Anti-platelet factor 4 immunoglobulin G levels in vaccine-induced immune thrombocytopenia and thrombosis: Persistent positivity through 7 months.

Background: Anti-platelet factor 4 (PF4) antibodies that activate platelets via FcγRIIA drive the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT). Evolution of these antibodies and their ability to activate platelets after initial treatment remains unknown. Objectives: To assess how clinical and platelet parameters, anti-PF4 antibody levels, and patient serum reactivity changes during follow-up after VITT presentation. Methods: We describe cases of seven discharged VITT patients that were followed from diagnosis up to 280 days (range 199-280) after vaccination. We measured anti-PF4 antibodies and PF4 levels in patient serum during follow-up and tested the ability of patient serum to activate healthy donor platelets and patient platelets over time. Results: Anti-PF4 immunoglobulin G antibody levels are very high at diagnosis (0.9-2.6 OD) and remain relatively high (>1.0 OD) in all patients, except one treated with rituximab, at 7 months post vaccination. All patients were on direct oral anticoagulants throughout follow-up and no patients had recurrent thrombosis. Patients' platelets during follow-up have normal FcγRIIA levels and responsiveness to platelet agonists. Patient diagnostic serum strongly activated control platelets, either alone or with PF4. Most follow-up serum alone was weaker at stimulating donor and patient platelets. However, follow-up serum beyond 150 days still strongly activated platelets with PF4 addition in three patients. Patient serum PF4 levels were lower than controls at diagnosis but returned within normal range by day 50. Conclusions: Explanations for reduced platelet activation during follow-up, despite similar total anti-PF4 antibody levels, remains unclear. Clinical implications of persistent anti-PF4 antibodies in VITT require further study.

Rituximab prophylaxis to prevent thrombotic thrombocytopenic purpura relapse: outcome and evaluation of dosing regimens.

Acute antibody-mediated thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy with high morbidity and mortality. Rituximab is highly effective as prophylaxis in patients at risk of acute TTP relapse, but the ideal dosing regimen is unknown. A multicenter retrospective cohort study evaluated outcomes of patients given rituximab prophylaxis to prevent TTP relapse. Rituximab was given in 76 episodes to 45 patients (34 women and 11 men). Four once-per-week infusions of standard- (375 mg/m2 [24 episodes]), reduced- (200 mg [19 episodes]), and intermediate- (500 mg [17 episodes]) dose rituximab were given; in the remaining 16 episodes, patients received 100 to 1000 mg rituximab in 1 to 5 doses. Patients were deemed at high risk of TTP relapse on the basis of ADAMTS13 activity dropping to ≤15% from the normal range. Preprophylaxis median ADAMTS13 level was 5% (range, <5% to 17%). Normalization of ADAMTS13 occurred in 78.9% of patients, with 92.1% having at least a partial response (ADAMTS13 ≥30%); 3 patients had no response. Over a median of 15 months (range, 1-141 months), there were only 3 TTP relapses (2 of these subacute) in the reduced dose group. Re-treatment with rituximab occurred in 50% of patient episodes at a median of 17.5 months (range, 9-112 months) after initial prophylaxis. There was a statistically higher rate of re-treatment in the reduced- vs standard-dose group: 0.38 vs 0.17 episodes per year, respectively. Treatment was generally well tolerated, infusional effects being the most commonly reported. Rituximab therapy is effective as prophylaxis for normalizing ADAMTS13 and is an additional measure for preventing acute TTP relapses in patients with immune TTP.

Quantum Monte Carlo Study of the Reactions of CH with Acrolein: Major and Minor Channels.

Acrolein is an important unsaturated hydrocarbon, containing both C═O and C═C bonds, and responsible for atmospheric pollution. A recent study of major reactions of CH with acrolein has been supplemented with computations of other reactions of the system. Similar to the previous approach, the quantum Monte Carlo (QMC) method in the accurate diffusion Monte Carlo (DMC) method was implemented. Single determinant wave functions were used as trial functions for the random walks. Rate coefficients and product branching ratios were computed by solving master equations using the MultiWell software suite. At room temperature, the dominant product channels are 2-methylvinyl + CO (P6), 1,3-butadienal + H (P2), and furan + H (P1). At elevated temperatures, 2,3-butadienal + H (P10) is also a major product. The chain decomposition pathway to form C3H4 + HCO was not competitive with the cyclization pathway at any of the temperatures studied. The DMC branching fractions of the products formed in the subject reaction are in reasonable accord with previous experimental and theoretical values. The computed rate coefficients were found to be independent of pressure at temperatures relevant to combustion (1500-2500 K).

A quantum Monte Carlo study of the reactions of CH with acrolein.

To assist understanding of combustion processes, we have investigated reactions of methylidyne (CH) with acrolein (CH2CHCHO) using the quantum Monte Carlo (QMC) and other computational methods. We present a theoretical study of the major reactions reported in a recent experiment on the subject system. Both DFT and MP2 computations are carried out, and the former approach is used to form the independent-particle part of the QMC trial wave function used in the diffusion Monte Carlo (DMC) variant of the QMC method. In agreement with experiment, we find that the dominant product channel leads to formation of C4H4O systems + H with leading products of furan + H and 1,3-butadienal + H. Equilibrium geometries, atomization energies, reaction barriers, transition states, and heats of reaction are computed using the DFT, MP2, and DMC approaches and compared to experiment. We find that DMC results are in close agreement with experiment. The kinetics of the subject reactions are determined by solving master equations with the MultiWell software suite.

Interval prediction of molecular properties in parametrized quantum chemistry.

The accurate evaluation of molecular properties lies at the core of predictive physical models. Most reliable quantum-chemical calculations are limited to smaller molecular systems while purely empirical approaches are limited in accuracy and reliability. A promising approach is to employ a quantum-mechanical formalism with simplifications and to compensate for the latter with parametrization. We propose a strategy of directly predicting the uncertainty interval for a property of interest, based on training-data uncertainties, which sidesteps the need for an optimum set of parameters.

Pathways to soot oxidation: reaction of OH with phenanthrene radicals.

Energetics and kinetics of the oxidation of possible soot surface sites by hydroxyl radicals were investigated theoretically. Energetics were calculated by employing density functional theory. Three candidate reactions were selected as suitable prototypes of soot oxidation by OH. The first two, OH + benzene and OH + benzene-phenol complex, did not produce pathways that lead to substantial CO expulsion. The third reaction, OH attack on the phenanthrene radical, had multiple pathways leading to CO elimination. The kinetics of the latter reaction system were determined by solving the master equations with the MultiWell suite of codes. The barrierless reaction rates of this system were computed using the VariFlex program. The computations were carried out over the ranges 1500-2500 K and 0.01-10 atm. At higher temperatures, above 2000 K, the oxidation of phenanthrene radicals by OH followed a chemically activated path. At temperatures lower than 2000 K, chemical activation was not sufficient to drive the reaction to products; reaction progress was impeded by intermediate adducts rapidly de-energizing before reaching products. In such cases, the reaction system was modeled by treating the accumulating adducts as distinct chemical species and computing their kinetics via thermal decomposition. The overall rate coefficient of phenanthrene radical oxidation by OH forming CO was found to be insensitive to pressure and temperature and is approximately 1 × 10(14) cm(3) mol(-1) s(-1). The oxidation of phenanthrene radicals by OH is shown to be controlled by two main processes: H atom migration/elimination and oxyradical decomposition. H atom migration and elimination made possible relatively rapid rearrangement of the aromatic edge to form oxyradicals with favorable decomposition rates. The reaction then continues down the fastest oxyradical pathways, eliminating CO.

From aromaticity to self-organized criticality in graphene.

The unique properties of graphene are rooted in its peculiar electronic structure where effects of electron delocalization are pivotal. We show that the traditional view of delocalization as formation of a local or global aromatic bonding framework has to be expanded in this case. A modification of the π-electron system of a finite-size graphene substrate results in a scale-invariant response in the relaxation of interatomic distances and reveals self-organized criticality as a mode of delocalized bonding. Graphene is shown to belong to a diverse class of finite-size extended systems with simple local interactions where complexity emerges spontaneously under very general conditions that can be a critical factor controlling observable properties such as chemical activity, electron transport, and spin-polarization.

Quantum Monte Carlo for the x-ray absorption spectrum of pyrrole at the nitrogen K-edge.

Fixed-node diffusion Monte Carlo (FNDMC) is used to simulate the x-ray absorption spectrum of a gas-phase pyrrole molecule at the nitrogen K-edge. Trial wave functions for core-excited states are constructed from ground-state Kohn-Sham determinants substituted with singly occupied natural orbitals from configuration interaction with single excitations calculations of the five lowest valence-excited triplet states. The FNDMC ionization potential (IP) is found to lie within 0.3 eV of the experimental value of 406.1 ± 0.1 eV. The transition energies to anti-bonding virtual orbitals match the experimental spectrum after alignment of IP values and agree with the existing assignments.

Thermal decomposition of pentacene oxyradicals.

The energetics and kinetics of the thermal decomposition of pentacene oxyradicals were studied using a combination of ab initio electronic structure theory and energy-transfer master equation modeling. The rate coefficients of pentacene oxyradical decomposition were computed for the range of 1500-2500 K and 0.01-10 atm and found to be both temperature and pressure dependent. The computational results reveal that oxyradicals with oxygen attached to the inner rings are kinetically more stable than those with oxygen attached to the outer rings. The latter decompose to produce CO at rates comparable to those of phenoxy radical, while CO is unlikely to be produced from oxyradicals with oxygen bonded to the inner rings.

A diffusion Monte Carlo study of the O-H bond dissociation of phenol.

The homolytic O-H bond dissociation energy (BDE) of phenol was determined from diffusion Monte Carlo (DMC) calculations using single determinant trial wave functions. DMC gives an O-H BDE of 87.0 +/- 0.3 kcal/mol when restricted Hartree-Fock orbitals are used and a BDE of 87.5 +/- 0.3 kcal/mol with restricted B3LYP Kohn-Sham orbitals. These results are in good agreement with the extrapolated B3P86 results of Costa Cabral and Canuto (88.3 kcal/mol), the recommended experimental value of Borges dos Santos and Martinho Simões (88.7 +/- 0.5 kcal/mol), and the G3 (88.2 kcal/mol), CBS-APNO (88.2 kcal/mol), CBS-QB3 (87.1 kcal/mol) results of Mulder.

Edge versus interior in the chemical bonding and magnetism of zigzag edged triangular graphene molecules.

Ab initio density functional theory calculations show that the CC bond lengths fall into three distinct groups: core, apex, and edge, irrespective of whether the molecular center is a single atom or a C(6)-ring. The core, with a geometry that approximates infinite graphene, extends to the penultimate triangular row of carbon atoms, except in the vicinity of an apex. Impressed on the core bonds starting at the center is a small increasing length oscillation. The perimeter CC bonds joined at the apex are the shortest in the molecule. The edge carbon atoms are separated from interior atoms by the longest bonds in the molecule. The spin density localized primarily on edge (not apex) carbons with attached hydrogen (A-sublattice) is likely the highest attainable in any graphene molecule. The CC bonds in the high spin section of the edges are uniform in length and longer than perimeter CC bonds in the zigzag edged linear acenes, hexangulenes, annulenes, and benzene. This is attributed to the large number of edge localized nonbonding molecular orbitals (NBMOs) that sequestered pi-charge making it unavailable for bonding.

Intramolecular competition in the photodissociation of C(3)D(3) radicals at 248 and 193 nm.

Motivated by recent experimental work, a theoretical study of the photodissociation of perdeuterated propargyl (D(2)CCD) and propynyl (D(3)CCC) radicals has been carried out, focusing on the C-C bond cleavage and D(2) loss channels. High-level ab initio calculations were carried out, and RRKM rate constants were calculated for isomerization and dissociation pathways. The resulting reaction barriers, microcanonical rate constants and product branching ratios are consistent with the experimental findings, supporting the overall mechanism of internal conversion followed by statistical dissociation on the ground state surface. We found loose transition states and very low exit barriers for two of the C-C bond cleavage channels and an additional CD(2) + CCD channel, which had not been reported previously. Our results probe the extent of propargyl and propynyl isomerization prior to dissociation at 248 and 193 nm and deliver a comprehensive picture of all ongoing molecular dynamics.

Onset of diradical character in small nanosized graphene patches.

A family of small graphene patches, i.e., rectangular polyaromatic hydrocarbons (PAHs), that have both zigzag and armchair edges is investigated to establish their ground state electronic structure. Broken symmetry density functional theory (DFT) and plane wave DFT were used to characterize the onset of diradical character via relative energies of open-shell and closed-shell singlet states. The perfect pairing (PP) active space approximation of coupled cluster theory was used to characterize diradical character on the basis of promotion of electrons from occupied to unoccupied molecular orbitals. The role of zigzag and armchair edges in the formation of open-shell singlet states is elucidated. In particular, it is found that elongation of the zigzag edge results in an increase of diradical character whereas elongation of the arm chair edge leads to a decrease of diradical character. Analysis of orbitals from PP calculations suggests that diradical states are formally Mobius aromatic multiconfigurational systems.

Quantitative characteristics of qualitative localized bonding patterns.

Patterns of localized and delocalized chemical bonding obtained using the recently proposed adaptive natural density partitioning (AdNDP) provide a qualitative description of electronic structure but miss any quantitative information. Descriptors, such as the electron localization function (ELF), provide quantitative characteristics of bonding and can enhance the usefulness of qualitative patterns. In the present study, we used ELF and a related construct, charge-density-weighted ELF (ELF rho), to characterize localized and delocalized bonding in a variety of systems. It is demonstrated that ELF rho yields a more detailed description than ELF when used to analyze bonding in aromatic, conflicting aromatic, and antiaromatic systems. Both canonical molecular orbitals (CMOs) and localized multicenter two-electron (nc-2e) bonds obtained in the latter case by AdNDP localization are used to calculate ELF rho.

Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study.

We investigated whether defects in the P2Y(12) ADP receptor gene (P2RY12) contribute to the bleeding tendency in 92 index cases enrolled in the European MCMDM-1VWD study. A heterozygous mutation, predicting a lysine to glutamate (K174E) substitution in P2Y(12), was identified in one case with mild type 1 von Willebrand disease (VWD) and a VWF defect. Platelets from the index case and relatives carrying the K174E defect changed shape in response to ADP, but showed reduced and reversible aggregation in response to 10 muM ADP, unlike the maximal, sustained aggregation observed in controls. The reduced response was associated with an approximate 50% reduction in binding of [(3)H]2MeS-ADP to P2Y(12), whereas binding to the P2Y(1) receptor was normal. A hemagglutinin-tagged K174E P2Y(12) variant showed surface expression in CHO cells, markedly reduced binding to [(3)H]2MeS-ADP, and minimal ADP-mediated inhibition of forskolin-induced adenylyl cyclase activity. Our results provide further evidence for locus heterogeneity in type 1 VWD.

Breathing orbital valence bond method in diffusion Monte Carlo: C-H bond dissociation of acetylene.

This study explores the use of breathing orbital valence bond (BOVB) trial wave functions for diffusion Monte Carlo (DMC). The approach is applied to the computation of the carbon-hydrogen (C-H) bond dissociation energy (BDE) of acetylene. DMC with BOVB trial wave functions yields a C-H BDE of 132.4 +/- 0.9 kcal/mol, which is in excellent accord with the recommended experimental value of 132.8 +/- 0.7 kcal/mol. These values are to be compared with DMC results obtained with single determinant trial wave functions, using Hartree-Fock orbitals (137.5 +/- 0.5 kcal/mol) and local spin density (LDA) Kohn-Sham orbitals (135.6 +/- 0.5 kcal/mol).