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Dupuytren's disease (DD) is a common, progressive fibroproliferative disease affecting the palmar fascia of the hands, causing fingers to irreversibly flex toward the palm with significant loss of function. Surgical treatments are limited; therefore, effective new therapies for DD are urgently required. To identify the key cellular and molecular pathways driving DD, we employed single-cell RNA sequencing, profiling the transcriptomes of 35,250 human single cells from DD, nonpathogenic fascia, and healthy dermis. We identify a DD-specific population of pathogenic PDPN + /FAP + mesenchymal cells displaying an elevated expression of fibrillar collagens and profibrogenic genes. In silico trajectory analysis reveals resident fibroblasts to be the source of this pathogenic population. To resolve the processes governing DD progression, genes differentially expressed during fibroblast differentiation were identified, including upregulated TNFRSF12A and transcription factor SCX. Knockdown of SCX and blockade of TNFRSF12A inhibited the proliferation and altered the profibrotic gene expression of cultured human FAP + mesenchymal cells, demonstrating a functional role for these genes in DD. The power of single-cell RNA sequencing is utilized to identify the major pathogenic mesenchymal subpopulations driving DD and the key molecular pathways regulating the DD-specific myofibroblast phenotype. Using this precision medicine approach, inhibition of TNFRSF12A has shown potential clinical utility in the treatment of DD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The relative performance of phase coherence (PC) and magnitude-squared coherence (MSC) for detection of steady-state evoked potentials was studied using 40 Hz auditory evoked potentials (AEPs) in 10 normal human subjects. In addition, simulation experiments were carried out to determine the effects of signal amplitude and phase variability on detection performance. All simulations showed MSC performance to be better than PC performance, with further improvements when MSC was supplemented with weighted averaging. However, human 40 Hz AEP data showed essentially identical detection performance for PC and MSC, with or without weighted averaging. These data support a "phase aggregation" model (at least near threshold) over the more usual model in which an AEP signal is added to a stationary noise. Human data collected under "no-stimulus" conditions agree well with theoretical distributions for both PC and MSC. For equal test time, long analysis periods (with less averaging) yielded equal performance to short analysis periods (with more averaging), for both PC and MSC.

Several different and related measures have been proposed for objective response detection in the frequency domain. We compared magnitude-squared coherence (MSC) to phase coherence (PC) using simulations with specified signal-to-noise ratios (SNRs) and varying numbers of subaverages; the performance measure was area under a receiver operating characteristic (ROC) curve. MSC was superior to PC; test time required for equivalent performance is about 3 times greater for PC than for MSC. MSC performance for a given final SNR increased with the number of subaverages, but reached a plateau at 16 subaverages. Simulations of noise non-stationarity (high-amplitude noise in some subaverages compared to the others) led to decreased performance advantage for MSC over PC. However, weighted averaging restored this advantage. MSC is shown to be a simple algebraic transform of Victor and Mast's (1991) "circular T2" statistic and of two earlier statistics; all have identical statistical power.

Dizziness is a common patient symptom and often remains medically unexplained even after an extensive work-up. The otologic disorders, psychiatric disorders, and functional disability of 75 patients presenting with dizziness to a community otolaryngology practice were assessed in 1991. The patients were classified according to the presence or absence of at least one current DSM-III-R psychiatric disorder and the presence or absence of a peripheral vestibular disorder. Decrements in mental health and role functioning, and increases in bodily pain and hypochondriacal focus were significantly associated with the presence of a psychiatric disorder and whether the etiology of dizziness was due to a peripheral vestibular dysfunction.

We have previously described the usefulness of the magnitude-squared coherence function in analysis of auditory evoked potentials (AEPs) (Ear Hear., 1989, 20: 2-13). For each frequency of interest, the coherence value can be compared to a 'critical value' to determine whether a response is present. Coherence functions must be smoothed across either multiple subaverages or adjacent frequencies (or both) to be reliable, but there are trade-offs: increasing the degree of smoothing increases computational time and (in the case of frequency smoothing) reduces spectral resolution. Using AEPs to clicks and amplitude-modulated tones we investigated the effects of variable degrees of smoothing on threshold estimates in 10 normal human subjects. Thresholds were found to be lower for coherence estimates than for visual detection and are also lower for longer data collection periods. However, there appears to be little if any advantage to segment smoothing beyond 8-16 subaverages. The optimal degree of frequency smoothing is more difficult to specify, depending on the spectrum of the AEP being analyzed (especially the rate of change of phase), and the spectral resolution of the analysis system.

Auditory evoked potentials (AEPs) to 40 Hz clicks and amplitude-modulated 500 Hz tones in human subjects were digitally filtered using an optimal ('Wiener') filter uniquely determined for each AEP. Use of coherence functions to compute coefficients appropriate for filtering grand average AEPs or subsets such as split-half averages is described. Wiener-filtered AEPs correlated better than unfiltered AEPs with split-half replicates and with reference AEPs (obtained with long data collection periods). Visual detection thresholds were lower (more sensitive) for the Wiener-filtered AEPs, but not as low as objectively determined thresholds using coherence values.

Binaural interaction (BI) in auditory evoked potentials was defined as any deviation from the predictions of a model which assumes two independent populations of neurons whose outputs are, in the far field, simply additive. Monaural responses are added to yield the model's prediction of binaurally evoked response; this trace is then subtracted from the actual binaural response to yield a difference trace which is considered to represent BI. In a previous study, strong BI was seen in guinea pig BSEP, maximal at about 4 msec latency; the interaction was greatest for simultaneous (delta t = 0) stimuli of equal intensitsy (delta I = 0). Sixteen normal young adults had BSEP and middle-latency auditory evoked potentials (middle AEP) recorded in response to binaural and monaural clicks. Although BI (in the 6 msec latency region) was observed in the difference trace for the majority of subjects' BSEP, there were no significant differences between binaural and predicted-binaural responses in the group means for individual peak amplitudes and latencies. In middle AEP, the amplitude of peak Pa was usually much smaller in binaurally evoked responses than in the predicted-binaural response. Four subjects had middle AEP which were felt to be predominantly myogenic on the basis of short latency and large amplitude; these responses demonstrated a reverse pattern of interaction, with binaural responses much larger than the monaural sums.

Binaural interaction (BI) in auditory brain-stem responses (ABRs) can be shown by comparing a binaurally elicited ABR to the algebraic sum of monaurally elicited ABRs. Subtracting the summed monaural ABR from binaural ABR yields a wave form assumed to contain response components attributable to BI. It has been suggested that acoustic crosstalk accounts for some of the 'BI' seen with this technique and that contralateral masking should be used during monaural stimulation to eliminate crosstalk. However, this practice might in itself confound the results, even if the masking noise were not intense enough to affect the opposite ear, by 'central masking' of brain-stem neural activity. We studied the effects of contralateral wide-band masking on BI/ABR in 10 normal adult subjects. Clicks were presented at levels from 55 to 115 dB peSPL, at 10 dB intervals. Masking was presented at 73 dB SPL (47 dB effective masking level); based on pilot studies of interaural attenuation, this was a level expected to be at, or just below, the threshold of audibility in the contralateral ear. BI/ABR wave forms were not noticeably affected by the addition of contralateral noise in the monaural trials. In addition, BI/ABR was seen (as previously reported) at levels well below any possibility of crossover artifact. Thus, BI/ABR is not simply attributable to crossover. Contralateral masking is not necessary in recording BI/ABR, within the limits of the stimuli and transducers used in this study.

Short-latency auditory responses were obtained by cross-correlation of continuous, pseudorandom noise stimuli with averaged scalp potentials from adults with normal hearing. Responses were recorded for spectrum levels of 14-74 dB for noise bandwidths from 800 to 6000 Hz. At the lowest intensity level of broadband noise, all 10 subjects showed replicable cross-correlation functions (CCFs), which were characterized by prominent positive peaks at delays (latencies) of 5-7 msec. Male subjects exhibited longer delays than females. Delay (latency) increased with decreasing stimulus intensity. Very early responses (less than 2 msec) attributable to cochlear microphonic, which were prominent in earlier work on guinea pigs, were not well seen in these human data. CCFs for responses to band-limited stimuli and off-line derivation of band-limited CCFs for responses evoked by broadband stimuli both showed that this technique is most sensitive to frequency-following behavior at low frequencies (less than 800 Hz). However, definite phase-locked responses to even the highest passband (3100-6200 Hz) were seen. These results support the use of the CCF technique as an efficient method of frequency-specific assessment of the auditory system.

Frequency-following responses (FFRs) to a low-frequency stimulus in 16 normal-hearing human subjects were cross-correlated with the stimulus in an attempt to yield more easily recognizable FFRs at lower intensity levels and increase threshold sensitivity. Cross-correlation of these responses with the stimulus did not improve threshold sensitivity and latencies obtained from the cross-correlated FFRs showed more variability and were uniformly shorter than those of standard FFR measurement.