Dynamics of small molecules within the F127 PEO-PPO-PEO triblock copolymer gel and sol phases studied at the molecular scale.

Triplet excited states of guest molecules with different hydrophobicities were used to probe the association and dissociation dynamics of these guests with F127 micelles in the gel and sol phases. The dynamics probed was on a longer length scale than amenable with fluorescence techniques, but at a shorter length scale than probed in translational diffusion studies. The mobility of the guests at the molecular scale showed that subtle changes in the guest's structure affect the guest's release time from the micelles, where the structural features of the guest are more important than the phase, gel vs. sol, of the system.

Mechanism of a Disassembly-Driven Sensing System Studied by Stopped-Flow Kinetics.

We carried out steady-state and stopped-flow photophysical measurements to determine the kinetics of a discrete disassembly driven turn-on fluorescent system. On and off rates for both DimerDye1 assembly and nicotine binding were determined. Relative rates for these competing processes provide insight on how this system can be optimized for sensing applications. Kinetics studies in artificial saliva showed that moving to more complex media has minimal effects on the sensing ability of the system.

Noninnocent Role of Na+ Ions in the Binding of the N-Phenyl-2-naphthylammonium Cation as a Ditopic Guest with Cucurbit[7]uril.

Na+ ions influence the mechanism for the binding of the ditopic guest N-phenyl-2-naphthylammonium cation (Ph-AH+-Np) to cucurbit[7]uril (CB[7]) by facilitating, at increased Na+ concentrations, the formation of a higher-order complex. Binding of the larger naphthyl moiety of Ph-AH+-Np forms the Ph-AH+-Np@CB[7] 1:1 complex (where "@" represents an inclusion complex) at low Na+ ion concentrations (≤5 mM), whereas the inclusion of the smaller phenyl moiety in CB[7] (CB[7]@Ph-AH+-Np) is transient. Ph-AH+-Np@CB[7] is formed by reactions with free CB[7] and CB[7]·Na+ (where "·" represents an exclusion complex) with displacement of the Na+ cation. Because of the latter reaction, the dissociation of Ph-AH+-Np@CB[7] is faster at higher Na+ concentrations. At high Na+ concentrations (≥25 mM), the Na+ ion stabilizes the inclusion of the phenyl moiety in CB[7] by capping the portal of CB[7]. The dynamics of the capped Na+·CB[7]@Ph-AH+-Np 1:1 complex is slower than in the absence of Na+ capping. This stabilization of the phenyl moiety inclusion in CB[7] by Na+ leads to the formation of the Na+·CB[7]@Ph-AH+-Np@CB[7] 2:1 host-guest complex, where each moiety of the ditopic guest is included in a different CB[7]. The opposing roles of Na+ cations in the formation of the two 1:1 complexes are essential for the switch in mechanism with changes in Na+ concentration and provide an example of systems chemistry, where new properties arise in the form of an increased diversity of complexes and altered complexation dynamics that depend on the system's composition.

2018 ACC/HRS/NASCI/SCAI/SCCT Expert Consensus Document on Optimal Use of Ionizing Radiation in Cardiovascular Imaging-Best Practices for Safety and Effectiveness, Part 2: Radiological Equipment Operation, Dose-Sparing Methodologies, Patient and Medical Personnel Protection.

The stimulus to create this document was the recognition that ionizing radiation-guided cardiovascular procedures are being performed with increasing frequency, leading to greater patient radiation exposure and, potentially, to greater exposure to clinical personnel. While the clinical benefit of these procedures is substantial, there is concern about the implications of medical radiation exposure. ACC leadership concluded that it is important to provide practitioners with an educational resource that assembles and interprets the current radiation knowledge base relevant to cardiovascular procedures. By applying this knowledge base, cardiovascular practitioners will be able to select procedures optimally, and minimize radiation exposure to patients and to clinical personnel. "Optimal Use of Ionizing Radiation in Cardiovascular Imaging - Best Practices for Safety and Effectiveness" is a comprehensive overview of ionizing radiation use in cardiovascular procedures and is published online. To provide the most value to our members, we divided the print version of this document into 2 focused parts. "Part I: Radiation Physics and Radiation Biology" addresses radiation physics, dosimetry and detrimental biologic effects. "Part II: Radiologic Equipment Operation, Dose-Sparing Methodologies, Patient and Medical Personnel Protection" covers the basics of operation and radiation delivery for the 3 cardiovascular imaging modalities (x-ray fluoroscopy, x-ray computed tomography, and nuclear scintigraphy). For each modality, it includes the determinants of radiation exposure and techniques to minimize exposure to both patients and to medical personnel.

2018 ACC/HRS/NASCI/SCAI/SCCT Expert Consensus Document on Optimal Use of Ionizing Radiation in Cardiovascular Imaging-Best Practices for Safety and Effectiveness, Part 1: Radiation Physics and Radiation Biology: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways Developed in Collaboration With Mended Hearts.

The stimulus to create this document was the recognition that ionizing radiation-guided cardiovascular procedures are being performed with increasing frequency, leading to greater patient radiation exposure and, potentially, to greater exposure for clinical personnel. Although the clinical benefit of these procedures is substantial, there is concern about the implications of medical radiation exposure. The American College of Cardiology leadership concluded that it is important to provide practitioners with an educational resource that assembles and interprets the current radiation knowledge base relevant to cardiovascular procedures. By applying this knowledge base, cardiovascular practitioners will be able to select procedures optimally, and minimize radiation exposure to patients and to clinical personnel. Optimal Use of Ionizing Radiation in Cardiovascular Imaging: Best Practices for Safety and Effectiveness is a comprehensive overview of ionizing radiation use in cardiovascular procedures and is published online. To provide the most value to our members, we divided the print version of this document into 2 focused parts. Part I: Radiation Physics and Radiation Biology addresses the issue of medical radiation exposure, the basics of radiation physics and dosimetry, and the basics of radiation biology and radiation-induced adverse effects. Part II: Radiological Equipment Operation, Dose-Sparing Methodologies, Patient and Medical Personnel Protection covers the basics of operation and radiation delivery for the 3 cardiovascular imaging modalities (x-ray fluoroscopy, x-ray computed tomography, and nuclear scintigraphy) and will be published in the next issue of the Journal.

New Insights into Peptide-Silver Nanoparticle Interaction: Deciphering the Role of Cysteine and Lysine in the Peptide Sequence.

We studied the interaction of four new pentapeptides with spherical silver nanoparticles. Our findings indicate that the combination of the thiol in Cys and amines in Lys/Arg residues is critical to providing stable protection for the silver surface. Molecular simulation reveals the atomic scale interactions that underlie the observed stabilizing effect of these peptides, while yielding qualitative agreement with experiment for ranking the affinity of the four pentapeptides for the silver surface.

Determination of the kinetics underlying the pKa shift for the 2-aminoanthracenium cation binding with cucurbit[7]uril.

The binding dynamics of the 2-aminoanthracenium cation (AH(+)) and 2-aminoanthracene (A) with cucurbit[7]uril (CB[7]) was studied using stopped-flow experiments. The kinetics was followed by measuring the fluorescence changes over time for AH(+) and A, which emit at different wavelengths. The studies at various pH values showed different mechanisms for the formation of the AH(+)@CB[7] complex, with this complex formed either by the binding of AH(+) or by the initial binding of A followed by protonation. In the latter case, it was possible to determine the protonation ((1.5 ± 0.4) × 10(9) M(-1) s(-1)) and deprotonation (89 ± 7 s(-1)) rate constants for complexed A/AH(+), which showed that the pKa shift of +3.1 for A/AH(+) in the complex is mainly due to a lower deprotonation rate constant.

Phototautomerization in pyrrolylphenylpyridine terphenyl systems.

[4-(2-Pyrrolyl)phenyl]pyridines 2-4 were synthesized and their photophysical properties and reactivity in phototautomerization reactions investigated by fluorescence spectroscopy and laser flash photolysis (LFP). The pKa for the protonation of the pyridine nitrogen in 2-4 was determined by UV-vis and fluorescence titration (pKa = 5.5 for 4). On excitation in polar protic solvents, 2-4 populate charge-transfer states leading to an enhanced basicity of the pyridine (pKa* ≈ 12) and enhanced acidity of pyrrole (pKa* ≈ 8-9) enabling excited-state proton transfer (ESPT). ESPT gives rise to phototautomers and significantly quenches the fluorescence of 2-4. Phototautomers 2-T and 4-T were detected by LFP with strong transient absorption maxima at 390 nm. Phototautomers 2-T and 4-T decayed by competing uni- and bimolecular reactions. However, at pH 11 the decay of 4-T followed exponential kinetics with a rate constant of 4.2 × 10(6) s(-1). The pyridinium salt 4H(+) forms a stable complex with cucurbit[7]uril (CB[7]) with 1:1 stoichiometry (ß11 = (1.0 ± 0.2) × 10(5) M(-1), [Na(+)] = 39 mM). Complexation to CB[7] increased the pKa for 4H(+) (pKa = 6.9) and changed its photochemical reactivity. Homolytic cleavage of the pyrrole NH leads to the formation of an N-radical because of the decreased acidity of the pyrrole in the inclusion complex.

Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial.

Importance: There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression. Objective: To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection. Design, Setting, and Participants: This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020. Intervention: Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care. Outcomes: The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements. Results: A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups. Conclusions and Relevance: In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT04342728.

What is the role of supplementation with ascorbic acid, zinc, vitamin D, or N-acetylcysteine for prevention or treatment of COVID-19?

Several agents intended to supplement dietary intake or endogenous molecules may have a theoretical role in preventing or treating COVID-19. Because of their potential to influence immune response, ascorbic acid (vitamin C), zinc, vitamin D, and N-acetylcysteine have been hypothesized to be useful for prevention or treatment of COVID-19. The authors outline the biologic plausibility, applicable clinical data, and potential role of each of these agents.

Nonlinear Dependence on Na+ Ions for the Binding Dynamics of Cucurbit[6]uril with the trans-1-Methyl-4-(4-hydroxystyryl)pyridinium Cation.

The binding dynamics of the trans-1-methyl-4-(4-hydroxystyryl)pyridinium cation (HSP+) to cucurbit[6]uril (CB[6]) in the presence of Na+ cations were studied to establish the effect of the relative concentrations of the system's components (HSP+, CB[6], and Na+) on these dynamics. The formation of the HSP+@CB[6] complex was temporally uncoupled from the photoisomerization of trans-HSP+, while a nonlinear effect of the Na+ cation concentration on the HSP+@CB[6] dynamics was observed. This nonlinearity is a consequence of Na+ having the opposite effect on the association and dissociation rate constants for the HSP+@CB[6] complex, creating a conceptual framework for using such nonlinearities to control multistep reactions in cucurbit[n]uril chemistry.

Dual-color immunocytochemistry (Ki-67 with LCA) for precise grading of pancreatic neuroendocrine tumors with applicability to small biopsies and cell blocks.

Ki-67 (MIB-1) immunostaining to quantify the proliferative index of neuroendocrine tumors (NETs) has been recommended (especially for small biopsies). However, this has a number of challenges with nonrepresentative Ki-67 index due to interference by Ki-67 immunoreactive proliferating lymphocytes infiltrating the tumor and also some proliferating stromal cells including endothelial cells in the background. Our pilot project showed that dual-color immunostaining with inclusion of leukocyte common antigen (LCA) (Ki-67: nuclear brown; LCA: cytoplasmic red) can facilitate the weeding out of lymphocyte interference. We analyzed the results with 23 surgical cases of pancreatic NETs. This was followed by poststudy examination of 11 cases of endoscopic ultrasound-guided fine-needle aspiration of the pancreatic NETs (PanNETs) to evaluate the findings of the study. Dual-color immunostaining for Ki-67 with LCA increased the precision of quantifying Ki-67 index, due to ability to exclude LCA immunoreactive lymphocytes. Other nontumor Ki-67 immunoreactive cells such as endothelial and stromal cells could be distinguished morphologically. Digital methods were also attempted, but this approach could not distinguish infiltrating lymphocytes and other cells in sections resulting in erroneous results. This study demonstrated that grading of PanNET can be performed with increased precision with dual-color Ki-67 immunostaining protocol standardized in this study. As evaluated on a few cytopathology cases, this protocol is especially useful for the evaluation of small biopsies and cell block sections of fine-needle aspiration biopsy material where 50 high-power fields cannot be evaluated but have >500 tumor cell nuclei.

Artificial Intelligence and Machine Learning in Arrhythmias and Cardiac Electrophysiology.

Artificial intelligence (AI) and machine learning (ML) in medicine are currently areas of intense exploration, showing potential to automate human tasks and even perform tasks beyond human capabilities. Literacy and understanding of AI/ML methods are becoming increasingly important to researchers and clinicians. The first objective of this review is to provide the novice reader with literacy of AI/ML methods and provide a foundation for how one might conduct an ML study. We provide a technical overview of some of the most commonly used terms, techniques, and challenges in AI/ML studies, with reference to recent studies in cardiac electrophysiology to illustrate key points. The second objective of this review is to use examples from recent literature to discuss how AI and ML are changing clinical practice and research in cardiac electrophysiology, with emphasis on disease detection and diagnosis, prediction of patient outcomes, and novel characterization of disease. The final objective is to highlight important considerations and challenges for appropriate validation, adoption, and deployment of AI technologies into clinical practice.

Steric Demand and Rate-determining Step for Photoenolization of Di-ortho-substituted Acetophenone Derivatives.

Laser flash photolysis of ketone 1 in argon-saturated methanol yields triplet biradical 1BR (τ = 63 ns) that intersystem crosses to form photoenols Z-1P (λmax = 350 nm, τ ~ 10 µs) and E-1P (λmax = 350 nm, τ > 6 ms). The activation barrier for Z-1P re-forming ketone 1 through a 1,5-H shift was determined as 7.7 ± 0.3 kcal mol-1 . In contrast, for ketone 2, which has a less sterically hindered carbonyl moiety, laser flash photolysis in argon-saturated methanol revealed the formation of biradical 2BR (λmax = 330 nm, τ ~ 303 ns) that intersystem crosses to form photoenol E-2P (λmax = 350 nm, τ > 42 µs), but photoenol Z-2P was not detected. However, in more viscous basic H-bond acceptor (BHA) solvent, such as hexamethylphosphoramide, triplet 2BR intersystem crosses to form both Z-2P (λmax = 370 nm, τ ~ 1.5 µs) and E-2P. Thus, laser flash photolysis of ketone 2 in methanol reveals that intersystem crossing from 2BR to form Z-2P is slower than the 1,5-H shift of Z-2P, whereas in viscous BHA solvents, the 1,5-H shift becomes slower than the intersystem crossing from 2BR to Z-2P. Density functional theory and coupled cluster calculations were performed to support the reaction mechanisms for photoenolization of ketones 1 and 2.

Triplet Excited States and Singlet Oxygen Production by Analogs of Red Wine Pyranoanthocyanins.

During the maturation of red wines, the anthocyanins of grapes are transformed into pyranoanthocyanins, which possess a pyranoflavylium cation as their basic chromophore. Photophysical properties of the singlet and triplet excited states of a series of synthetic pyranoflavylium cations were determined at room temperature in acetonitrile solution acidified with 0.10 mol dm-3 trifluoroacetic acid (TFA, to inhibit competitive excited state proton transfer) and at 77 K in a rigid TFA-acidified isopropanol glass. In solution, the triplet states of these pyranoflavylium cations are efficiently quenched by molecular oxygen, resulting in sensitized formation of singlet oxygen, as confirmed by direct detection of the triplet-state decay by laser flash photolysis and of singlet oxygen monomol emission in the near infrared. The strong visible light absorption, the relatively small singlet-triplet energy differences, the excited state redox potentials and the reasonably long lifetimes of pyranoflavylium triplet states in the absence of molecular oxygen suggest that they might be useful as triplet sensitizers and/or as cationic redox initiators in polar aprotic solvents like acetonitrile.

Tuning the Binding Dynamics of a Guest-Octaacid Capsule through Noncovalent Anchoring.

Hydrophobic or hydrophilic substituents have different effects on the binding dynamics of pyrene derivatives with a 2:1 capsule formed from two octaacid cavitands, showing a subtle interplay of different kinetic factors. Anchoring of the methyl group of 1-methylpyrene within one cavitand slowed the association and dissociation dynamics of the 1:1 complex by at least 1000 times when compared to the 1:1 complex for pyrene. This slow down for the transient formation of the 1:1 complex is responsible for the overall increase in stability of the 2:1 complex without affecting the overall capsule dissociation. For 1-pyrenemethanol, its residence time in the 2:1 capsule is shorter compared to that of pyrene despite both guests having similar equilibrium constants for the binding of the second cavitand, suggesting that the hydroxymethyl substituent close to the equatorial region of the capsule can interact with water during the partial opening of the capsule.