Comparison of medical resources and costs among patients with coronary heart disease and impaired glucose tolerance in the Acarbose Cardiovascular Evaluation trial.

BACKGROUND: The Acarbose Cardiovascular Evaluation (ACE) trial (ISRCTN91899513) evaluated the alpha-glucosidase inhibitor acarbose, compared with placebo, in 6522 patients with coronary heart disease and impaired glucose tolerance in China and showed a reduced incidence of diabetes. We assessed the within-trial medical resource use and costs, and quality-adjusted life years (QALYs). METHODS: Resource use data were collected prospectively within the ACE trial. Hospitalizations, medications, and outpatient visits were valued using Chinese unit costs. Medication use was measured in drug days, with cardiovascular and diabetes drugs summed across the trial by participant. Health-related quality of life was captured using the EuroQol-5 Dimension-3 Level questionnaire. Regression analyses were used to compare resource use, costs, and QALYs, accounting for regional variation. Costs and QALYs were discounted at 3% yearly. RESULTS: Hospitalizations were 6% higher in the acarbose arm during the trial (rate ratio 1.06, p = .009), but there were no significant differences in total inpatient days (rate ratio 1.04, p = .30). Total costs per participant, including study drug, were significantly higher for acarbose (¥ [Yuan] 56 480, £6213), compared with placebo (¥48 079, £5289; mean ratio 1.18, p < 0.001). QALYs reported by participants in the acarbose arm (3.96 QALYs) were marginally higher than in the placebo arm (3.95 QALYs), but the difference was not statistically significant (0.01 QALYs; p = .58). CONCLUSIONS: Acarbose, compared with placebo, participants cost more due to study drug costs and reported no statistically significant difference in QALYs. These higher within-trial costs could potentially be offset in future by savings from the acarbose-related lower incidence of diabetes.

An Investigation of Acoustic Back-Coupling in Human Phonation on a Synthetic Larynx Model.

In the human phonation process, acoustic standing waves in the vocal tract can influence the fluid flow through the glottis as well as vocal fold oscillation. To investigate the amount of acoustic back-coupling, the supraglottal flow field has been recorded via high-speed particle image velocimetry (PIV) in a synthetic larynx model for several configurations with different vocal tract lengths. Based on the obtained velocity fields, acoustic source terms were computed. Additionally, the sound radiation into the far field was recorded via microphone measurements and the vocal fold oscillation via high-speed camera recordings. The PIV measurements revealed that near a vocal tract resonance frequency fR, the vocal fold oscillation frequency fo (and therefore also the flow field's fundamental frequency) jumps onto fR. This is accompanied by a substantial relative increase in aeroacoustic sound generation efficiency. Furthermore, the measurements show that fo-fR-coupling increases vocal efficiency, signal-to-noise ratio, harmonics-to-noise ratio and cepstral peak prominence. At the same time, the glottal volume flow needed for stable vocal fold oscillation decreases strongly. All of this results in an improved voice quality and phonation efficiency so that a person phonating with fo-fR-coupling can phonate longer and with better voice quality.

On the Alignment of Acoustic and Coupled Mechanic-Acoustic Eigenmodes in Phonation by Supraglottal Duct Variations.

Sound generation in human phonation and the underlying fluid-structure-acoustic interaction that describes the sound production mechanism are not fully understood. A previous experimental study, with a silicone made vocal fold model connected to a straight vocal tract pipe of fixed length, showed that vibroacoustic coupling can cause a deviation in the vocal fold vibration frequency. This occurred when the fundamental frequency of the vocal fold motion was close to the lowest acoustic resonance frequency of the pipe. What is not fully understood is how the vibroacoustic coupling is influenced by a varying vocal tract length. Presuming that this effect is a pure coupling of the acoustical effects, a numerical simulation model is established based on the computation of the mechanical-acoustic eigenvalue. With varying pipe lengths, the lowest acoustic resonance frequency was adjusted in the experiments and so in the simulation setup. In doing so, the evolution of the vocal folds' coupled eigenvalues and eigenmodes is investigated, which confirms the experimental findings. Finally, it was shown that for normal phonation conditions, the mechanical mode is the most efficient vibration pattern whenever the acoustic resonance of the pipe (lowest formant) is far away from the vocal folds' vibration frequency. Whenever the lowest formant is slightly lower than the mechanical vocal fold eigenfrequency, the coupled vocal fold motion pattern at the formant frequency dominates.

Anisotropic minimum dissipation subgrid-scale model in hybrid aeroacoustic simulations of human phonation.

This article deals with large-eddy simulations of three-dimensional incompressible laryngeal flow followed by acoustic simulations of human phonation of five cardinal English vowels, /ɑ, æ, i, o, u/. The flow and aeroacoustic simulations were performed in OpenFOAM and in-house code openCFS, respectively. Given the large variety of scales in the flow and acoustics, the simulation is separated into two steps: (1) computing the flow in the larynx using the finite volume method on a fine moving grid with 2.2 million elements, followed by (2) computing the sound sources separately and wave propagation to the radiation zone around the mouth using the finite element method on a coarse static grid with 33 000 elements. The numerical results showed that the anisotropic minimum dissipation model, which is not well known since it is not available in common CFD software, predicted stronger sound pressure levels at higher harmonics, and especially at first two formants, than the wall-adapting local eddy-viscosity model. The model on turbulent flow in the larynx was employed and a positive impact on the quality of simulated vowels was found.

Error detection and filtering of incompressible flow simulations for aeroacoustic predictions of human voice.

The presented filtering technique is proposed to detect errors and correct outliers inside the acoustic sources, respectively, the first time derivative of the incompressible pressure obtained from large eddy simulations with prescribed vocal fold motion using overlay mesh methods. Regarding the perturbed convective wave equation, the time derivative of the incompressible pressure is the primary sound source in the human phonation process. However, the incompressible pressure can be erroneous and have outliers when fulfilling the divergence-free constraint of the velocity field. This error is primarily occurring for non-conserving prescribed vocal fold motions. Therefore, the method based on a continuous stationary random process was designed to detect rare events in the time derivative of the pressure. The detected events are then localized and treated by a defined window function to increase their probability. As a consequence, the data quality of the non-linearly filtered data is enhanced significantly. Furthermore, the proposed method can also be used to assess convergence of the aeroacoustic source terms, and detect regions and time intervals, which show a non-converging behavior by an impulse-like structure.

3D-FV-FE Aeroacoustic Larynx Model for Investigation of Functional Based Voice Disorders.

For the clinical analysis of underlying mechanisms of voice disorders, we developed a numerical aeroacoustic larynx model, called simVoice, that mimics commonly observed functional laryngeal disorders as glottal insufficiency and vibrational left-right asymmetries. The model is a combination of the Finite Volume (FV) CFD solver Star-CCM+ and the Finite Element (FE) aeroacoustic solver CFS++. simVoice models turbulence using Large Eddy Simulations (LES) and the acoustic wave propagation with the perturbed convective wave equation (PCWE). Its geometry corresponds to a simplified larynx and a vocal tract model representing the vowel /a/. The oscillations of the vocal folds are externally driven. In total, 10 configurations with different degrees of functional-based disorders were simulated and analyzed. The energy transfer between the glottal airflow and the vocal folds decreases with an increasing glottal insufficiency and potentially reflects the higher effort during speech for patients being concerned. This loss of energy transfer may also have an essential influence on the quality of the sound signal as expressed by decreasing sound pressure level (SPL), Cepstral Peak Prominence (CPP), and Vocal Efficiency (VE). Asymmetry in the vocal fold oscillations also reduces the quality of the sound signal. However, simVoice confirmed previous clinical and experimental observations that a high level of glottal insufficiency worsens the acoustic signal quality more than oscillatory left-right asymmetry. Both symptoms in combination will further reduce the quality of the sound signal. In summary, simVoice allows for detailed analysis of the origins of disordered voice production and hence fosters the further understanding of laryngeal physiology, including occurring dependencies. A current walltime of 10 h/cycle is, with a prospective increase in computing power, auspicious for a future clinical use of simVoice.

Helmholtz's decomposition for compressible flows and its application to computational aeroacoustics.

The Helmholtz decomposition, a fundamental theorem in vector analysis, separates a given vector field into an irrotational (longitudinal, compressible) and a solenoidal (transverse, vortical) part. The main challenge of this decomposition is the restricted and finite flow domain without vanishing flow velocity at the boundaries. To achieve a unique and L 2 -orthogonal decomposition, we enforce the correct boundary conditions and provide its physical interpretation. Based on this formulation for bounded domains, the flow velocity is decomposed. Combining the results with Goldstein's aeroacoustic theory, we model the non-radiating base flow by the transverse part. Thereby, this approach allows a precise physical definition of the acoustic source terms for computational aeroacoustics via the non-radiating base flow. In a final simulation example, Helmholtz's decomposition of compressible flow data using the finite element method is applied to an overflowed rectangular cavity at Mach 0.8. The results show a reasonable agreement with the source data and illustrate the distinct parts of the Helmholtz decomposition.

Aeroacoustic source term computation based on radial basis functions.

In low Mach number aeroacoustics, the known disparity of length scales makes it possible to apply well-suited simulation models using different meshes for flow and acoustics. The workflow of these hybrid methodologies include performing an unsteady flow simulation, computing the acoustic sources, and simulating the acoustic field. Therefore, hybrid methods seek for robust and flexible procedures, providing a conservative mesh to mesh interpolation of the sources while ensuring high computational efficiency. We propose a highly specialized radial basis function interpolation for the challenges during hybrid simulations. First, the computationally efficient local radial basis function interpolation in conjunction with a connectivity-based neighbor search technique is presented. Second, we discuss the computation of spatial derivatives based on radial basis functions. These derivatives are computed in a local-global approach, using a Gaussian kernel on local point stencils. Third, radial basis function interpolation and derivatives are used to compute complex aeroacoustic source terms. These ingredients are necessary to provide flexible source term calculations that robustly connect flow and acoustics. Finally, the capabilities of the presented approach are shown in a numerical experiment with a co-rotating vortex pair.

Hybrid aeroacoustic approach for the efficient numerical simulation of human phonation.

A hybrid aeroacoustic approach was developed for the efficient numerical computation of human phonation. In the first step, an incompressible flow simulation on a three-dimensional (3 D) computational grid, which is capable of resolving all relevant turbulent scales, is performed using STARCCM+ and finite volume method. In the second step, the acoustic source terms on the flow grid are computed and a conservative interpolation to the acoustic grid is performed. Finally, the perturbed convective wave equation is solved to obtain the acoustic field in 3 D with the finite element solver CFS++. Thereby, the conservative transformation of the acoustic sources from the flow grid to the acoustic grid is a key step to allow coarse acoustic grids without reducing accuracy. For this transformation, two different interpolation strategies are compared and grid convergence is assessed. Overall, 16 simulation setups are compared. The initial (267 000 degrees of freedom) and the optimized (21 265 degrees of freedom) simulation setup were validated by measurements of a synthetic larynx model. To conclude, the total computational time of the acoustic simulation is reduced by 95% compared to the initial simulation setup without a significant reduction of accuracy, being 7%, in the frequency range of interest.

Ion-Mobility Mass Spectrometry for the Rapid Determination of the Topology of Interlocked and Knotted Molecules.

A rapid screening method based on traveling-wave ion-mobility spectrometry (TWIMS) combined with tandem mass spectrometry provides insight into the topology of interlocked and knotted molecules, even when they exist in complex mixtures, such as interconverting dynamic combinatorial libraries. A TWIMS characterization of structure-indicative fragments generated by collision-induced dissociation (CID) together with a floppiness parameter defined based on parent- and fragment-ion arrival times provide a straightforward topology identification. To demonstrate its broad applicability, this approach is applied here to six Hopf and two Solomon links, a trefoil knot, and a [3]catenate.

Strong Emission Enhancement in pH-Responsive 2:2 Cucurbit[8]uril Complexes.

Organic fluorophores, particularly stimuli-responsive molecules, are very interesting for biological and material sciences applications, but frequently limited by aggregation- and rotation-caused photoluminescence quenching. A series of easily accessible bipyridinium fluorophores, whose emission is quenched by a twisted intramolecular charge-transfer (TICT) mechanism, is reported. Encapsulation in a cucurbit[7]uril host gave a 1:1 complex exhibiting a moderate emission increase due to destabilization of the TICT state inside the apolar cucurbituril cavity. A much stronger fluorescence enhancement is observed in 2:2 complexes with the larger cucurbit[8]uril, which is caused by additional conformational restriction of rotations around the aryl/aryl bonds. Because the cucurbituril complexes are pH switchable, this system represents an efficient supramolecular ON/OFF fluorescence switch.

Orthogonal switching of self-sorting processes in a stimuli-responsive library of cucurbit[8]uril complexes.

The self-sorting processes in dynamic libraries of cucurbit[8]uril complexes can be switched in an orthogonal way by external stimuli. Protonated phenylpyridine guests form a 2 : 1 homoternary π-donor-π-acceptor complex, while deprotonation makes it a partner for ethylviologen in a 1 : 1 : 1 heteroternary complex. Reduction of the viologen instead generates a 2 : 1 homoternary complex of viologen radical-cations.

Novel Alkoxy-Substituted Dipyrrins and Near-IR BODIPY Dyes-Preparation and Photophysical Properties.

Starting from 3-alkoxy-2-aryl-substituted pyrroles and aromatic aldehydes, a collection of new dipyrrins was prepared. Under the standard conditions of Treibs, these were converted into the corresponding boron dipyrrins (BODIPYs). Compounds of this type with alkoxy groups at C-3 position of both pyrrole subunits are new and hence the photophysical properties of this collection of novel dipyrrins and BODIPY dyes were investigated. The dipyrrins show absorption maxima up to 596 nm and emissions of up to 677 nm. For the BODIPY series a remarkable effect of the alkoxy groups was identified, resulting in red shifts for absorptions and emissions. The compound substituted with two 2-thien-2-yl groups and a meso-C6 F5 substituent shows an absorption maximum at 725 nm and emits at 754 nm and thus is a new representative of a near-IR BODIPY dye related to certain aza-BODIPYs. Our results demonstrate the influence of the alkoxy groups on the spectroscopic data and reveal the potential of 3-alkoxy-2-aryl-substituted pyrroles for the design of new fluorophores.

PolyWhips: Directional Particle Transport by Gradient-Directed Growth and Stiffening of Supramolecular Assemblies.

Growth of rigid rods occurs via supramolecular assembly of a nonconjugated π-donor π-acceptor monomer and is triggered by a NaCl gradient. The mechanical stiffness of this material is controlled by the local salt concentration and is ion specific. The continuous and well-controlled growth process is exploited to power the directional transport of sub-millimeter polymer particles.

The Delicate Balance of Preorganisation and Adaptability in Multiply Bonded Host-Guest Complexes.

Rigidity and preorganisation are believed to be required for high affinity in multiply bonded supramolecular complexes as they help reduce the entropic penalty of the binding event. This comes at the price that such rigid complexes are sensitive to small geometric mismatches. In marked contrast, nature uses more flexible building blocks. Thus, one might consider putting the rigidity/high-affinity notion to the test. Multivalent crown/ammonium complexes are ideal for this purpose as the monovalent interaction is well understood. A series of divalent complexes with different spacer lengths and rigidities has thus been analysed to correlate chelate cooperativities and spacer properties. Too long spacers reduce chelate cooperativity compared to exactly matching ones. However, in contrast to expectation, flexible guests bind with chelate cooperativities clearly exceeding those of rigid structures. Flexible spacers adapt to small geometric host-guest mismatches. Spacer-spacer interactions help overcome the entropic penalty of conformational fixation during binding and a delicate balance of preorganisation and adaptability is at play in multivalent complexes.