Postoperative Restrictive Opioid Protocols and Durable Changes in Opioid Prescribing and Chronic Opioid Use.

Importance: Changes in postsurgical opioid prescribing practices may help reduce chronic opioid use in surgical patients. Objective: To investigate whether postsurgical acute pain across different surgical subspecialties can be managed effectively after hospital discharge with an opioid supply of 3 or fewer days and whether this reduction in prescribed opioids is associated with reduced new, persistent opioid use. Design, Setting, and Participants: In this prospective cohort study with a case-control design, a restrictive opioid prescription protocol (ROPP) specifying an opioid supply of 3 or fewer days after discharge from surgery along with standardized patient education was implemented across all surgical services at a tertiary-care comprehensive cancer center. Participants were all patients who underwent surgery from August 1, 2018, to July 31, 2019. Main Outcomes and Measures: Main outcomes were the rate of compliance with the ROPP in each surgical service, the mean number of prescription days and refill requests, type of opioid prescribed, and rate of conversion to chronic opioid use determined via a state-run opioid prescription program. Postsurgical complications were also measured. Results: A total of 4068 patients (mean [SD] age, 61.0 [13.8] years; 2528 women [62.1%]) were included, with 2017 in the pre-ROPP group (August 1, 2018, to January 31, 2019) and 2051 in the post-ROPP group (February 1, 2019, to July 31, 2019). The rate of compliance with the protocol was 95%. After implementation of the ROPP, mean opioid prescription days decreased from a mean (SD) of 3.9 (4.5) days in the pre-ROPP group to 1.9 (3.6) days in the post-ROPP group (P < .001). The ROPP implementation led to a 45% decrease in prescribed opioids after surgery (mean [SD], 157.22 [338.06] mean morphine milligram equivalents [MME] before ROPP vs 83.54 [395.70] MME after ROPP; P < .001). Patients in the post-ROPP cohort requested fewer refills (367 of 2051 [17.9%] vs 422 of 2017 [20.9%] in the pre-ROPP cohort; P = .02). There was no statistically significant difference in surgical complications. The conversion rate to chronic opioid use decreased following ROPP implementation among both opioid-naive patients with cancer (11.3% [143 of 1267] to 4.5% [118 of 2645]; P < .001) and those without cancer (6.1% [19 of 310] to 2.7% [16 of 600]; P = .02). Conclusions and Relevance: In this cohort study, prescribing an opioid supply of 3 or fewer days to surgical patients after hospital discharge was feasible for most patients, led to a significant decrease in the number of opioids prescribed after surgery, and was associated with a significantly decreased conversion to long-term opioid use without concomitant increases in refill requests or significant compromises in surgical recovery.

GenESysV: a fast, intuitive and scalable genome exploration open source tool for variants generated from high-throughput sequencing projects.

BACKGROUND: High throughput sequencing technologies have been increasingly used in basic genetic research as well as in clinical applications. More and more variants underlying Mendelian and complex diseases are being discovered and documented using these technologies. However, identifying and obtaining a short list of candidate disease-causing variants remains challenging for most of the users after variant calling, especially for people without computational skills. RESULTS: We developed GenESysV (Genome Exploration System for Variants) as a scalable, intuitive and user-friendly open source tool. It can be used in any high throughput sequencing or genotyping project for storing, managing, prioritizing and efficient retrieval of variants of interest. GenESysV is designed for use by researchers from a wide range of disciplines and computational skills, including wet-lab scientists, clinicians, and bioinformaticians. CONCLUSIONS: GenESysV is the first tool to be able to handle genomic variant dataset ranging in size from a few to thousands of samples and still maintain fast data importation and good query performance. It has a very intuitive graphical user interface and can also be used in studies where secured data access is an important concern. We believe this tool will benefit the human disease research community to speed up discoveries for genetic variants underlying human genetic disorders.

Optimal Path Search for Recurrence Relation in Cartesian Gaussian Integrals.

In quantum chemistry applications the computation of analytical integrals with Gaussian basis functions such as electron repulsion integrals is often the rate-determining step. In this work we developed a general search algorithm to find the optimal path for the recurrence relations in the integral evaluation. This optimal path uses the least amount of intermediate integrals for building the recurrence relations to improve the computational efficiency. We also developed a redundant integral removal technique, and an efficient hybrid scheme to compute incomplete Gamma functions. A software implementation of these algorithms is able to generate efficient integral code for electron repulsion integrals and other types of integrals used in quantum chemistry. Because the algorithms are independent of the details of the recurrence relations, the software can be easily modified to generate new types of analytical integrals.

Comparison of the performance of exact-exchange-based density functional methods.

How to describe nondynamic electron correlation is still a major challenge to density functional theory (DFT). Recent models designed particularly for this problem, such as Becke'05 (B05) and Perdew-Staroverov-Tao-Scuseria (PSTS) functionals employ the exact-exchange density, the efficient calculation of which is technically quite challenging. We have recently implemented self-consistently the B05 functional based on an efficient resolution-identity (RI) technique. In this study, we report a self-consistent RI implementation of the PSTS functional. In contrast to its original implementation, our version brings no limitation on the choice of the basis set. We have also implemented the Mori-Sanchez-Cohen-Yang-2 (MCY2) functional, another recent DFT method that includes full exact exchange. The performance of PSTS, B05, and MCY2 is validated on thermochemistry, reaction barriers, and dissociation energy curves, with an emphasis on nondynamic correlation effects in the discussion. All three methods perform rather well in general, B05 and MCY2 being on average somewhat better than PSTS. We include also results with other functionals that represent various aspects of the development in this field in recent years, including B3LYP, M06-HF, M06-2X, ωB97X, and TPSSh. The performance of the heavy-parameterized functionals M06-2X and ωB97X is on average better than that of B05, MCY2, and PSTS for standard thermodynamic properties and reactions, while the latter functionals do better in hydrogen abstraction reactions and dissociation processes. In particular, B05 is found to be the only functional that yields qualitatively correct dissociation curves for two-center symmetric radicals like He(2)(+). Finally, we compare the performance of all these functionals on a strongly correlated exemplary case system, the NO dimer. Only PSTS, B05, and MCY2 describe the system qualitatively correctly. Overall, this new type of functionals show good promise of overcoming some of the difficulties DFT encounters for systems with strong nondynamic correlation.

Combined QM/MM study of thyroid and steroid hormone analogue interactions with αvß3 integrin.

Recent biochemical studies have identified a cell surface receptor for thyroid and steroid hormones that bind near the arginine-glycine-aspartate (RGD) recognition site on the heterodimeric αvß3 integrin. To further characterize the intermolecular interactions for a series of hormone analogues, combined quantum mechanical and molecular mechanical (QM/MM) methods were used to calculate their interaction energies. All calculations were performed in the presence of either calcium (Ca(2+)) or magnesium (Mg(2+)) ions. These data reveal that 3,5'-triiodothyronine (T(3)) and 3,5,3',5'-tetraiodothyroacetic acid (T(4)ac) bound in two different modes, occupying two alternate sites, one of which is along the Arg side chain of the RGD cyclic peptide site. These orientations differ from those of the other ligands whose alternate binding modes placed the ligands deeper within the RGD binding pocket. These observations are consistent with biological data that indicate the presence of two discrete binding sites that control distinct downstream signal transduction pathways for T(3).

Reactions within fluorobenzene-ammonia heterocluster ions: experiment and theory.

Reactions occurring within gas phase fluorobenenze-ammonia heterocluster cations (FC(6)H(5)-(NH(3))(n=1-4)) have been studied through the use of a triple quadrupole mass spectrometer as well as employing density functional theory (DFT). Collision induced dissociation (CID) experiments were conducted in which mass selected cluster ions are accelerated into a cell containing argon gas and the resulting products then subsequently mass analyzed. Two dominate reaction channels are observed. The first is simple evaporative loss of neutral ammonia from the cluster ion. The second involves a substitution reaction occurring within the cluster ion to form the aniline cation, C(6)H(5)NH(2)(+), where the reactivity was found to vary as a function of cluster size. DFT calculations have been performed to both help analyze the structure and the reactivity of these cluster ions. Pronounced differences in activation energies were found that provide an explanation for the observed variation of reactivity as a function of cluster size. An ad hoc model based upon the Arrhenius equation was developed to fit both the experimental collision energy dependence of the reaction and the observed lowering of the reaction barrier to aniline formation as a function of cluster size.

Reactions within p-difluorobenzene/methanol heterocluster ions: a detailed experimental and theoretical investigation.

The reactivity of p-difluorobenzene/methanol cluster ions has been investigated by using triple quadrupole mass spectrometry and DFT calculations. The present study was performed in light of a recent investigation of p-difluorobenzene/methanol (P = F-C(6)H(4)-F and M = CH(3)OH) heterocluster ions where the solvent-catalyzed formation of p-fluoroanisole (A = CH(3)O-C(6)H(4)-F) was observed in P(M)(2)(+) clusters and not in PM(+) clusters. The results of our mass selected cluster ion study and theoretical calculations confirm that a single extra molecule of methanol can lower the reaction activation energy barrier in agreement with previous work for smaller clusters (PM(+) and P(M)(2)(+)). However, we also observe that P(M)(3)(+) and P(M)(4)(+) clusters undergo evaporative loss of neutral methanol to establish the P(M)(2)(+) cluster before reacting. P(M)(n>4)(+) clusters are capable of reacting through multiple pathways, in some cases generating a 1,4-dimethoxybenzene (B = CH(3)O-C(6)H(4)-OCH(3)) product via two separate substitution reactions within the same cluster ion. DFT calculations were employed to model the structures of the parent cluster ions, and transition state calculations were used to evaluate the activation energy for the p-fluoroanisole-forming substitution reaction. The calculations suggest that the reaction proceeds through a transition state containing a six-member hydrogen-bonded ring involving a reacting methanol and a second methanol that significantly lowers the activation energy.

Size-restricted proton transfer within toluene-methanol cluster ions.

To understand the interaction between toluene and methanol, the chemical reactivity of [(C6H5CH3)(CH3OH) n=1-7](+) cluster ions has been investigated via tandem quadrupole mass spectrometry and through calculations. Collision Induced Dissociation (CID) experiments show that the dissociated intracluster proton transfer reaction from the toluene cation to methanol clusters, forming protonated methanol clusters, only occurs for n = 2-4. For n = 5-7, CID spectra reveal that these larger clusters have to sequentially lose methanol monomers until they reach n = 4 to initiate the deprotonation of the toluene cation. Metastable decay data indicate that for n = 3 and n = 4 (CH3OH)3H(+) is the preferred fragment ion. The calculational results reveal that both the gross proton affinity of the methanol subcluster and the structure of the cluster itself play an important role in driving this proton transfer reaction. When n = 3, the cooperative effect of the methanols in the subcluster provides the most important contribution to allow the intracluster proton transfer reaction to occur with little or no energy barrier. As n >or= 4, the methanol subcluster is able to form ring structures to stabilize the cluster structures so that direct proton transfer is not a favored process. The preferred reaction product, the (CH3OH)3H(+) cluster ion, indicates that this size-restricted reaction is driven by both the proton affinity and the enhanced stability of the resulting product.

Combined QM/MM calculations of active-site vibrations in binding process of P450cam to putidaredoxin.

Combined QM/MM calculations of the active-site of cytochrome P450cam have been performed before and after the binding of P450cam to putidaredoxin. The calculations were carried out for both a 5-coordinated and a 6-coordinated active-site of cytochrome P450cam, with either a water molecule or a carbon monoxide molecule as a 6th distal ligand. An experimentally observed increase in the Fe-S stretching frequency that occurs after cytochrome P450cam binds to putidaredoxin, has been reproduced in our study. Experimentally observed changes in the Fe-C and C-O vibration frequencies that occur after binding of both proteins, have also been reproduced in our study. The computed increase of the Fe-S and Fe-C stretching frequencies is correlated with a corresponding decrease of the Fe-S and Fe-C interatomic distances. According to our calculations, for the active-site with carbon monoxide in the triplet electronic state, the binding process increases the spin densities on the iron and sulfur atoms, which changes the Fe-C and C-O stretching frequencies in opposite directions, in agreement with experimental data.

Enhancement of a Lewis acid-base interaction via solvation: ammonia molecules and the benzene radical cation.

The interaction between ammonia and the benzene radical cation has been investigated by gas-phase studies of mass selected ion clusters {C(6)H(6)-(NH(3))(n=0-8)}(+) via tandem quadrupole mass spectrometry and through calculations. Experiments show a special stability for the cluster ion that contains four ammonias: {C(6)H(6)(NH(3))(4)}(+). Calculations provide evidence that the first ammonia forms a weak dative bond to the cyclohexadienyl radical cation, {C(6)H(6)-NH(3)}(+), where there is a transfer of electrons from ammonia to benzene. Additional solvating ammonia molecules form stabilizing hydrogen bonds to the ring-bound ammonia {C(6)H(6)-NH(3)}(+).(NH(3))(n), which cause cooperative changes in the structure of the cluster complex. Free ammonia is a weak hydrogen bond donor, but electron transfer from NH(3) to the benzene ring that strengthens the dative bond will increase the hydrogen acidity and the strength of the cluster hydrogen bonds to the added ammonia. A progressive "tightening" of this dative bond is observed upon addition of the first, second, and third ammonia to give a cluster stabilized by three N-(+)H x N hydrogen bonds. This shows that the energetic cost of tightening the dative bond is recovered with dividends in the formation of stable cluster hydrogen bonds.

Advances in methods and algorithms in a modern quantum chemistry program package.

Advances in theory and algorithms for electronic structure calculations must be incorporated into program packages to enable them to become routinely used by the broader chemical community. This work reviews advances made over the past five years or so that constitute the major improvements contained in a new release of the Q-Chem quantum chemistry package, together with illustrative timings and applications. Specific developments discussed include fast methods for density functional theory calculations, linear scaling evaluation of energies, NMR chemical shifts and electric properties, fast auxiliary basis function methods for correlated energies and gradients, equation-of-motion coupled cluster methods for ground and excited states, geminal wavefunctions, embedding methods and techniques for exploring potential energy surfaces.

Lennard-Jones parameters for the combined QM/MM method using the B3LYP/6-31G*/AMBER potential.

A combined DFT quantum mechanical and AMBER molecular mechanical potential (QM/MM) is presented for use in molecular modeling and molecular simulations of large biological systems. In our approach we evaluate Lennard-Jones parameters describing the interaction between the quantum mechanical (QM) part of a system, which is described at the B3LYP/6-31+G* level of theory, and the molecular mechanical (MM) part of the system, described by the AMBER force field. The Lennard-Jones parameters for this potential are obtained by calculating hydrogen bond energies and hydrogen bond geometries for a large set of bimolecular systems, in which one hydrogen bond monomer is described quantum mechanically and the other is treated molecular mechanically. We have investigated more than 100 different bimolecular systems, finding very good agreement between hydrogen bond energies and geometries obtained from the combined QM/MM calculations and results obtained at the QM level of theory, especially with respect to geometry. Therefore, based on the Lennard-Jones parameters obtained in our study, we anticipate that the B3LYP/6-31+G*/AMBER potential will be a precise tool to explore intermolecular interactions inside a protein environment.