Oval and round window reinforcement surgery leads to improvements in sound tolerance and quality of life for hyperacusis patients.

PURPOSE: Hyperacusis is an audiological disorder in which patients become persistently sensitive and intolerant to everyday environmental sounds. For those patients that fail conservative options, a minimally invasive surgical procedure has been developed. MATERIALS & METHODS: Retrospective case series of 73 adult patients with hyperacusis who underwent oval and round window reinforcement surgery between 1/2017-6/2023. Small pieces of temporalis fascia were used to reinforce the round and oval windows. Patients were separated into two groups based on their preoperative speech Loudness Discomfort Level (LDL). Patients with a preoperative speech LDL ≤ 70 dB were placed in the "low LDL group" whereas patients with a preoperative speech LDL >70 dB were placed in the "high LDL group." Preoperative and one-week postoperative audiogram and speech LDLs were compared. Quality of life was assessed using the Glasgow Benefit Inventory (GBI) survey. RESULTS: 73 patients met inclusion criteria - 21 patients in the low LDL group and 52 in the high LDL group. Patients in the high LDL group significantly improved their LDLs by an average of 3.5 dB (P < 0.0001). 42 patients (80.8 %) in the high LDL group had improvement and would recommend the surgery for hyperacusis. Patients in the low LDL group significantly improved their LDL by an average of 12.9 dB (P = 0.032). Ten patients (47.6 %) from the low LDL group experienced improvement and would recommend hyperacusis surgery. CONCLUSION: Many patients with hyperacusis who undergo oval and round window reinforcement can receive significant improvement in sound tolerance and quality of life. Patients with a pre-op speech LDL > 70 dB have the greatest potential for improvement with surgery (80.8 %), probably because their hyperacusis was less severe. In the high LDL group(>70dB) the improvement in 1-10 scale went from 8.6 pre-op to 2.4 post op. In the low LDL group(<70dB) went from 9.2 pre-op to 6.8 post-op. These findings were consistent with the GBI results.

Structure and bonding in rhodium coordination compounds: a 103Rh solid-state NMR and relativistic DFT study.

This study demonstrates the application of 103Rh solid-state NMR (SSNMR) spectroscopy to inorganic and organometallic coordination compounds, in combination with relativistic density functional theory (DFT) calculations of 103Rh chemical shift tensors and their analysis with natural bond orbital (NBO) and natural localized molecular orbital (NLMO) protocols, to develop correlations between 103Rh chemical shift tensors, molecular structure, and Rh-ligand bonding. 103Rh is one of the least receptive NMR nuclides, and consequently, there are very few reports in the literature. We introduce robust 103Rh SSNMR protocols for stationary samples, which use the broadband adiabatic inversion-cross polarization (BRAIN-CP) pulse sequence and wideband uniform-rate smooth-truncation (WURST) pulses for excitation, refocusing, and polarization transfer, and demonstrate the acquisition of 103Rh SSNMR spectra of unprecedented signal-to-noise and uniformity. The 103Rh chemical shift tensors determined from these spectra are complemented by NBO/NLMO analyses of contributions of individual orbitals to the 103Rh magnetic shielding tensors to understand their relationship to structure and bonding. Finally, we discuss the potential for these experimental and theoretical protocols for investigating a wide range of materials containing the platinum group elements.

An unusual ionic cocrystal of ponatinib hydrochloride: characterization by single-crystal X-ray diffraction and ultra-high field NMR spectroscopy.

This study describes the discovery of a unique ionic cocrystal of the active pharmaceutical ingredient (API) ponatinib hydrochloride (pon·HCl), and characterization using single-crystal X-ray diffraction (SCXRD) and solid-state NMR (SSNMR) spectroscopy. Pon·HCl is a multicomponent crystal that features an unusual stoichiometry, with an asymmetric unit containing both monocations and dications of the ponatinib molecule, three water molecules, and three chloride ions. Structural features include (i) a charged imidazopyridazine moiety that forms a hydrogen bond between the ponatinib monocations and dications and (ii) a chloride ion that does not feature hydrogen bonds involving any organic moiety, instead being situated in a "square" arrangement with three water molecules. Multinuclear SSNMR, featuring high and ultra-high fields up to 35.2 T, provides the groundwork for structural interpretation of complex multicomponent crystals in the absence of diffraction data. A 13C CP/MAS spectrum confirms the presence of two crystallographically distinct ponatinib molecules, whereas 1D 1H and 2D 1H-1H DQ-SQ spectra identify and assign the unusually deshielded imidazopyridazine proton. 1D 35Cl spectra obtained at multiple fields confirm the presence of three distinct chloride ions, with density functional theory calculations providing key relationships between the SSNMR spectra and H⋯Cl- hydrogen bonding arrangements. A 2D 35Cl → 1H D-RINEPT spectrum confirms the spatial proximities between the chloride ions, water molecules, and amine moieties. This all suggests future application of multinuclear SSNMR at high and ultra-high fields to the study of complex API solid forms for which SCXRD data are unavailable, with potential application to heterogeneous mixtures or amorphous solid dispersions.

Carbon-13 chemical shift tensor measurements for nitrogen-dense compounds.

This paper reports the principal values of the 13 C chemical shift tensors for five nitrogen-dense compounds (i.e., cytosine, uracil, imidazole, guanidine hydrochloride, and aminoguanidine hydrochloride). Although these are all fundamentally important compounds, the majority do not have 13 C chemical shift tensors reported in the literature. The chemical shift tensors are obtained from 1 H→13 C cross-polarization magic-angle spinning (CP/MAS) experiments that were conducted at a high field of 18.8 T to suppress the effects of 14 N-13 C residual dipolar coupling. Quantum chemical calculations using density functional theory are used to obtain the 13 C magnetic shielding tensors for these compounds. The best agreement with experiment arises from calculations using the hybrid functional PBE0 or the double-hybrid functional PBE0-DH, along with the triple-zeta basis sets TZ2P or pc-3, respectively, and intermolecular effects modeled using large clusters of molecules with electrostatic embedding through the COSMO approach. These measurements are part of an ongoing effort to expand the catalog of accurate 13 C chemical shift tensor measurements, with the aim of creating a database that may be useful for benchmarking the accuracy of quantum chemical calculations, developing nuclear magnetic resonance (NMR) crystallography protocols, or aiding in applications involving machine learning or data mining. This work was conducted at the National High Magnetic Field Laboratory as part of a 2-week school for introducing undergraduate students to practical laboratory experience that will prepare them for scientific careers or postgraduate studies.

Hearing Rehabilitation in Vestibular Schwannoma.

The most common complaint among patients with vestibular schwannoma (VS) is hearing loss. This significantly affects the quality of life before, during, and after treatment for patients with VS. Untreated hearing loss in VS patients may even lead to depression and feelings of social isolation. A variety of devices are available for hearing rehabilitation for patients with vestibular schwannoma. These include contralateral routing of hearing signals (CROSs), bone-anchored hearing devices, auditory brainstem implants (ABI), and cochlear implants. In the United States, ABI is approved for patients 12 years of age and older with neurofibromatosis type 2. In the past few years, cochlear implantation has been offered simultaneously or sequentially with tumor resection or irradiation, or even to patients whose VS have been monitored with serial imaging. However, determining the functional integrity of the auditory nerve in patients with vestibular schwannoma is a challenge. This review article consists of (1) the pathophysiology of vestibular schwannoma (VS), (2) hearing loss in VS, (3) treatment of VS and associated hearing loss, (4) options for auditory rehabilitation in patients with VS with their individual benefits and limitations, and (5) challenges in hearing rehabilitation in this cohort of patients to determine auditory nerve functionality. (6) Future directions.

Helping Patients Understand Their Dizziness: Assessment of a Three-Dimensional Printed Vestibular Model.

To assess the improvement in patient understanding with use of a three-dimensional printed vestibular model as a teaching tool and to evaluate the effects of educational approach on dizziness-related disabilities. Single center randomized controlled trial set in the Otolaryngology ambulatory care clinic located at a tertiary care, teaching institution in Shreveport, Louisiana. Patients with a current or suspected diagnosis of benign paroxysmal positional vertigo who met inclusion criteria were randomized to either the three-dimensional model group or the control group. Each group received the same education session about dizziness, with the three-dimensional model being used as a visual aid in the experimental group. The control group received only verbal education. Outcome measures included patient understanding of benign paroxysmal positional vertigo etiology, comfort level with symptom prevention, anxiety related to vertigo symptoms, and how likely the patient was to recommend the teaching session to another individual suffering from vertigo. Pre-session and post-session surveys were administered to all patients to assess outcome measures. Eight patients were enrolled in the experimental group, and eight patients were enrolled in the control group. On post-survey data, the experimental group reported increased understanding of symptom etiology (p = 0.0289), increased comfort level with preventing symptoms (p = 0.2999), a larger decrease in symptom related anxiety (p = 0.0453) and were more likely to recommend the education session (p = 0.2807) compared to the control group. Three-dimensional printed vestibular model demonstrates promise for patient education and reducing related anxiety. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03325-5.

Ototoxicity Review: A Growing Number of Non-Platinum-Based Chemo- and Immunotherapies.

OBJECTIVE: To raise awareness of the growing list of non-platinum-based chemo- and immunotherapeutic agents that have been associated with ototoxicity and to introduce the possible mechanism of ototoxicity of these agents. DATA SOURCES: PubMed, Embase, and Web of Science. REVIEW METHODS: A systematic review was performed following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses). PubMed, Embase, and Web of Science databases were searched for published reports of ototoxicity from non-platinum-based chemo- and immunotherapeutic agents in adult and pediatric patients. Therapies that utilized any platinum-based agent were excluded. CONCLUSIONS: Ototoxicity from non-platinum-based chemo- and immunotherapies is an evolving problem. There were 54 reports-39 case reports and 15 cohort studies-documenting ototoxicity from 7 agents/combination therapies. Of these reports, 37 (69%) were published within the last 15 years (after 2005). No recovery of hearing was documented in 21 of 56 cases (38%). Pretreatment audiograms were uncommon (19/54 studies, 35%), despite documented ototoxic associations. IMPLICATIONS FOR PRACTICE: There is a growing number of novel, ototoxic, non-platinum-based chemo- and immunotherapeutic agents with various potential mechanisms of action. Otolaryngologists will need to prioritize awareness of these agents. This growing list of agents, many of which have reversible effects, suggest a need for standardized ototoxicity monitor protocols so that appropriate and timely management options can be implemented.

Hydrates of active pharmaceutical ingredients: A 35Cl and 2H solid-state NMR and DFT study.

This study uses 35Cl and 2H solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations to characterize the molecular-level structures and dynamics of hydrates of active pharmaceutical ingredients (APIs). We use 35Cl SSNMR to measure the EFG tensors of the chloride ions to characterize hydrated forms of hydrochloride salts of APIs, along with two corresponding anhydrous forms. DFT calculations are used to refine the crystal structures of the APIs and determine relationships between the 35Cl EFG tensors and the spatial arrangements of proximate hydrogen bonds, which are particularly influenced by interactions with water molecules. We find that the relationship between 35Cl EFG tensors and local hydrogen bonding geometries is complex, but meaningful structure/property relationships can be garnered through use of DFT calculations. Specifically, for every case in which such a comparison could be made, we find that the hydrate has a smaller magnitude of CQ than the corresponding anhydrous form, indicating a chloride ion environment with a ground-state electron density of higher spherical symmetry in the former. Finally, variable-temperature 35Cl and 2H SSNMR experiments on a deuterium-exchanged sample of the API cimetidine hydrochloride monohydrate are used to monitor temperature-dependent influences on the spectra that may arise from motional influences on the 35Cl and 2H EFG tensors. From the 2H SSNMR spectra, we determine that the motions of water molecules are characterized by jump-like motions about their C2 rotational axes that occur on timescales that are unlikely to influence the 35Cl central-transition (+1/2 ↔︎ -1/2) powder patterns (this is confirmed by 35Cl SSNMR). Together, these methods show great promise for the future study of APIs in their bulk and dosage forms, especially variable hydrates in which crystallographic water content varies with external conditions such as humidity.

Nutraceuticals in Bulk and Dosage Forms: Analysis by 35Cl and 14N Solid-State NMR and DFT Calculations.

This study uses 35Cl and 14N solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations for the structural characterization of chloride salts of nutraceuticals in their bulk and dosage forms. For eight nutraceuticals, we measure the 35Cl EFG tensor parameters of the chloride ions and use plane-wave DFT calculations to elucidate relationships between NMR parameters and molecular-level structure, which provide rapid NMR crystallographic assessments of structural features. We employ both 35Cl direct excitation and 1H→35Cl cross-polarization methods to characterize a dosage form containing α-d-glucosamine HCl, observe possible impurity and/or adulterant phases, and quantify the weight percent of the active ingredient. To complement this, we also investigate 14N SSNMR spectroscopy and DFT calculations to characterize nitrogen atoms in the nutraceuticals. This includes a discussion of targeted acquisition experimental protocols (i.e., acquiring a select region of the overall pattern that features key discontinuities) that allow ultrawideline spectra to be acquired rapidly, even for unreceptive samples (i.e., those with long values of T1(14N), short values of T2eff(14N), or very broad patterns). It is hoped that these experimental and computational protocols will be useful for the characterization of various solid forms of nutraceuticals (i.e., salts, polymorphs, hydrates, solvates, cocrystals, amorphous solid dispersions, etc.), help detect impurity and counterfeit solid phases in dosage forms, and serve as a foundation for future NMR crystallographic studies of nutraceutical solid forms, including studies using ab initio crystal structure prediction algorithms.

Tissue Preservation Techniques for Bone-Anchored Hearing Aid Surgery.

OBJECTIVE: Compare outcomes of surgical techniques in percutaneous bone-anchored hearing implant surgery. STUDY DESIGN: Matched retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Electronic review of adult and pediatric patients who underwent bone conduction device surgery by either the Minimally-invasive Ponto Surgery (MIPS) technique or the linear incision with no soft tissue removal (LnSTR) technique or between August 2015 and April 2018 at our facility. INTERVENTION: Patients in MIPS group underwent Minimally invasive Ponto Surgery (MIPS) technique, while those in LnSTR group underwent LnSTR technique. MAIN OUTCOME MEASURE: Major outcome was presence/severity of localized skin reaction. Secondary outcomes included cosmetic outcome, revision surgery, minor adverse events, device utilization, and postoperative aided speech recognition thresholds (SRTs) across 250 to 4000 Hertz (Hz). RESULTS: Fifty patients met inclusion criteria. There was a significantly lower rate of localized cutaneous reactions for the MIPS group (4.5%) compared with LnSTR group (33.3%; p = 0.026). Rate of revision surgery was significantly less for MIPS (13.6%) compared with LnSTR (20.8%; p = 0.008). Occurrence of poor cosmetic outcome was noted significantly less for the MIPS group (9.1%) compared with LnSTR patients (20.8%; p = 0.005). Minor adverse events and aided SRTs were comparable between groups. CONCLUSIONS: MIPS leads to a statistically significant decrease in localized cutaneous reaction compared with LnSTR. Both the LnSTR and MIPS techniques are safe and effective in the treatment of hearing loss, however MIPS may be superior in certain cases by offering improved healing, decreasing needs for wound care, and possibly decreasing need for frequent follow up.

Dispersion-Corrected DFT Methods for Applications in Nuclear Magnetic Resonance Crystallography.

Nuclear electric field gradient (EFG) tensor parameters depend strongly on electronic structures, making their calculation from first principles an excellent metric for the prediction, refinement, and optimization of crystal structures. Here, we use plane-wave density functional theory (DFT) calculations of EFG tensors in organic solids to optimize the Grimme (D2) and Tkatchenko-Scheffler (TS) atomic-pairwise force field dispersion corrections. Refinements using these new force field correction methods result in better representations of true crystal structures, as gauged by calculations of 177 14N, 17O, and 35Cl EFG tensors from 95 materials. The most striking result is the degree by which calculations of 35Cl EFG tensors of chloride ions match with experiment, due to the ability of these new methods to properly locate the positions of hydrogen atoms participating in H···Cl- hydrogen bonds. These refined structures also feature atomic coordinates that are more similar to those of neutron diffraction structures than those obtained from calculations that do not employ the optimized force fields. Additionally, we assess the quality of these new energy-minimization protocols for the prediction of 15N magnetic shielding tensors and unit cell volumes, which complement the larger analysis using EFG tensors, since these quantities have different physical origins. It is hoped that these results will be useful in future nuclear magnetic resonance (NMR) crystallographic studies and will be of great interest to a wide variety of researchers, in fields including NMR spectroscopy, computational chemistry, crystallography, pharmaceutical sciences, and crystal engineering.

Chemical Shift Tensors of Cimetidine Form A Modeled with Density Functional Theory Calculations: Implications for NMR Crystallography.

The principal components of the 13C chemical shift tensors for the ten crystallographically distinct carbon atoms of the active pharmaceutical ingredient cimetidine Form A have been measured using the FIREMAT technique. Density functional theory (DFT) calculations of 13C and 15N magnetic shielding tensors are used to assign the 13C and 15N peaks. DFT calculations were performed on cimetidine and a training set of organic crystals using both plane-wave and cluster-based approaches. The former set of calculations allowed several structural refinement strategies to be employed, including calculations utilizing a dispersion-corrected force field that was parametrized using 13C and 15N magnetic shielding tensors. The latter set of calculations featured the use of resource-intensive hybrid-DFT methods for the calculation of magnetic shielding tensors. Calculations on structures refined using the new force-field correction result in improved values of 15N magnetic shielding tensors (as gauged by agreement with experimental chemical shift tensors), although little improvement is seen in the prediction of 13C shielding tensors. Calculations of 13C and 15N magnetic shielding tensors using hybrid functionals show better agreement with experimental values in comparison to those using GGA functionals, independent of the method of structural refinement; the shielding of carbon atoms bonded to nitrogen are especially improved using hybrid DFT methods.

High-resolution 13 C and 43 Ca solid-state NMR and computational studies of the ethylene glycol solvate of atorvastatin calcium.

We report 43 Ca and 13 C solid-state nuclear magnetic resonance (NMR) spectroscopic studies of the ethylene glycol solvate of atorvastatin calcium. The 13 C and 43 Ca chemical shift and 43 Ca quadrupolar coupling tensor parameters are reported. The results are interpreted in terms of the reported X-ray diffraction crystal structure of the solvate and are compared with the NMR parameters of atorvastatin calcium trihydrate, the active pharmaceutical ingredient in Lipitor®. Hartree-Fock and density functional theory calculations of the NMR parameters based on a cluster model derived from the optimized X-ray diffraction crystal structure of the ethylene glycol solvate of atorvastatin calcium are in reasonable agreement with the experimental 43 Ca and 13 C NMR measurables.

On the use of frequency-swept pulses and pulses designed with optimal control theory for the acquisition of ultra-wideline NMR spectra.

Frequency-swept (FS) pulses, such as wideband uniform-rate smooth-truncation (WURST) pulses, have found much success for the acquisition of ultra-wideline (UW) solid-state NMR spectra. In this preliminary study, new pulses and pulse sequences are explored in simulation and experimentally for several nuclei exhibiting UWNMR powder patterns under static conditions, including 119Sn (I = 1/2), 195Pt (I = 1/2), 2H (I = 1), and 71Ga (I = 3/2). First, hyperbolic secant (HS) and tanh/tan (THT) pulses are tested and implemented as excitation and refocusing pulses in spin-echo and Carr-Purcell/Meiboom Gill (CPMG)-type sequences, and shown to have comparable performances to analogous WURST pulses. Second, optimal control theory (OCT) is utilized for the design of new Optimal Control Theory Optimized Broadband Excitation and Refocusing (OCTOBER) pulses, using carefully parameterized WURST, THT, and HS pulses as starting points. Some of the new OCTOBER pulses used in spin-echo sequences are capable of efficient broadband excitation and refocusing, in some cases resulting in spectra with increased signal enhancements over those obtained in experiments using conventional FS pulses. Finally, careful consideration of the spin dynamics of several systems, by monitoring of the time evolution of the density matrix via the Liouville-von Neumann equation and analysis of the time-resolved Fourier transforms of the pulses, lends insight into the underlying mechanisms of the FS and OCTOBER pulses. This is crucial for understanding their performance in terms of generating uniformly excited patterns of high signal intensity, and for identifying trends that may offer pathways to generalized parameterization and/or new pulse shapes.

A new NMR crystallographic approach to reveal the calcium local structure of atorvastatin calcium.

We combine experimental and computational determination of 43Ca solid-state NMR parameters (chemical shift tensors, quadrupolar coupling tensors, and Euler angles) to constrain the structure of the local calcium-ligand coordination environment. A new 43Ca NMR crystallographic approach which includes an extensive survey of the Cambridge Structural Database and a new symmetry benchmark is developed to enhance the selectivity of structural screening. The application of this method to quadrupolar NMR crystallographic investigations is demonstrated by unearthing the calcium local structure of the active pharmaceutical ingredient atorvastatin calcium trihydrate, the active ingredient in Lipitor®, in the absence of diffraction data. This method has been tested by applying it to calcium acetate monohydrate which has a known structure.

A DFT/ZORA Study of Cadmium Magnetic Shielding Tensors: Analysis of Relativistic Effects and Electronic-State Approximations.

Theoretical considerations are discussed for the accurate prediction of cadmium magnetic shielding tensors using relativistic density functional theory (DFT). Comparison is made between calculations that model the extended lattice of the cadmium-containing solids using periodic boundary conditions and pseudopotentials with calculations that use clusters of atoms. The all-electron cluster-based calculations afford an opportunity to examine the importance of (i) relativistic effects on cadmium magnetic shielding tensors, as introduced through the ZORA Hamiltonian at either the scalar (SC) or spin-orbit (SO) levels and (ii) variation in the class of the DFT approximation. Twenty-three combinations of pseudopotentials or all-electron methods, DFT functionals, and relativistic treatments are assessed for the prediction of the principal components of the magnetic shielding tensors of 30 cadmium sites. We find that the inclusion of SO coupling can increase the cadmium magnetic shielding by as much as ca. 1100 ppm for a certain principal values; these effects are most pronounced for cadmium sites featuring bonds to other heavy atoms such as cadmium, iodine, or selenium. The best agreement with experimental values is found at the ZORA SO level in combination with a hybrid DFT method featuring a large admixture of Hartree-Fock exchange such as BH&HLYP. Finally, a theoretical examination is presented of the magnetic shielding tensor of the Cd(I) site in Cd2(AlCl4)2.

Curcumin gum formulation for prevention of oral cavity head and neck squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Head and neck squamous cell carcinoma represents the sixth most common cancer. As a result of field cancerization, second primaries and recurrences are high. Hence, research has focused on chemoprevention. Curcumin, a polyphenol compound with anticarcinogenic properties, is one such promising nutraceutical. As poor bioavailability limits curcumin's use, a novel gum formulation was tested allowing for direct mucosal absorption into the bloodstream. This preliminary study validates curcumin gum efficacy by assessing release and transmucosal absorption, along with measuring its effects on serum cytokine levels. STUDY DESIGN: Clinical trial. METHODS: Protocols consisting of initial chew (chewing gum for 30 minutes) and revised chew (alternating chewing and parking gum against buccal mucosa for 30 minutes) were tested in healthy volunteers. High-performance liquid chromatography measured remnant curcumin in chewed gum, serum, and saliva. Serum levels were assayed for 15 proinflammatory cytokines via multiplex analysis. RESULTS: Revised chew samples demonstrated significantly higher curcumin release and absorption (P = .0078). Curcumin serum levels were significantly higher at 4 hours in samples > 2.0 g of curcumin release (P = .01). As saliva levels decreased, a concurrent increase in serum levels was observed, with no significance in the inverse relationship (P = .1423). When evaluating differences between gender, race, and age, the Asian population showed significantly lower curcumin release and serum levels (P = .009). CXCL1 (GRO-α) and TNF-α were significantly decreased in serum after chewing the gum (P = .036, P < .001, respectively). CONCLUSIONS: Enhanced mucosal contact appears critical in improving curcumin release and absorption. CXCL1 and TNF-α both represent potential biomarkers for the future study of curcumin chemoprevention. LEVEL OF EVIDENCE: 2b Laryngoscope, 129:1597-1603, 2019.

19F Magic Angle Spinning NMR Spectroscopy and Density Functional Theory Calculations of Fluorosubstituted Tryptophans: Integrating Experiment and Theory for Accurate Determination of Chemical Shift Tensors.

The 19F chemical shift is a sensitive NMR probe of structure and electronic environment in organic and biological molecules. In this report, we examine chemical shift parameters of 4F-, 5F-, 6F-, and 7F-substituted crystalline tryptophan by magic angle spinning (MAS) solid-state NMR spectroscopy and density functional theory. Significant narrowing of the 19F lines was observed under fast MAS conditions, at spinning frequencies above 50 kHz. The parameters characterizing the 19F chemical shift tensor are sensitive to the position of the fluorine in the aromatic ring and, to a lesser extent, the chirality of the molecule. Accurate calculations of 19F magnetic shielding tensors require the PBE0 functional with a 50% admixture of a Hartree-Fock exchange term, as well as taking account of the local crystal symmetry. The methodology developed will be beneficial for 19F-based MAS NMR structural analysis of proteins and protein assemblies.