule of farnesene suggesting that the structure may mimic an intermediate along the reaction coordinate. The curled-up conformation of tetraethylene glycol was accompanied by dramatic rotamer shifts among active-site residues. Most notably, W56 was observed to undergo a 90° rotation between the 2FFPP complex and apo-enzyme structures, suggesting that it contributes to steric interactions that help curl the tetraethylene glycol molecule in the active site, and by extension perhaps also a derivative of the FPP substrate in the normal course of the cyclization reaction. In support of this proposal, the CS W56L variant lost the ability to cyclize the FPP substrate and produced only the linear terpene products farnesol and α- and ß-farnesene.

Adjusting Atrial Size Parameters for Body Surface Area: Does it Affect the Association With Pulmonary Embolism-related Adverse Events?

PURPOSE: Small left atrial (LA) volume was recently reported to be one of the best predictors of acute pulmonary embolism (PE)-related adverse events (AE). There is currently no data available regarding the impact that body surface area (BSA)-indexing of atrial measurements has on the association with PE-related adverse events. Our aim is to assess the impact of indexing atrial measurements to BSA on the association between computed tomography (CT) atrial measurements and AE. MATERIALS AND METHODS: Retrospective study (IRB: 2015P000425). A database of hospitalized patients with acute PE diagnosed on CT pulmonary angiography (CTPA) between May 2007 and December 2014 was reviewed. Right and left atrial volume, largest axial area, and axial diameters were measured. Patients undergo both echocardiographies (from which the BSA was extracted) and CTPAs within 48 hours of the procedure. The patient's body weight was measured during each admission. LA measurements were correlated to AE (defined as the need for advanced therapy or PE-related mortality at 30 days) before and after indexing for BSA. The area under the ROC curve was calculated to determine the predictive value of the atrial measurements in predicting AE. RESULTS: The study included 490 acute PE patients; 62 (12.7%) had AE. There was a significant association of reduced BSA-indexed and non-indexed LA volume (both <0.001), area (<0.001 and 0.001, respectively), and short-axis diameters (both <0.001), and their respective RA/LA ratios (all <0.001) with AE. The AUC values were similar for BSA-indexed and non-indexed LA volume, diameters, and area with LA volume measurements being the best predictor of adverse outcomes (BSA-indexed AUC=0.68 and non-indexed AUC=0.66), followed by non-indexed LA short-axis diameter (indexed AUC=0.65, non-indexed AUC=0.64), and LA area (indexed AUC=0.64, non-indexed AUC=0.63). CONCLUSION: Adjusting for BSA does not substantially affect the predictive ability of atrial measurements on 30-day PE-related adverse events, and therefore, this adjustment is not necessary in clinical practice. While LA volume is the better predictor of AE, LA short-axis diameter has a similar predictive value and is more practical to perform clinically.

A Case of S1Q3T3-A Classic Nonspecific Electrocardiogram Finding.

This case report describes a patient in their 40s with a history of end-stage kidney disease secondary to hypertension and diabetes who presented with fatigue, cough, weakness, and dyspnea on exertion and was subsequently diagnosed with acute disseminated cryptococcal infection.

Prevalence and Predictors of Inappropriate Antithrombotic Prescription in Patients Presenting With Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: A growing proportion of the US population is on antithrombotic therapy (AT), most significantly within the older subpopulation. Decision to use AT is a balance between the intended benefits and known bleeding risk, especially after traumatic brain injury (TBI). Preinjury inappropriate AT offers no benefit for the patient and also increases the risk of intracranial hemorrhage and worse outcome in the setting of TBI. Our objective was to examine the prevalence and predictors of inappropriate AT among patients presenting with TBI to a Level-1 Trauma Center. METHODS: A retrospective chart review was performed on all patients with TBI and preinjury AT who presented to our institution between January 2016 and September 2020. Demographic and clinical data were collected. Appropriateness of AT was determined through established clinical guidelines. Clinical predictors were determined by logistic regression. RESULTS: Of 141 included patients, 41.8% were female (n = 59) and the average age (mean ± SD) was 80.6 ± 9.9. The prescribed antithrombotic agents included aspirin (25.5%, n = 36), clopidogrel (22.7%, n = 32), warfarin (46.8%, n = 66), dabigatran (2.1%, n = 3), rivaroxaban (Janssen) (10.6%, n = 15), and apixaban (Bristol-Myers Squibb Co.) (18.4%, n = 26). The indications for AT were atrial fibrillation (66.7%, n = 94), venous thromboembolism (13.4%, n = 19), cardiac stent (8.5%, n = 12), and myocardial infarction/residual coronary disease (11.3%, n = 16). Inappropriate antithrombotic therapy use varied significantly by antithrombotic indication ( P < .001) with the highest rates seen with venous thromboembolism. Predictive factors also include age ( P = .005) with higher rates younger than 65 years and older than 85 years and female sex ( P = .049). Race and antithrombotic agent were not significant predictors. CONCLUSION: Overall, 1 in 10 patients presenting with TBI were found to be on inappropriate AT. Our study is the first to describe this problem and warrants investigation into possible workflow interventions to prevent post-TBI continuation of inappropriate AT.

The spatial ventricular gradient is associated with adverse outcomes in acute pulmonary embolism.

BACKGROUND: The spatial ventricular gradient (SVG) is a vectorcardiographic measurement that reflects cardiac loading conditions via electromechanical coupling. OBJECTIVES: We hypothesized that the SVG is correlated with right ventricular (RV) strain and is prognostic of adverse events in patients with acute pulmonary embolism (PE). METHODS: Retrospective, single-center study of patients with acute PE. Electrocardiogram (ECG), imaging, and outcome data were obtained. SVG components were regressed on tricuspid annular plane systolic excursion (TAPSE), qualitative RV dysfunction, and RV/left ventricular (LV) ratio. Odds of adverse outcomes (30-day mortality, vasopressor requirement, or advanced therapy) after PE were regressed on demographics, RV/LV ratios, traditional ECG signs of RV dysfunction, and SVG components using a logit model. RESULTS: ECGs from 317 patients (48% male, age 63.1 ± 16.6 years) with acute PE were analyzed; 36 patients (11.4%) experienced an adverse event. Worse RV hypokinesis, larger RV/LV ratio, and smaller TAPSE were associated with smaller SVG X and Y components, larger SVG Z components, and smaller SVG vector magnitude (p < .001 for all). In multivariable logistic regression, odds of adverse events after PE decreased with increasing SVG magnitude and TAPSE (OR 0.32 and 0.54 per standard deviation increase; p = .03 and p = .004, respectively). Receiver operating characteristic (ROC) analysis showed that, when combined with imaging, replacing traditional ECG criteria with the SVG significantly improved the area under the ROC from 0.70 to 0.77 (p = .01). CONCLUSION: The SVG is correlated with RV dysfunction and adverse outcomes in acute PE and has a better prognostic value than traditional ECG markers.

An inline deep learning based free-breathing ECG-free cine for exercise cardiovascular magnetic resonance.

BACKGROUND: Exercise cardiovascular magnetic resonance (Ex-CMR) is a promising stress imaging test for coronary artery disease (CAD). However, Ex-CMR requires accelerated imaging techniques that result in significant aliasing artifacts. Our goal was to develop and evaluate a free-breathing and electrocardiogram (ECG)-free real-time cine with deep learning (DL)-based radial acceleration for Ex-CMR. METHODS: A 3D (2D + time) convolutional neural network was implemented to suppress artifacts from aliased radial cine images. The network was trained using synthetic real-time radial cine images simulated using breath-hold, ECG-gated segmented Cartesian k-space data acquired at 3 T from 503 patients at rest. A prototype real-time radial sequence with acceleration rate = 12 was used to collect images with inline DL reconstruction. Performance was evaluated in 8 healthy subjects in whom only rest images were collected. Subsequently, 14 subjects (6 healthy and 8 patients with suspected CAD) were prospectively recruited for an Ex-CMR to evaluate image quality. At rest (n = 22), standard breath-hold ECG-gated Cartesian segmented cine and free-breathing ECG-free real-time radial cine images were acquired. During post-exercise stress (n = 14), only real-time radial cine images were acquired. Three readers evaluated residual artifact level in all collected images on a 4-point Likert scale (1-non-diagnostic, 2-severe, 3-moderate, 4-minimal). RESULTS: The DL model substantially suppressed artifacts in real-time radial cine images acquired at rest and during post-exercise stress. In real-time images at rest, 89.4% of scores were moderate to minimal. The mean score was 3.3 ± 0.7, representing increased (P < 0.001) artifacts compared to standard cine (3.9 ± 0.3). In real-time images during post-exercise stress, 84.6% of scores were moderate to minimal, and the mean artifact level score was 3.1 ± 0.6. Comparison of left-ventricular (LV) measures derived from standard and real-time cine at rest showed differences in LV end-diastolic volume (3.0 mL [- 11.7, 17.8], P = 0.320) that were not significantly different from zero. Differences in measures of LV end-systolic volume (7.0 mL [- 1.3, 15.3], P < 0.001) and LV ejection fraction (- 5.0% [- 11.1, 1.0], P < 0.001) were significant. Total inline reconstruction time of real-time radial images was 16.6 ms per frame. CONCLUSIONS: Our proof-of-concept study demonstrated the feasibility of inline real-time cine with DL-based radial acceleration for Ex-CMR.

Evidence for Left Atrial Volume Being an Indicator of Adverse Events in Patients With Acute Pulmonary Embolism: Retrospective Case-control Pilot Study.

PURPOSE: To assess the association between computed tomography pulmonary angiography (CTPA) atrial measurements and both 30-day pulmonary embolism (PE)-related adverse events and mortality, and non-PE-related mortality, and to identify the best predictors of these outcomes by comparing atrial measurements and widely used clinical and imaging variables. PATIENTS AND METHODS: Retrospective single-center pilot study. Acute PE patients diagnosed on CTPA who also had a transthoracic echocardiogram, electrocardiogram, and troponin T were included. CTPA left atrial (LA) and right atrial (RA) volume and short-axis diameter were measured and compared between outcome groups, along with right ventricular/left ventricular diameter ratio, interventricular septal bowing, tricuspid annular plane systolic excursion, electrocardiogram, and troponin T. RESULTS: A total of 350 patients. LA volume and diameter were associated with PE-related adverse events (P≤0.01). LA volume was the only atrial measurement associated with PE-related mortality (P=0.03), with no atrial measurements associated with non-PE-related mortality. Troponin was most associated with PE-related adverse events and mortality (both area under the curve [AUC]=0.77). On multivariate analysis, combination models did not greatly improve PE-related adverse events prediction compared with troponin alone. For PE-related mortality, the best models were the combination of troponin, age, and either LA volume (AUC=0.86) or diameter (AUC=0.87). CONCLUSION: Among patients with acute PE, CTPA LA volume is the only imaging parameter associated with PE-related mortality and is the best imaging predictor of this outcome. Reduced CTPA LA volume and diameter, along with increased RA/LA volume and diameter ratios, are significantly associated with 30-day PE-related adverse events, but not with non-PE-related mortality.

Adaptive mechanisms of plant specialized metabolism connecting chemistry to function.

As sessile organisms, plants evolved elaborate metabolic systems that produce a plethora of specialized metabolites as a means to survive challenging terrestrial environments. Decades of research have revealed the genetic and biochemical basis for a multitude of plant specialized metabolic pathways. Nevertheless, knowledge is still limited concerning the selective advantages provided by individual and collective specialized metabolites to the reproductive success of diverse host plants. Here we review the biological functions conferred by various classes of plant specialized metabolites in the context of the interaction of plants with their surrounding environment. To achieve optimal multifunctionality of diverse specialized metabolic processes, plants use various adaptive mechanisms at subcellular, cellular, tissue, organ and interspecies levels. Understanding these mechanisms and the evolutionary trajectories underlying their occurrence in nature will ultimately enable efficient bioengineering of desirable metabolic traits in chassis organisms.

Wide Complex Tachycardia in a Young Woman.

A 27-year-old woman presented with palpitations and was found to have episodes of a non-sustained wide complex tachycardia. In this report, we discuss a differential diagnosis for the patient's wide complex tachycardia and the important ECG findings which lead to her diagnosis. (Level of Difficulty: Advanced.).

Quality and diagnostic performance of coronary computed tomography angiogram (CCTA): A comparison between pre-liver and pre-kidney transplant patients.

PURPOSE: Assess and compare the quality and diagnostic performance of CCTA between pre-liver and pre-kidney transplant patients, and gauge impact of CCTA on ICA requirements. METHODS: Patients without known coronary artery disease (CAD) were selected for CCTA if considered high-risk or after abnormal stress testing. All pre-liver and pre-kidney CCTAs between March 2018 and August 2020 were retrospectively included. CCTA quality was qualitatively graded as excellent/good/fair/poor, and CAD graded as < or ≥50% stenosis. Heart rate, coronary artery calcium (CAC) scores, and fractional flow reserve CT (FFRCT) results were collected. CAD stenosis was graded on invasive coronary angiogram (ICA) images, with ≥50% stenosis defined as significant. RESULTS: 162 pre-transplant patients (91 pre-liver, 71 pre-kidney). Pre-kidney patients had poorer CCTA quality (p = 0.04) and higher heart rate (median: 65 bpm vs 60 bpm, p < 0.001). Out of 147 diagnostic CCTAs (pre-liver: 84, pre-kidney: 63), 73 (49.7%) had a ≥50% stenosis (pre-liver: 38 (45.2%), pre-kidney:35 (55.6%)). 12/38 (31.6%) had a significantly reduced FFRCT, and 19/53 (35.8%) had ≥50% stenosis on ICA. Among patients whose CCTA was diagnostic and had ICA, stenosis severity was concordant in 10/23 (43.5%) pre-liver and 10/25 (40%) pre-kidney patients. All discordant cases had stenosis 'over-called' on CCTA. CONCLUSION: Diagnostic-quality CCTAs in high-risk pre-transplant patients are achievable and can greatly reduce ICA requirements by excluding significant CAD. CCTA quality is poorer in pre-kidney transplant patients compared to pre-liver, possibly due to higher heart rate.

Post-Cardiac Surgery Atrial Fibrillation: Risks, Mechanisms, Prevention, and Management.

Atrial fibrillation (AF) is the most common complication of cardiac surgery (CS). There are numerous risk factors, proposed mechanisms, and financial/clinical implications of post-CS AF (PCSAF). Management involves 2 arms: prevention and treatment. This review highlights and summarizes previous literature on PCSAF and challenges the standard dogma regarding anticoagulation, particularly in the short term.

Anticoagulation and amiodarone for new atrial fibrillation after coronary artery bypass grafting: Prescription patterns and 30-day outcomes in the United States and Canada.

OBJECTIVE: We sought to elucidate national practice patterns regarding anticoagulation and antiarrhythmic medication use at discharge and examine short-term patient outcomes. METHODS: In this retrospective cohort study, we analyzed the data of patients from the Society of Thoracic Surgeons Adult Cardiac Surgery Database from July 2011 to June 2018 who underwent first-time isolated coronary artery bypass graft surgery (CABG) and developed new post-CABG atrial fibrillation (AF) without significant complications. In total, 166,747 patients met study criteria. We examined 30-day outcomes. RESULTS: In total, 166,747 patients were analyzed and divided into 4 groups based on discharge medications: amiodarone with or without anticoagulation, anticoagulation alone, and neither. Demographic characteristics were similar among the 4 groups. In total, 25.7% of patients were discharged on anticoagulation with an average CHA2DS2-VASc score of 3.2 ± 1.3. Anticoagulation use at discharge was not associated with lower 30-day stroke readmissions (adjusted odds ratio [AOR], 0.87; 95% confidence interval [CI], 0.65-1.16; P = .35). Adjusted 30-day readmissions for major bleeding were significantly more common in anticoagulated patients (AOR, 4.30; 95% CI, 3.69-5.03; P < .0001). Among those discharged off anticoagulation, there was no significant difference in adjusted 30-day stroke rates based on amiodarone use at discharge (AOR, 1.19; 95% CI, 0.85-1.66; P = .31). CONCLUSIONS: Post-CABG anticoagulation for new AF is associated with increased bleeding and no difference in stroke at 30 days. Prospective randomized studies are needed to formalize safe and efficacious short- and long-term management strategies.

N-terminal pro-B-type natriuretic peptide is a specific predictor of appropriate device therapies in patients with primary prevention implantable cardioverter-defibrillators.

BACKGROUND: Sudden death risk stratification of patients with left ventricular systolic dysfunction remains challenging. Retrospective studies have suggested N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be a useful risk stratification tool. OBJECTIVE: The purpose of this study was to ascertain the utility of NT-proBNP as a predictor of appropriate implantable cardioverter-defibrillator (ICD) therapies in primary prevention ICD recipients. METHODS: This was a prospective study of 342 stable patients with left ventricular ejection fraction ≤40% who received a primary prevention ICD. NT-proBNP assay was performed at the time of device implant and used as a dichotomized variable (1st-3rd NT-proBNP quartiles vs 4th NT-proBNP quartile) to predict primary (appropriate ICD therapies) and secondary (death, ICD-deactivation, chronic inotropic support, transplant) outcomes. RESULTS: Median follow-up was 35.0 months (interquartile range 15.2-55.3). In unadjusted analyses, NT-proBNP predicted both primary (hazard ratio [HR] 1.89; 95% confidence interval [CI] 1.00-3.56); P = .049) and secondary outcomes (HR 2.13; 95% CI 1.18-3.85; P =.012). Multivariable analysis reaffirmed NT-proBNP as a primary outcome predictor (HR 4.31; 95% CI 1.92-9.70; P <.001) but not as a secondary outcome predictor (HR 1.23; 95% CI 0.61-2.50; P = .564). Instead, secondary outcome was predicted by patient age and renal function. In an unadjusted subanalysis limited to patients with blood urea nitrogen <30 mg/dL, NT-proBNP remained a primary endpoint predictor (HR 2.51; 95% CI 1.25-5.05; P = .010) but not a secondary endpoint predictor (HR 1.34; 95% CI 0.52-3.44; P = .541). Receiver operating analyses at 2- and 3-year follow-up timepoints confirmed that NT-proBNP significantly improved the performance of multivariable models designed to predict future appropriate ICD therapies. CONCLUSION: In multivariable analysis, NT-proBNP is a reasonable and specific predictor of future appropriate device therapies in primary prevention ICD recipients. In contrast, adjusted NT-proBNP does not predict all-cause mortality.

Risk assessment of acute pulmonary embolism utilizing coronary artery calcifications in patients that have undergone CT pulmonary angiography and transthoracic echocardiography.

OBJECTIVE: To evaluate the relation of coronary artery calcifications (CAC) on non-ECG-gated CT pulmonary angiography (CTPA) with short-term mortality in patients with acute pulmonary embolism (PE). METHODS: We retrospectively included all in-patients between May 2007 and December 2014 with an ICD-9 code for acute PE and CTPA and transthoracic echocardiography available. CAC was qualitatively graded as absent, mild, moderate, or severe. Relations of CAC with overall and PE-related 30-day mortality were assessed using logistic regression analyses. The independence of those relations was assessed using a nested approach, first adjusting for age and gender, then for RV strain, peak troponin T, and cardiovascular risk factors for an overall model. RESULTS: Four hundred seventy-nine patients were included (63 ± 16 years, 52.8% women, 47.2% men). In total, 253 (52.8%) had CAC-mild: 143 (29.9%); moderate: 89 (18.6%); severe: 21 (4.4%). Overall mortality was 8.8% (n = 42) with higher mortality with any CAC (12.6% vs. 4.4% without; odds ratio [OR] 3.1 [95%CI 2.1-14.5]; p = 0.002). Mortality with severe (19.0%; OR 5.1 [95%CI 1.4-17.9]; p = 0.011), moderate (11.2%; OR 2.7 [95%CI 1.1-6.8]; p = 0.031), and mild CAC (12.6%; OR 3.1 [95%CI 1.4-6.9]; p = 0.006) was higher than without. OR adjusted for age and gender was 2.7 (95%CI 1.0-7.1; p = 0.050) and 2.6 (95%CI 0.9-7.1; p = 0.069) for the overall model. PE-related mortality was 4.0% (n = 19) with higher mortality with any CAC (5.9% vs. 1.8% without; OR 3.5 [95%CI 1.1-10.7]; p = 0.028). PE-related mortality with severe CAC was 9.5% (OR 5.8 [95%CI 1.0-34.0]; p = 0.049), with moderate CAC 6.7% (OR 4.0 [95%CI 1.1-14.6]; p = 0.033), and with mild 4.9% (OR 2.9 [95%CI 0.8-9.9]; p = 0.099). OR adjusted for age and gender was 4.2 (95%CI 0.9-20.7; p = 0.074) and 3.4 (95%CI 0.7-17.4; p = 0.141) for the overall model. Patients with sub-massive PE showed similar results. CONCLUSION: CAC is frequent in acute PE patients and associated with short-term mortality. Visual assessment of CAC may serve as an easy, readily available tool for early risk stratification in those patients. KEY POINTS: • Coronary artery calcification assessed on computed tomography pulmonary angiography is frequent in patients with acute pulmonary embolism. • Coronary artery calcification assessed on computed tomography pulmonary angiography is associated with 30-day overall and PE-related mortality in patients with acute pulmonary embolism. • Coronary artery calcification assessed on computed tomography pulmonary angiography may serve as an additional, easy readily available tool for early risk stratification in those patients.

Reversal of Alpha-Synuclein Fibrillization by Protein Disulfide Isomerase.

Aggregates of α-synuclein contribute to the etiology of Parkinson's Disease. Protein disulfide isomerase (PDI), a chaperone and oxidoreductase, blocks the aggregation of α-synuclein. An S-nitrosylated form of PDI that cannot function as a chaperone is associated with elevated levels of aggregated α-synuclein and is found in brains afflicted with Parkinson's Disease. The protective role of PDI in Parkinson's Disease and other neurodegenerative disorders is linked to its chaperone function, yet the mechanism of neuroprotection remains unclear. Using Thioflavin-T fluorescence and transmission electron microscopy, we show here for the first time that PDI can break down nascent fibrils of α-synuclein. Mature fibrils were not affected by PDI. Another PDI family member, ERp57, could prevent but not reverse α-synuclein aggregation. The disaggregase activity of PDI was effective at a 1:50 molar ratio of PDI:α-synuclein and was blocked by S-nitrosylation. PDI could not reverse the aggregation of malate dehydrogenase, which indicated its disaggregase activity does not operate on all substrates. These findings establish a previously unrecognized disaggregase property of PDI that could underlie its neuroprotective function.

Mechanism Underlying Anti-Markovnikov Addition in the Reaction of Pentalenene Synthase.

Most terpene synthase reactions follow Markovnikov rules for formation of high-energy carbenium ion intermediates. However, there are notable exceptions. For example, pentalenene synthase (PS) undergoes an initial anti-Markovnikov cyclization reaction followed by a 1,2-hydride shift to form an intermediate humulyl cation with positive charge on the secondary carbon C9 atom of the farnesyl diphosphate substrate. The mechanism by which these enzymes stabilize and guide the regioselectivity of secondary carbocations has not heretofore been elucidated. In an effort to better understand these reactions, we grew crystals of apo-PS, soaked them with the nonreactive substrate analogue 12,13-difluorofarnesyl diphosphate, and determined the X-ray structure of the resulting complex at 2.2 Å resolution. The most striking feature of the active site structure is that C9 is perfectly positioned to make a C-H···π interaction with the side chain benzene ring of residue F76; this would enhance hyperconjugation to stabilize a developing cation at C10 and thus support the anti-Markovnikov regioselectivity of the cyclization. The benzene ring is also positioned to catalyze the migration of H to C10 and stabilize a C9 carbocation. On the opposite face of C9, further cation stabilization is possible via interactions with the main chain carbonyl of I177 and the neighboring intramolecular C6═C7 bond. Mutagenesis experiments also support a role for residue 76 in these interactions, but most interesting is the F76W mutant, whose crystal structure clearly shows C9 and C10 centered above the fused benzene and pyrrole rings of the indole side chain, respectively, such that a carbocation at either position could be stabilized in this complex, and two anti-Markovnikov products, pentalenene and humulene, are formed. Finally, we show that there is a rough correlation (although not absolute) of an aromatic side chain (F or Y) at position 76 in related terpene synthases from Streptomyces that catalyze similar anti-Markovnikov addition reactions.

Mitral annular plane systolic excursion and tricuspid annular plane systolic excursion for risk stratification of acute pulmonary embolism.

INTRODUCTION: Risk stratification for acute pulmonary embolism (PE) incorporates metrics of right ventricle (RV) function. Significant RV dysfunction influences left ventricular (LV) function, though LV function metrics are not utilized for stratifying outcomes in patients with PE. Mitral annular plane systolic excursion (MAPSE) is a linear echocardiographic (TTE) measure that evaluates longitudinal LV function and may aid in risk stratification for acute PE. METHODS: Using a single-center database of patients with PE from 2007 to 2014, MAPSE was calculated for all TTE's available with sufficient quality (n = 362). A MAPSE of ≥11 mm was used as a normal reference. Thirty-day adverse outcomes were defined as administration of vasopressor, fibrinolytic therapy, open embolectomy, or 30-day PE-related mortality. Odds ratios (OR) and adjusted OR (AOR) were calculated using logistic regression analysis. Tricuspid annular plane systolic excursion (TAPSE) measurements were incorporated to determine the additive benefit of MAPSE. RESULTS: Compared with the reference MAPSE ≥ 11 mm and LVEF > 50%, patients with MAPSE < 11 mm and an LVEF > 50% had worse outcomes (AOR 2.94 [95% CI: 1.08-7.98], P = 0.035). Among patients with LVEF > 50%, the presence of both a MAPSE < 11 mm and TAPSE < 16 mm was associated with greater odds of adverse outcomes compared with isolated depressed TAPSE (AOR 10.75 [95% CI: 3.06-37.8], P < 0.01 vs AOR 1.68 [95% CI: 0.18-15.6], P = 0.65). CONCLUSION: A depressed MAPSE, in patients with preserved LVEF, is associated with worse outcomes in patients with acute PE. The addition of MAPSE to TAPSE appears to have a greater prognostic value than either alone and may further aid in risk stratification, but for confirmation further prospective data are needed.