The influence of weight-bearing status on post-operative mobility and outcomes in geriatric hip fracture.

PURPOSE: We hypothesized that unrestricted or full weight-bearing (FWB) in hip fracture would increase the opportunity to mobilize on post-operative day 1 (POD1mob) and be associated with better outcomes compared with restricted weight-bearing (RWB). METHODS: Over 4 years, 1514 geriatric hip fracture patients aged 65 and above were prospectively recruited. Outcomes were compared between FWB and RWB patients. The primary outcome was 30-day mortality. Secondary outcomes were immobility-related adverse events, length of stay (LOS), and reoperation for failure. Causal effect modelling and multivariate regression with mediation analyses were performed to examine the relation between weight-bearing status (WBS), POD1mob, and known mortality predictors. RESULTS: FWB was allowed in 1421 (96%) of 1479 surgically treated patients and RWB enforced in 58 (4%) patients. Mortality within 30 days occurred in 141 (9.9%) of FWB and 3 (5.2%) of RWB patients. In adjusted analysis, RWB did not influence 30-day mortality (OR 0.42, 95% CI 0.15-01.13, p = 0.293), with the WBS accounting for 91% of the total effect on mortality and 9% contributed from how WBS influenced the POD1mob. RWB was significantly related to increased DVT (OR 7.81, 95% CI: 1.81-33.71 p = 0.002) but no other secondary outcomes. Patients that did not have the opportunity to mobilize had increased 30-day mortality (OR 2.31, 95% CI 1.53-3.48 p < 0.001). CONCLUSION: Restricted weight-bearing was not associated with increased 30-day mortality. Only a small proportion of this effect was mediated by POD1mob. Whilst post-surgical WBS may be difficult to influence for cultural reasons, POD1mob is an easily modifiable target that is likely to have a greater effect on 30-day mortality. LEVEL OF EVIDENCE: Level III, observational study.

Benefits of Beta-Blockade in Sepsis and Septic Shock: A Systematic Review.

BACKGROUND: Sepsis and septic shock are inflammatory disorders associated with high rates of mortality. Patients with sepsis and septic shock frequently become tachycardic as a result of the utilization of vasopressor therapy and cardiac overcompensation owing to hypotension, predisposing patients to an increased risk of atrial fibrillation. Previously, it was thought that beta-blocker therapy in patients with sepsis would exacerbate hypotension; however, recent studies have shown that may not be the case. OBJECTIVE: This review aims to ascertain whether beta-blocker therapy reduces heart rate in patients with sepsis without a corresponding decrease in blood pressure, and if beta-blockade has a beneficial effect on mortality. METHODS: Several databases including Cochrane, EMBASE, PubMed, SCOPUS, and Web of Science were scoured for trials pertaining to the utilization of beta-blockers in sepsis and septic shock, and trials that were either prospective or controlled were included in this review. RESULTS: In the initial search, 1839 articles were found, and those were subsequently reduced to 14 trials (five randomized controlled trials, nine non-randomized trials) that were deemed appropriate for inclusion in this review. All included trials displayed beneficial effects on heart rate without any detriments to blood pressure. Of the six trials that assessed mortality, four showed substantial benefits. CONCLUSION: The majority of the trials assessed in this review displayed beneficial results for beta-blocker use in patients with sepsis. However, owing to the deficit of large-scale randomized controlled trials addressing this topic, further research is needed to ensure the veracity of these results.

The Bee Microbiome: Impact on Bee Health and Model for Evolution and Ecology of Host-Microbe Interactions.

As pollinators, bees are cornerstones for terrestrial ecosystem stability and key components in agricultural productivity. All animals, including bees, are associated with a diverse community of microbes, commonly referred to as the microbiome. The bee microbiome is likely to be a crucial factor affecting host health. However, with the exception of a few pathogens, the impacts of most members of the bee microbiome on host health are poorly understood. Further, the evolutionary and ecological forces that shape and change the microbiome are unclear. Here, we discuss recent progress in our understanding of the bee microbiome, and we present challenges associated with its investigation. We conclude that global coordination of research efforts is needed to fully understand the complex and highly dynamic nature of the interplay between the bee microbiome, its host, and the environment. High-throughput sequencing technologies are ideal for exploring complex biological systems, including host-microbe interactions. To maximize their value and to improve assessment of the factors affecting bee health, sequence data should be archived, curated, and analyzed in ways that promote the synthesis of different studies. To this end, the BeeBiome consortium aims to develop an online database which would provide reference sequences, archive metadata, and host analytical resources. The goal would be to support applied and fundamental research on bees and their associated microbes and to provide a collaborative framework for sharing primary data from different research programs, thus furthering our understanding of the bee microbiome and its impact on pollinator health.

Role played by isopropyl substituents in stabilizing the putative triple bond in Ar'EEAr' [E = Si, Ge, Sn; Ar' = C6H3-2,6-(C6H3-2,6-Pr(i)2)2] and Ar*PbPbAr* [Ar* = C6H3-2,6-(C6H2-2,4,6-Pr(i)3)2].

A theoretical study of the bonding in ArEEAr (where E = Si, Ge, Sn, Pb; Ar = terphenyl ligand) revealed for the first time why bulky isopropyl substituents electronically are required in order to isolate stable ArEEAr species. This was accomplished by combining the natural orbitals for chemical valence (NOCV) method with the extended transition state (ETS) scheme. The NOCV-ETS analysis was based on two ArE fragments in their doublet ground state with the configuration σ(2)π(1). For E = Si, Ge, and Sn, it revealed one π-bond perpendicular to the CEEC plane and two σ/π-type bonds in the plane, whereas the ArPbPbAr system was found to have a single σ bond with a C-Pb-Pb trans-bent angle close to 90°. While similar bonding pictures have been obtained in previous model studies with Ar = H and CH3, the NOCV-ETS scheme was able to obtain quantitative estimates for the strength of various σ/π components without artificial truncations or twisting of the system. More importantly, NOCV-ETS analysis was able to show that the electronic influence of the isopropyl substituents on the σ/π components differs little from that found in a system where they are replaced by hydrogen. Instead, the favorable role of the isopropyl substituents is due to dispersive van der Waals attractions between Pr(i) groups on aryl rings attached to different E atoms as well as hyperconjugation involving donation into σ* orbitals on Pr(i). Dispersive interaction amounts to -27.5 kcal/mol (Si), -29.1 kcal/mol (Ge), -26.2 kcal/mol (Sn), and -44.0 kcal/mol (Pb). The larger dispersive stabilization for Pb reflects the fact that the longer Pb-Pb and Pb-C bonds sterically allow for more isopropyl groups with Ar = C6H3-2,6-(C6H2-2,4,6-Pr(i)3)2. This is compared to the other elements where Ar = C6H3-2,6-(C6H3-2,6-Pr(i)2)2. It is finally concluded from the analysis that real ArEEAr systems reveal little character of the EE bond in contrast to the findings of previous studies on model systems.

Modeling Transition Metal Reactions with Range-Separated Functionals.

The performance of range-separated functionals for the calculation of reaction profiles of organometallic compounds is considered. Sets of high-level computational results are used as reference data for the most part. The benchmark data include a number of reactions involving small molecules reacting with the Pd atom, PdCl(-), PdCl2, and a Ni atom, the reaction of a model Grubbs catalyst, and the ligand binding in a real Grubbs catalyst. Range-separated functionals are found to improve upon most standard local functionals especially if an optimized range-separation parameter is used. They do not represent an improvement upon the better-performed global hybrid functionals or a local functional that includes a larger number of adjustable parameters. Some unusual results for molecule-molecule interaction energies are observed and explained by a detailed analysis of the contributions to the bonding energies. The influence of range separation on the barriers and reaction energies is also investigated.

Calculation of exchange coupling constants in triply-bridged dinuclear Cu(II) compounds based on spin-flip constricted variational density functional theory.

The performance of the second-order spin-flip constricted variational density functional theory (SF-CV(2)-DFT) for the calculation of the exchange coupling constant (J) is assessed by application to a series of triply bridged Cu(II) dinuclear complexes. A comparison of the J values based on SF-CV(2)-DFT with those obtained by the broken symmetry (BS) DFT method and experiment is provided. It is demonstrated that our methodology constitutes a viable alternative to the BS-DFT method. The strong dependence of the calculated exchange coupling constants on the applied functionals is demonstrated. Both SF-CV(2)-DFT and BS-DFT affords the best agreement with experiment for hybrid functionals.

Molecular and vibrational structure of tetroxo d0 metal complexes in their excited states. a study based on time-dependent density functional calculations and Franck-Condon theory.

We have applied time dependent density functional theory to study excited state structures of the tetroxo d(0) transition metal complexes MnO(4)(-), TcO(4)(-), RuO(4), and OsO(4). The excited state geometry optimization was based on a newly implemented scheme [Seth et al. Theor. Chem. Acc. 2011, 129, 331]. The first excited state has a C(3v) geometry for all investigated complexes and is due to a "charge transfer" transition from the oxygen based HOMO to the metal based LUMO. The second excited state can uniformly be characterized by "charge transfer" from the oxygen HOMO-1 to the metal LUMO with a D(2d) geometry for TcO(4)(-), RuO(4), and OsO(4) and two C(2v) geometries for MnO(4)(-). It is finally found that the third excited state of MnO(4)(-) representing the HOMO to metal based LUMO+1 orbital transition has a D(2d) geometry. On the basis of the calculated excited state structures and vibrational modes, the Franck-Condon method was used to simulate the vibronic structure of the absorption spectra for the tetroxo d(0) transition metal complexes. The Franck-Condon scheme seems to reproduce the salient features of the experimental spectra as well as the simulated vibronic structure for MnO(4)(-) generated from an alternative scheme [Neugebauer J. J. Phys. Chem. A 2005, 109, 1168] that does not apply the Franck-Condon approximation.

Range-Separated Exchange Functionals with Slater-Type Functions.

An implementation of range-separated density functionals utilizing the Yukawa potential and Slater-type functions is described. The density-functional part of the range-separated regime is straightforward. The exact exchange part makes use of established methods for evaluating exchange integrals over Slater-type functions but still requires new one- and two-center integrals. Equations for the one-center integrals are derived. The two-center integrals are evaluated through a combination of new equations and techniques taken from procedures for evaluating two-center Coulomb integrals over Slater-type functions. In a first application, the performance of range-separated functionals in the prediction of transition metal thermochemistry is evaluated using a database of average ligand removal energies. The range-separated functionals perform better than a GGA parent and similarly to commonly used hybrid and meta-hybrid functionals. The results were relatively insensitive to the chosen value of the attenuation parameter.

Calculation of the exchange coupling constants of copper binuclear systems based on spin-flip constricted variational density functional theory.

We have recently developed a methodology for the calculation of exchange coupling constants J in weakly interacting polynuclear metal clusters. The method is based on unrestricted and restricted second order spin-flip constricted variational density functional theory (SF-CV(2)-DFT) and is here applied to eight binuclear copper systems. Comparison of the SF-CV(2)-DFT results with experiment and with results obtained from other DFT and wave function based methods has been made. Restricted SF-CV(2)-DFT with the BH&HLYP functional yields consistently J values in excellent agreement with experiment. The results acquired from this scheme are comparable in quality to those obtained by accurate multi-reference wave function methodologies such as difference dedicated configuration interaction and the complete active space with second-order perturbation theory.

A discrete interaction model/quantum mechanical method to describe the interaction of metal nanoparticles and molecular absorption.

A frequency-dependent quantum mechanics/molecular mechanics method for the calculation of response properties of molecules adsorbed on metal nanoparticles is presented. This discrete interaction model/quantum mechanics (DIM/QM) method represents the nanoparticle atomistically, thus accounting for the local environment of the nanoparticle surface on the optical properties of the adsorbed molecule. Using the DIM/QM method, we investigate the coupling between the absorption of a silver nanoparticle and of a substituted naphthoquinone. This system is chosen since it shows strong coupling due to a molecular absorption peak that overlaps with the plasmon excitation in the metal nanoparticle. We show that there is a strong dependence not only on the distance of the molecule from the metal nanoparticle but also on its orientation relative to the nanoparticle. We find that when the transition dipole moment of an excitation is oriented towards the nanoparticle there is a significant increase in the molecular absorption as a result of coupling to the metal nanoparticle. In contrast, we find that the molecular absorption is decreased when the transition dipole moment is oriented parallel to the metal nanoparticle. The coupling between the molecule and the metal nanoparticle is found to be surprisingly long range and important on a length scale comparable to the size of the metal nanoparticle. A simple analytical model that describes the molecule and the metal nanoparticle as two interacting point objects is found to be in excellent agreement with the full DIM/QM calculations over the entire range studied. The results presented here are important for understanding plasmon-exciton hybridization, plasmon enhanced photochemistry, and single-molecule surface-enhanced Raman scattering.

First principle simulation of the temperature dependent magnetic circular dichroism of a trinuclear copper complex in the presence of zero field splitting.

We present a test of a recently developed density functional theory (DFT) based methodology for the calculation of magnetic circular dichroism (MCD) spectra in the presence of zero-field splitting (ZFS). The absorption and MCD spectra of the trinuclear copper complex µ(3)O ([Cu(3)(L)(µ(3)-O)](4+)), which models the native intermediate produced in the catalytic cycle of the multicopper oxidases, have been simulated from first principle within the framework of adiabatic time dependent density functional theory. The effects of the ZFS of the quartet (4)A(2) ground state on the theoretical MCD spectrum of µ(3)O have been analyzed. The simulated spectra are consistent with the experimental ones. The theoretical assignments of the MCD spectra are based on direct simulation as well as a detailed analysis of the molecular orbitals in µ(3)O. Some of the assignments differ from those given in previous studies. The ZFS effects in the presence of a strong external magnetic field (7 T) prove negligible. The change of the sign of the ZFS changes systematically the intensity of the MCD bands of the z-polarized excitations. The effect of the ZFS on the x,y-polarized excitations is not uniform.

Bis[(1S)-1,4-azanediyl-1-(9-deazaadenin-9-yl)-1,4-dideoxy-5-methylsulfanyl-D-ribitol] tetrakis(hydrochloride) monohydrate: structure, DFT energy and ligand docking results of a potent methylthioadenosine phosphorylase inhibitor found in different molecular conformations.

The title compound, abbreviated as 5'ThiomethylImmA, is a potent inhibitor of methylthioadenosine phosphorylase [Singh et al. (2004). Biochemistry, 43, 9-18]. The synchrotron study reported here shows that the hydrochloride salt crystallizes with two independent, nearly superimposable, dications as a monohydrate with formula 2C(12)H(19)N(5)O(2)S(2+)·4Cl(-)·H(2)O. Hydrogen bonding utilizing the H atoms of the dication is found to favour certain molecular conformations in the salt, which are significantly different from those found as bound in the enzyme. Ligand docking studies starting from either of these dications or related neutral structures successfully place the conformationally revised structures in the enzyme active site but only under particular hydrogen-bonding and molecular flexibility criteria. Density functional theory calculations verify the energy similarity of the independent cations and confirm the significant energy cost of the required conformational change to the enzyme bound form. The results suggest that using crystallographically determined free ligand coordinates as starting parameters for modelling may have serious limitations.

A discrete interaction model/quantum mechanical method for describing response properties of molecules adsorbed on metal nanoparticles.

A new polarizable quantum mechanics/molecular mechanics method for the calculation of response properties of molecules adsorbed on metal nanoparticles is presented. This method, which we denote the discrete interaction model/quantum mechanics (DIM/QM) method, represents the nanoparticle atomistically which enables the modeling of the influence of the local environment of a nanoparticle surface on the optical properties of a molecule. Using DIM/QM, we investigate the excitation energies of rhodamine-6G (R6G) and crystal violet (CV) adsorbed on silver and gold nanoparticles of different quasispherical shapes and sizes. The metal nanoparticle is characterized by its static total polarizability, a reasonable approximation for frequencies far from the plasmon resonance. We observe that for both R6G and CV, the presence of the nanoparticle shifts the strongest excitation to the red approximately 40 nm and also increases the oscillator strength of that excitation. The shifts in excitation energies due to the nanoparticle surface are found to be comparable to those due to solvation. We find that these shifts decay quickly as the molecule is moved away from the surface. We also find that the wavelength shift is largest when the transition dipole moment is aligned with the edges of the nanoparticle surface where the electric field is expected to be the largest. These results show that the molecular excitations are sensitive to the local environment on the nanoparticle as well as the specific orientation of the molecule relative to the surface.

Density functional theory study of the magnetic circular dichroism spectra of molybdenyl complexes.

We report a density functional theory (DFT) study of the magnetic circular dichroism (MCD) spectra for four molybdenyl complexes: [MoOCl(4)](-), [MoO(S(2)C(2)H(4))(2)](-), [(Tp*)MoO(bdt)], and [(L3S)MoO(bdt)] (Tp* = hydrotris (3,5-dimethyl-1-pyrazolyl) borate; L3S = (2-dimethylethane-thiolate)bis(3,5-dimethylpyrazolyl)-methane; bdt =1,2-benzenedithiolate). The simulation of the temperature dependent MCD-bands (C-terms) that give rise to the spectra was performed using a method based on time-dependent DFT. In this method, the C-parameters are calculated by including spin-orbit perturbations. On the basis of the theoretical calculations, new or additional assignments are made for the MCD spectra of the complexes; specially for [(L3S)MoO(bdt)], for which case only tentative assignments of the excitations have been proposed in recent years.

A magnetic and electronic circular dichroism study of azurin, plastocyanin, cucumber basic protein, and nitrite reductase based on time-dependent density functional theory calculations.

The excitation, circular dichroism, magnetic circular dichroism (MCD) and electron paramagnetic resonance (EPR) spectra of small models of four blue copper proteins are simulated on the TDDFT/BP86 level. X-Ray diffraction geometries are used for the modeling of the blue copper sites in azurin, plastocyanin, cucumber basic protein, and nitrite reductase. Comparison with experimental data reveals that the calculations reproduce most of the qualitative trends of the observed experimental spectra with some discrepancies in the orbital decompositions and the values of the excitation energies, the g( parallel) components of the g tensor, and the components of the A tensor. These discrepancies are discussed relative to deficiencies in the time-dependent density functional theory (TDDFT) methodology, as opposed to previous studies which address them as a result of insufficient model size or poor performance of the BP86 functional. In addition, attempts are made to elucidate the correlation between the MCD and EPR signals.

Density functional theory study of the electron paramagnetic resonance parameters and the magnetic circular dichroism spectrum for model compounds of dimethyl sulfoxide reductase.

We report a density functional theory (DFT) study of electron paramagnetic resonance (EPR) parameters for complexes modeling the paramagnetic center Mo(V) of the molybdoenzyme dimethyl sulfoxide reductase. We pay special attention to the Mo-OH link to find the most likely geometry and orientation of the metal center in the enzyme and provide an analysis of the physical origin of the g-values in terms of magnetically induced orbital mixing. We also present a study of the magnetic circular dichroism (MCD) spectrum for a complex that models the Mo(V) center of the enzyme. The calculation of the MCD-parameters that give rise to the spectrum was performed using a newly implemented method based on time-dependent DFT. On the basis of the theoretical calculations, it was possible to give a full assignment of the bands of the MCD spectrum for the enzyme.

Controlling the non-resonant chemical mechanism of SERS using a molecular photoswitch.

In this work we present a detailed investigation of the Raman properties of a dithienylethene photoswitch interacting with a small gold cluster (Au(19)(+)) using time-dependent density functional theory (TD-DFT). The enhancement mechanism (CHEM) due to the molecule-surface chemical coupling in surface-enhanced Raman scattering (SERS) has been characterized for this system. We demonstrate that it is possible to control the CHEM enhancement by switching the photoswitch from its closed form to its open form. The open form of the photoswitch is found to be the strongest Raman scatterer when adsorbed on the surface whereas the opposite is found for the free molecule. This trend is explained using a simple two-state approximation. In this model the CHEM enhancement scales roughly as (omega(X)/omega(e)(4)), where omega(X) is the HOMO-LUMO gap of the free molecule and omega(e) is an average excitation between the HOMO of the photoswitch and the LUMO of the metal. We propose that the ability of this photoswitch to switch reversibly from open to closed will make it an excellent probe to control the CHEM enhancement of SERS.

On the relation between time-dependent and variational density functional theory approaches for the determination of excitation energies and transition moments.

It is shown that it is possible to derive the basic eigenvalue equation of adiabatic time-dependent density functional theory within the Tamm-Dancoff approximation (TD-DFT/TD) from a variational principle. The variational principle is applied to the regular Kohn-Sham formulation of DFT energy expression for a single Slater determinant and leads to the same energy spectrum as TD-DFT/TD. It is further shown that this variational approach affords the same electric and magnetic transition moments as TD-DFT/TD. The variational scheme can also be applied without the Tamm-Dancoff approximation. Practical implementations of TD-DFT are limited to second order response theory which introduces errors in transition energies for charge transfer and Rydberg excitations. It is indicated that higher order terms can be incorporated into the variational approach. It is also discussed how the current variational method is related to traditional DFT schemes based on variational principles such as DeltaSCF-DFT, and how they can be combined.

A theoretical study of the magnetic circular dichroism spectrum for sulfite oxidase based on time-dependent density functional theory.

We present a theoretical study of the temperature-dependent magnetic circular dichroism (MCD) spectrum for complexes modeling the molybdoenzyme sulfite-oxidase (1) in its Mo(V) oxidation state. The theoretical study was based on a newly implemented time-dependent density functional method that takes into account first-order perturbations due to spin-orbit coupling and a constant magnetic field. It was possible, on the basis of the theoretical calculations, to give a full assignment of the MCD spectrum for 1 and interpret the C term of each band in the experimental MCD spectrum in terms of spin-orbit couplings between specific excited states and between excited states and the ground state.

Magnetic circular dichroism spectrum of plastocyanin by calculation.

The magnetic circular dichroism (MCD) spectrum of the metalloenzyme plastocyanin is calculated using time-dependent density functional theory. The calculation reproduces most of the main features of the experimental spectrum. The calculated spectrum is analyzed to elucidate the contributions to the spectrum and the source of the MCD intensity. As expected, the temperature-dependent MCD intensity is found to be dominant. More surprisingly, contributions from the ground-state mixing with excited states are found to be significant.