Decision Criteria for Large Vessel Occlusion Using Transcranial Doppler Waveform Morphology

Background: The current lack of effective tools for prehospital identification of Large Vessel Occlusion (LVO) represents a significant barrier to efficient triage of stroke patients and detriment to treatment efficacy. The validation of objective Transcranial Doppler (TCD) metrics for LVO detection could provide first responders with requisite tools for informing stroke transfer decisions, dramatically improving patient care.Objective: To compare the diagnostic efficacy of two such candidate metrics: Velocity Asymmetry Index (VAI), which quantifies disparity of blood flow velocity across the cerebral hemispheres, and Velocity Curvature Index (VCI), a recently proposed TCD morphological biomarker. Additionally, we investigate a simple decision tree combining both metrics.Methods: We retrospectively compare accuracy/sensitivity/specificity (ACC/SEN/SPE) of each method (relative to standard CT-Angiography) in detecting LVO in a population of 66 subjects presenting with stroke symptoms (33 with CTA-confirmed LVO), enrolled consecutively at Erlanger Southeast Regional Stroke Center in Chattanooga, TN.Results: Individual VCI and VAI metrics demonstrated robust performance, with area under receiver operating characteristic curve (ROC-AUC) of 94% and 88%, respectively. Additionally, leave-one-out cross-validation at optimal identified thresholds resulted in 88% ACC (88% SEN) for VCI, vs. 79% ACC (76% SEN) for VAI. When combined, the resultant decision tree achieved 91% ACC (94% SEN).Discussion: We conclude VCI to be superior to VAI for LVO detection, and provide evidence that simple decision criteria incorporating both metrics may further optimize.Performance: Our results suggest that machine-learning approaches to TCD morphological analysis may soon enable robust prehospital LVO identification.Registration: Was not required for this feasibility study

Direct Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C−H Bond Activation

Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct functionalization of nitrogen heterocycles through C−H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents with diverse functional groups onto the heterocycle scaffold. Working together, our two groups have developed a family of Rh-catalyzed heterocycle alkylation and arylation reactions that are notable for their high level of functional-group compatibility. This Account describes our work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods. We initially discovered an intramolecular Rh-catalyzed C-2 alkylation of azoles by alkenyl groups. That reaction provided access to a number of di-, tri-, and tetracyclic azole derivatives. We then developed conditions that exploited microwave heating to expedite these reactions. While investigating the mechanism of this transformation, we discovered that a novel substrate-derived Rh−N-heterocyclic carbene (NHC) complex was involved as an intermediate. We then synthesized analogous Rh−NHC complexes directly by treating precursors to the intermediate [RhCl(PCy3)2] with N-methylbenzimidazole, 3-methyl-3,4-dihydroquinazoline, and 1-methyl-1,4-benzodiazepine-2-one. Extensive kinetic analysis and DFT calculations supported a mechanism for carbene formation in which the catalytically active RhCl(PCy3)2 fragment coordinates to the heterocycle before intramolecular activation of the C−H bond occurs. The resulting Rh−H intermediate ultimately tautomerizes to the observed carbene complex. With this mechanistic information and the discovery that acid cocatalysts accelerate the alkylation, we developed conditions that efficiently and intermolecularly alkylate a variety of heterocycles, including azoles, azolines, dihydroquinazolines, pyridines, and quinolines, with a wide range of functionalized olefins. We demonstrated the utility of this methodology in the synthesis of natural products, drug candidates, and other biologically active molecules. In addition, we developed conditions to directly arylate these heterocycles with aryl halides. Our initial conditions that used PCy3 as a ligand were successful only for aryl iodides. However, efforts designed to avoid catalyst decomposition led to the development of ligands based on 9-phosphabicyclo[4.2.1]nonane (phoban) that also facilitated the coupling of aryl bromides. We then replicated the unique coordination environment, stability, and catalytic activity of this complex using the much simpler tetrahydrophosphepine ligands and developed conditions that coupled aryl bromides bearing diverse functional groups without the use of a glovebox or purified reagents. With further mechanistic inquiry, we anticipate that researchers will better understand the details of the aforementioned Rh-catalyzed C−H bond functionalization reactions, resulting in the design of more efficient and robust catalysts, expanded substrate scope, and new transformations

Effect of a dry purge step on the analysis by dynamic headspace - GC-MS of the volatile fraction of a cheese

A dry purge procedure was used to eliminate water during the analysis of the volatile fraction of a water-rich cheese, by dynamic headspace-GC-MS. The impact of the duration of this procedure on chromatographic profile was studied for durations ranging from 0 to 50 minutes. A dry purge duration of 3 minutes sufficed to reduce the water peak area and improve the quality of the chromatographic signal. However, the dry purge procedure induced marked modifications to the chromatographic profile of the cheese throughout the range of component polarities

Effect of adding hygroscopic salts on the analysis of the volatile fraction of cheese

We investigated the effect of adding hygroscopic salts on the analysis by dynamic headspace - gas chromatography - mass spectrometry of the volatile fraction of cheese. We tested five salts: calcium chloride, magnesium sulfate, potassium carbonate, sodium chloride and sodium sulfate. Relative humidity of the headspace, pH value of the matrix, desorption of volatile components and their odor were modified differently according to the salt used. Adding magnesium sulfate or potassium carbonate respectively released carboxylic acids and amino compounds from the matrix, whereas calcium chloride restricted the overall desorption of the volatile components. Sodium sulfate and sodium chloride had little effect