Vibrotactile Thresholds on the Wrist for Vibrations Normal to the Skin.

In order to facilitate the development of wrist-worn vibrotactile devices, detailed knowledge about how vibrations are perceived by the users is needed. In particular, perceptual thresholds in amplitude are really important. Thresholds have been measured in the literature for other areas of the body, but given the variability reported between areas (shape of the threshold curve, position of maximum sensitivity), thresholds on the wrist can not be inferred from previous measurements and must be measured. The amplitude thresholds for vibrations normal to the skin surface were evaluated on 28 participants, with a three interval forced choice method. They were measured for 7 frequencies that are classical in the literature about vibrotactile perception (25, 40, 80, 160, 250, 320, and 640 Hz). The classical U-shape of the amplitude-threshold curve is observed, with a maximum sensitivity at around 160 Hz, which differs from other body areas, but confirms recent results obtained for vibrations parallel to the skin surface of the same body area. The sensitivity thresholds of vibrotactile signals appear to be in the micrometer range.

Permethrin Steal Effect by Unmasked Corneocytic Keratin in Topical Therapy of Scabies.

INTRODUCTION: The use of epicutaneously applied permethrin in the treatment of common scabies is considered to be the first-line therapy. Due to increasing clinical treatment failure, the development of genetic resistance to permethrin in Sarcoptes scabiei var. hominis has been postulated. In addition, metabolic resistance and pharmacokinetic limitations by parasitic digestion and reactive thickening of stratum corneum are suspected to cause a reduction in cutaneous bioavailability. METHODS: Since lipophilic permethrin is known to form hydrophobic interactions with proteins via van der Waals interactions, a similar interaction was assumed and investigated for permethrin and the protein keratin. Using keratin particles extracted from animal material, a model for hyperkeratotic and parasitic digested scabies skin was developed. Using fluorescence-labeled keratin and ³H-permethrin, their interaction potential was validated by loading and unloading experiments. Additionally, the impact of keratin to permethrin penetration was investigated based on an in vitro model using Franz diffusion cells. RESULTS: For the first time, keratin particles were introduced as a model for dyskeratotic skin, as we were able to show, the keratin particles' interaction potential with permethrin but no penetration behavior into the stratum corneum. Moreover, comparative penetration experiments of a reference formulation with and without added keratin or keratin-adherent permethrin showed that keratin causes a steal effect for permethrin, leading to a relevant reduction in cutaneous bioavailability in the target compartment. CONCLUSION: The results provide further evidence for a relevant pharmacokinetic influencing factor in the epicutaneous application of permethrin and a rationale for the necessity of keratolytic pretreatment in hyperkeratotic skin for the effective use of topical permethrin application in scabies.

Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor.

The zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal tissue homeostasis meprin α performs key roles in inflammation, immunity, and extracellular matrix remodelling. Dysregulated meprin α is associated with acute kidney injury, sepsis, urinary tract infection, metastatic colorectal carcinoma, and inflammatory bowel disease. Accordingly, meprin α is the target of drug discovery programs. In contrast to meprin ß, meprin α is secreted into the extracellular space, whereupon it oligomerises to form giant assemblies and is the largest extracellular protease identified to date (~6 MDa). Here, using cryo-electron microscopy, we determine the high-resolution structure of the zymogen and mature form of meprin α, as well as the structure of the active form in complex with a prototype small molecule inhibitor and human fetuin-B. Our data reveal that meprin α forms a giant, flexible, left-handed helical assembly of roughly 22 nm in diameter. We find that oligomerisation improves proteolytic and thermal stability but does not impact substrate specificity or enzymatic activity. Furthermore, structural comparison with meprin ß reveal unique features of the active site of meprin α, and helical assembly more broadly.

Perception of violin soundpost tightness through playing and listening tests.

This study involved playing and listening (using recorded sounds) experiments to investigate how changes in soundpost length (for a fixed soundpost position) affect the perceptual qualities of the violin and what the threshold of change is below which players and luthiers do not perceive differences. A length-adjustable carbon fiber soundpost was employed. During the playing experiment, subjects played a provided violin on which the soundpost length was modified by the experimenter to find their optimal soundpost lengths. Then the experimenter varied the soundpost length randomly in ten trials within ±0.11 mm around their optimal lengths and asked subjects to always compare with the previous setting. The results showed that subjects' optimal soundpost lengths varied from 0.132 to 0.616 mm relative to the original length (53 mm), but subjects could not recognize length variation of 0.11 mm or less at above chance levels. During the listening experiment, subjects listened to 16 pairs of recordings through a computer interface and were asked, for each pair, whether the violin setup was the same or different. The results showed that subjects could differentiate soundpost lengths with a difference of about 0.198 mm at better than chance level.

Structure and Dynamics of Meprin ß in Complex with a Hydroxamate-Based Inhibitor.

The astacin protease Meprin ß represents an emerging target for drug development due to its potential involvement in disorders such as acute and chronic kidney injury and fibrosis. Here, we elaborate on the structural basis of inhibition by a specific Meprin ß inhibitor. Our analysis of the crystal structure suggests different binding modes of the inhibitor to the active site. This flexibility is caused, at least in part, by movement of the C-terminal region of the protease domain (CTD). The CTD movement narrows the active site cleft upon inhibitor binding. Compared with other astacin proteases, among these the highly homologous isoenzyme Meprin α, differences in the subsites account for the unique selectivity of the inhibitor. Although the inhibitor shows substantial flexibility in orientation within the active site, the structural data as well as binding analyses, including molecular dynamics simulations, support a contribution of electrostatic interactions, presumably by arginine residues, to binding and specificity. Collectively, the results presented here and previously support an induced fit and substantial movement of the CTD upon ligand binding and, possibly, during catalysis. To the best of our knowledge, we here present the first structure of a Meprin ß holoenzyme containing a zinc ion and a specific inhibitor bound to the active site. The structural data will guide rational drug design and the discovery of highly potent Meprin inhibitors.

Listener evaluations of violins made from composites.

For centuries, wood, and more specifically spruce, has been the material of choice for violin top plates. Lately, carbon fiber instruments have entered the market. Some studies show that composite materials have potential advantages for making instruments [Damodaran, Lessard, and Babu, Acoust. Aust. 43, 117-122 (2015)]. However, no studies exist that evaluate violins made of different composite materials as judged by listeners. For this study, six prototype violins, differing only by the material of the top plate, were manufactured in a controlled laboratory setting. The six prototype violins were judged by experienced listeners in two double-blind experiments. In contrast to popular opinion that violins made from carbon have or lack a specific sound quality, the study provides insights in the diverse sounds and timbres violins from fiber-reinforced polymers can create. It allows an investigation of the links between the perception and the variations in material properties of the soundboards. Additionally, as neither players nor listeners are acquainted with these instruments, these results provide an interesting view on what type of qualities of violin-like sounds are preferred by listeners.

Effect of back wood choice on the perceived quality of steel-string acoustic guitars.

Some of the most prized woods used for the backs and sides of acoustic guitars are expensive, rare, and from unsustainable sources. It is unclear to what extent back woods contribute to the sound and playability qualities of acoustic guitars. Six steel-string acoustic guitars were built for this study to the same design and material specifications except for the back/side plates which were made of woods varying widely in availability and price (Brazilian rosewood, Indian rosewood, mahogany, maple, sapele, and walnut). Bridge-admittance measurements revealed small differences between the modal properties of the guitars which could be largely attributed to residual manufacturing variability rather than to the back/side plates. Overall sound quality ratings, given by 52 guitarists in a dimly lit room while wearing welder's goggles to prevent visual identification, were very similar between the six guitars. The results of a blinded ABX discrimination test, performed by another subset of 31 guitarists, indicate that guitarists could not easily distinguish the guitars by their sound or feel. Overall, the results suggest that the species of wood used for the back and sides of a steel-string acoustic guitar has only a marginal impact on its body mode properties and perceived sound.

Perceptual evaluation of violins: A psycholinguistic analysis of preference verbal descriptions by experienced musicians.

In this paper, how the notion of violin quality is conveyed in spontaneous verbalizations by experienced violinists during preference judgments is investigated. The aims of the study were to better understand how musicians conceptualize violin quality, what aspects of the sound and the playing experience are essential, and what associations are formed between perceptual evaluation and physical description. Upon comparing violins of varying make and age, players were interviewed about their preferences using open-ended questions. Concepts of violin quality were identified and categorized based on the syntactic and linguistic analysis of musicians' responses. While perceived variations in how a violin sounds and feels, and consequently conceptualization structures, rely on the variations in style and expertise of different violinists, the broader semantic categories emerging from sensory descriptions remain common across performers with diverse musical profiles, reflecting a shared perception of physical parameter patterns that allowed the development of a musician-driven framework for understanding how the dynamic behavior of a violin might relate to its perceived quality. Implications for timbre perception and the crossmodal audio-tactile sensation of sound in music performance are discussed.

Listener evaluations of new and Old Italian violins.

Old Italian violins are routinely credited with playing qualities supposedly unobtainable in new instruments. These qualities include the ability to project their sound more effectively in a concert hall-despite seeming relatively quiet under the ear of the player-compared with new violins. Although researchers have long tried to explain the "mystery" of Stradivari's sound, it is only recently that studies have addressed the fundamental assumption of tonal superiority. Results from two studies show that, under blind conditions, experienced violinists tend to prefer playing new violins over Old Italians. Moreover, they are unable to tell new from old at better than chance levels. This study explores the relative merits of Stradivari and new violins from the perspective of listeners in a hall. Projection and preference are taken as the two broadest criteria by which listeners might meaningfully compare violins. Which violins are heard better, and which are preferred? In two separate experiments, three new violins were compared with three by Stradivari. Projection was tested both with and without orchestral accompaniment. Projection and preference were judged simultaneously by dividing listeners into two groups. Results are unambiguous. The new violins projected better than the Stradivaris whether tested with orchestra or without, the new violins were generally preferred by the listeners, and the listeners could not reliably distinguish new from old. The single best-projecting violin was considered the loudest under the ear by players, and on average, violins that were quieter under the ear were found to project less well.

Investigating the role of auditory and tactile modalities in violin quality evaluation.

The role of auditory and tactile modalities involved in violin playing and evaluation was investigated in an experiment employing a blind violin evaluation task under different conditions: i) normal playing conditions, ii) playing with auditory masking, and iii) playing with vibrotactile masking. Under each condition, 20 violinists evaluated five violins according to criteria related to violin playing and sound characteristics and rated their overall quality and relative preference. Results show that both auditory and vibrotactile feedback are important in the violinists' evaluations but that their relative importance depends on the violinist, the violin and the type of evaluation (different criteria ratings or preference). In this way, the overall quality ratings were found to be accurately predicted by the rating criteria, which also proved to be perceptually relevant to violinists, but were poorly correlated with the preference ratings; this suggests that the two types of ratings (overall quality vs preference) may stem from different decision-making strategies. Furthermore, the experimental design confirmed that violinists agree more on the importance of criteria in their overall evaluation than on their actual ratings for different violins. In particular, greater agreement was found on the importance of criteria related to the sound of the violin. Nevertheless, this study reveals that there are fundamental differences in the way players interpret and evaluate each criterion, which may explain why correlating physical properties with perceptual properties has been challenging so far in the field of musical acoustics.

Influence of vibrotactile feedback on some perceptual features of violins.

This paper investigated how auditory and vibrotactile feedback information is integrated within the context of violin quality evaluation. Fifteen violinists evaluated three violins on four criteria-"Rich Sound," "Loud and Powerful," "Alive and Responsive," and "Pleasure"-during a perceptual experiment. Violinists first evaluated the violins one at a time under three experimental conditions: (1) playing, (2) listening to it (played by a professional player) in an active way by fingering the score on an isolated neck, (3) same as (2) with vibrotactile feedback provided at the isolated neck. Violinists were then asked to evaluate the violins through pairwise comparisons under condition (3): Each violin was paired with itself while the level of vibrations of the isolated neck was either the original one or divided by two. The first part of the experiment demonstrated that Loud and Powerful judgments were affected by the presence of vibrations given that violins were rated louder in condition (3) than in (2). In the second part, violins were rated more positively with original vibration level at the isolated neck than with half the level, for all criteria but Alive and Responsive. Consistently with sensory interaction, the magnitude of the enhancement remained relatively constant across violins.

Soloist evaluations of six Old Italian and six new violins.

Many researchers have sought explanations for the purported tonal superiority of Old Italian violins by investigating varnish and wood properties, plate tuning systems, and the spectral balance of the radiated sound. Nevertheless, the fundamental premise of tonal superiority has been investigated scientifically only once very recently, and results showed a general preference for new violins and that players were unable to reliably distinguish new violins from old. The study was, however, relatively small in terms of the number of violins tested (six), the time allotted to each player (an hour), and the size of the test space (a hotel room). In this study, 10 renowned soloists each blind-tested six Old Italian violins (including five by Stradivari) and six new during two 75-min sessions--the first in a rehearsal room, the second in a 300-seat concert hall. When asked to choose a violin to replace their own for a hypothetical concert tour, 6 of the 10 soloists chose a new instrument. A single new violin was easily the most-preferred of the 12. On average, soloists rated their favorite new violins more highly than their favorite old for playability, articulation, and projection, and at least equal to old in terms of timbre. Soloists failed to distinguish new from old at better than chance levels. These results confirm and extend those of the earlier study and present a striking challenge to near-canonical beliefs about Old Italian violins.

Long-term outcome of patients with active ankylosing spondylitis with etanercept-sustained efficacy and safety after seven years.

INTRODUCTION: Data from clinical studies on the long-term efficacy and safety of anti-tumor necrosis factor (TNF)-α therapy in patients with ankylosing spondylitis (AS) are scarce. This is the first report on continuous treatment with the TNFα fusion protein etanercept over seven years (y). METHODS: Overall, 26 patients with active AS were initially treated with etanercept 2 × 25 mg s.c./week with no concomitant disease modifying anti-rheumatic drugs (DMARDs) or steroids. The clinical response was assessed by standardized parameters. The primary outcome was the proportion of patients in the Spondyloarthritis International Society (ASAS) partial remission at seven years. AS disease activity scores (ASDAS) for status and improvement were compared to conventional outcome measures. RESULTS: Overall, 21/26 patients (81%) completed two years of treatment and 16/26 patients (62%) completed seven years. In the completer analysis, 31% patients were in ASAS partial remission at seven years, while 44% patients showed an ASDAS inactive disease status. Mean Bath AS activity index (BASDAI) scores, which were elevated at baseline (6.3 ± 0.9), showed constant improvement and remained low: 3.1 ± 2.5 at two years and 2.5 ± 2.2 at seven years, while ASDAS also improved (3.9 ± 0.7 at baseline, 1.8 ± 0.9 at two years, 1.6 ± 0.8 at seven years), all P <0.001. From the 10 dropouts, only 5 patients discontinued treatment due to adverse events. Patients who completed the study had lower baseline Bath AS function index (BASFI) scores vs. patients who discontinued. No other clinical parameter at baseline could predict any long-term outcome. CONCLUSIONS: This study confirms the clinical efficacy and safety of etanercept in patients with active AS over seven years of continuous treatment. After seven years, more than half of the initially treated patients remained on anti-TNF therapy, and one-third were in partial remission. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01289743

Perceptual evaluation of violins: a quantitative analysis of preference judgments by experienced players.

The overall goal of the research presented here is to better understand how players evaluate violins within the wider context of finding relationships between measurable vibrational properties of instruments and their perceived qualities. In this study, the reliability of skilled musicians to evaluate the qualities of a violin was examined. In a first experiment, violinists were allowed to freely play a set of different violins and were then asked to rank the instruments by preference. Results showed that players were self-consistent, but a large amount of inter-individual variability was present. A second experiment was then conducted to investigate the origin of inter-individual differences in the preference for violins and to measure the extent to which different attributes of the instrument influence preference. Again, results showed large inter-individual variations in the preference for violins, as well as in assessing various characteristics of the instruments. Despite the significant lack of agreement in preference and the variability in how different criteria are evaluated between individuals, violin players tend to agree on the relevance of sound "richness" and, to a lesser extent, "dynamic range" for determining preference.

Exploring violin sound quality: investigating English timbre descriptors and correlating resynthesized acoustical modifications with perceptual properties.

Performers often discuss the sound quality of a violin or the sound obtained by particular playing techniques, calling upon a diverse vocabulary. This study explores the verbal descriptions, made by performers, of the distinctive timbres of different violins. Sixty-one common descriptors were collected and then arranged by violinists on a map, so that words with similar meanings lay close together, and those with different meanings lay far apart. The results of multidimensional scaling demonstrated consistent use among violinists of many words, and highlighted which words are used for similar purposes. These terms and their relations were then used to investigate the perceptual effect of acoustical modifications of violin sounds produced by roving of the levels in five one-octave wide bands, 190-380, 380-760, 760-1520, 1520-3040, and 3040-6080 Hz. Pairs of sounds were presented, and each participant was asked to indicate which of the sounds was more bright, clear, harsh, nasal, or good (in separate runs for each descriptor). Increased brightness and clarity were associated with moderately increased levels in bands 4 and 5, whereas increased harshness was associated with a strongly increased level in band 4. Judgments differed across participants for the qualities nasal and good.

Player preferences among new and old violins.

Most violinists believe that instruments by Stradivari and Guarneri "del Gesu" are tonally superior to other violins--and to new violins in particular. Many mechanical and acoustical factors have been proposed to account for this superiority; however, the fundamental premise of tonal superiority has not yet been properly investigated. Player's judgments about a Stradivari's sound may be biased by the violin's extraordinary monetary value and historical importance, but no studies designed to preclude such biasing factors have yet been published. We asked 21 experienced violinists to compare violins by Stradivari and Guarneri del Gesu with high-quality new instruments. The resulting preferences were based on the violinists' individual experiences of playing the instruments under double-blind conditions in a room with relatively dry acoustics. We found that (i) the most-preferred violin was new; (ii) the least-preferred was by Stradivari; (iii) there was scant correlation between an instrument's age and monetary value and its perceived quality; and (iv) most players seemed unable to tell whether their most-preferred instrument was new or old. These results present a striking challenge to conventional wisdom. Differences in taste among individual players, along with differences in playing qualities among individual instruments, appear more important than any general differences between new and old violins. Rather than searching for the "secret" of Stradivari, future research might best focused on how violinists evaluate instruments, on which specific playing qualities are most important to them, and on how these qualities relate to measurable attributes of the instruments, whether old or new.

Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years--early clinical response predicts long-term outcome.

OBJECTIVES: To report for the first time on the efficacy and safety of anti-TNF therapy after 8 years of follow-up in patients with active AS, and analyse possible short-term predictors for long-term clinical outcomes. METHODS: In this open-label extension of a randomized controlled trial, proportions of the initially included 69 patients with active AS were treated with infliximab 5 mg/kg i.v./6 weeks for 8 years. The last report was published after 5 years. All analyses were based on completers. RESULTS: Overall, 33 (48%) patients completed 8 years. Their mean (s.d.) BASDAI [2.6 (1.9)], BASFI [3.3 (2.6)] and BASMI [2.7 (2.4)] remained low at Year 8. At the end of Year 8, most patients were either in partial remission (n = 8, 24%) or had low disease activity (BASDAI < 3; n = 21, 64%). No new serious adverse events occurred within the past 3 years. Adverse events were the most frequent reason for dropout (56%). There were no differences between completers and dropouts at baseline, but the latter had higher BASFI values at dropout. No baseline parameter was associated with good long-term response to infliximab, but lower BASDAI levels after 12 weeks were predictive of a higher probability of partial remission [odds ratio (OR) 2.9, 95% CI 1.3, 6.3, P = 0.007], low disease activity (OR 1.7, 95% CI 1.2, 2.3, P = 0.005) or remaining on treatment (OR 0.79, 95% CI 0.61, 1.01, P = 0.06) after 8 years. CONCLUSION: Almost half of the initially treated patients remained on anti-TNF therapy for 8 years, and almost 90% were in partial remission or had low disease activity. Short-term response (low BASDAI at 3 months) is predictive of outcome after 8 years. Infliximab therapy was safe over 8 years.

Perceptual studies of violin body damping and vibrato.

This work explored how the perception of violin notes is influenced by the magnitude of the applied vibrato and by the level of damping of the violin resonance modes. Damping influences the "peakiness" of the frequency response, and vibrato interacts with this peakiness by producing fluctuations in spectral content as well as in frequency and amplitude. Initially, it was shown that thresholds for detecting a change in vibrato amplitude were independent of body damping, and thresholds for detecting a change in body damping were independent of vibrato amplitude. A study of perceptual similarity using triadic comparison showed that vibrato amplitude and damping were largely perceived as independent dimensions. A series of listening tests was conducted employing synthesized, recorded, or live performance to probe perceptual responses in terms of "liveliness" and preference. The results do not support the conclusion that liveliness results from the combination of the use of vibrato and a "peaky" violin response. Judgments based on listening to single notes showed inconsistent patterns for liveliness, while preferences were highest for damping that was slightly less than for a reference (real) violin. In contrast, judgments by players based on many notes showed preference for damping close to the reference value.

Perceptual thresholds for detecting modifications applied to the acoustical properties of a violin.

This study is the first step in the psychoacoustic exploration of perceptual differences between the sounds of different violins. A method was used which enabled the same performance to be replayed on different "virtual violins," so that the relationships between acoustical characteristics of violins and perceived qualities could be explored. Recordings of real performances were made using a bridge-mounted force transducer, giving an accurate representation of the signal from the violin string. These were then played through filters corresponding to the admittance curves of different violins. Initially, limits of listener performance in detecting changes in acoustical characteristics were characterized. These consisted of shifts in frequency or increases in amplitude of single modes or frequency bands that have been proposed previously to be significant in the perception of violin sound quality. Thresholds were significantly lower for musically trained than for nontrained subjects but were not significantly affected by the violin used as a baseline. Thresholds for the musicians typically ranged from 3 to 6 dB for amplitude changes and 1.5%-20% for frequency changes. Interpretation of the results using excitation patterns showed that thresholds for the best subjects were quite well predicted by a multichannel model based on optimal processing.