Pflacco: Feature-Based Landscape Analysis of Continuous and Constrained Optimization Problems in Python.

The herein proposed Python package pflacco provides a set of numerical features to characterize single-objective continuous and constrained optimization problems. Thereby, pflacco addresses two major challenges in the area optimization. Firstly, it provides the means to develop an understanding of a given problem instance, which is crucial for designing, selecting, or configuring optimization algorithms in general. Secondly, these numerical features can be utilized in the research streams of automated algorithm selection and configuration. While the majority of these landscape features is already available in the R package flacco, our Python implementation offers these tools to an even wider audience and thereby promotes research interests and novel avenues in the area of optimization.

Evaluation of genotype by environment interactions on milk production traits of Holstein cows in southern Brazil.

OBJECTIVE: This study assessed the possible existence of genotype by environment interactions for milk, fat and protein yields in Holstein cattle raised in one of the most important milk production basins in Brazil. METHODS: Changes in the genetic parameters and breeding values were evaluated for 57,967 animals from three distinct regions of southern Brazil, divided according to differences in climate. The genotype by environment interaction was determined by genetic correlations between regions, estimated by the restricted maximum likelihood, considering the animal model. Bull rankings were investigated to verify the ratio of coincident selected animals between regions for each trait. RESULTS: The estimates of heritability coefficients were similar between two regions, but were lower in the third evaluated area, for all traits. Genetic correlations between regions were high, ranging from 0.91 to 0.99 for milk, fat and protein yields, representing the absence of a genotype by environment interaction for productive traits. The percentage of selection error between regions for the top 10% of animals ranged from 0.88% to 2.07% for milk yield, 0.99% to 2.46% for fat yield and 0.59% to 3.15% for protein yield. CONCLUSION: A slight change in genotype between areas was expected since no significant genotype by environment interactions were identified, facilitating the process of selecting Holstein cattle in southern Brazil.

Organ of Corti vibration within the intact gerbil cochlea measured by volumetric optical coherence tomography and vibrometry.

There is indirect evidence that the mammalian cochlea in the low-frequency apical and the more commonly studied high-frequency basal regions function in fundamentally different ways. Here, we directly tested this hypothesis by measuring sound-induced vibrations of the organ of Corti (OoC) at three turns of the gerbil cochlea using volumetric optical coherence tomography vibrometry (VOCTV), an approach that permits noninvasive imaging through the bone. In the apical turn, there was little frequency selectivity, and the displacement-vs.-frequency curves had low-pass filter characteristics with a corner frequency of ~0.5-0.9 kHz. The vibratory magnitudes increased compressively with increasing stimulus intensity at all frequencies. In the middle turn, responses were similar except for a slight peak in the response at ~2.5 kHz. The gain was ~50 dB at the peak and 30-40 dB at lower frequencies. In the basal turn, responses were sharply tuned and compressively nonlinear, consistent with observations in the literature. These data demonstrated that there is a transition of the mechanical response of the OoC along the length of the cochlea such that frequency tuning is sharper in the base than in the apex. Because the responses are fundamentally different, it is not appropriate to simply frequency shift vibratory data measured at one cochlear location to predict the cochlear responses at other locations. Furthermore, this means that the number of hair cells stimulated by sound is larger for low-frequency stimuli and smaller for high-frequency stimuli for the same intensity level. Thus the mechanisms of central processing of sounds must vary with frequency. NEW & NOTEWORTHY A volumetric optical coherence tomography and vibrometry system was used to probe cochlear mechanics within the intact gerbil cochlea. We found a gradual transition of the mechanical response of the organ of Corti along the length of the cochlea such that tuning at the base is dramatically sharper than that at the apex. These data help to explain discrepancies in the literature regarding how the cochlea processes low-frequency sounds.

Noninvasive in vivo imaging reveals differences between tectorial membrane and basilar membrane traveling waves in the mouse cochlea.

Sound is encoded within the auditory portion of the inner ear, the cochlea, after propagating down its length as a traveling wave. For over half a century, vibratory measurements to study cochlear traveling waves have been made using invasive approaches such as laser Doppler vibrometry. Although these studies have provided critical information regarding the nonlinear processes within the living cochlea that increase the amplitude of vibration and sharpen frequency tuning, the data have typically been limited to point measurements of basilar membrane vibration. In addition, opening the cochlea may alter its function and affect the findings. Here we describe volumetric optical coherence tomography vibrometry, a technique that overcomes these limitations by providing depth-resolved displacement measurements at 200 kHz inside a 3D volume of tissue with picometer sensitivity. We studied the mouse cochlea by imaging noninvasively through the surrounding bone to measure sound-induced vibrations of the sensory structures in vivo, and report, to our knowledge, the first measures of tectorial membrane vibration within the unopened cochlea. We found that the tectorial membrane sustains traveling wave propagation. Compared with basilar membrane traveling waves, tectorial membrane traveling waves have larger dynamic ranges, sharper frequency tuning, and apically shifted positions of peak vibration. These findings explain discrepancies between previously published basilar membrane vibration and auditory nerve single unit data. Because the tectorial membrane directly overlies the inner hair cell stereociliary bundles, these data provide the most accurate characterization of the stimulus shaping the afferent auditory response available to date.

Two-Dimensional Cochlear Micromechanics Measured In Vivo Demonstrate Radial Tuning within the Mouse Organ of Corti.

UNLABELLED: The exquisite sensitivity and frequency discrimination of mammalian hearing underlie the ability to understand complex speech in noise. This requires force generation by cochlear outer hair cells (OHCs) to amplify the basilar membrane traveling wave; however, it is unclear how amplification is achieved with sharp frequency tuning. Here we investigated the origin of tuning by measuring sound-induced 2-D vibrations within the mouse organ of Corti in vivo Our goal was to determine the transfer function relating the radial shear between the structures that deflect the OHC bundle, the tectorial membrane and reticular lamina, to the transverse motion of the basilar membrane. We found that, after normalizing their responses to the vibration of the basilar membrane, the radial vibrations of the tectorial membrane and reticular lamina were tuned. The radial tuning peaked at a higher frequency than transverse basilar membrane tuning in the passive, postmortem condition. The radial tuning was similar in dead mice, indicating that this reflected passive, not active, mechanics. These findings were exaggerated in Tecta(C1509G/C1509G) mice, where the tectorial membrane is detached from OHC stereocilia, arguing that the tuning of radial vibrations within the hair cell epithelium is distinct from tectorial membrane tuning. Together, these results reveal a passive, frequency-dependent contribution to cochlear filtering that is independent of basilar membrane filtering. These data argue that passive mechanics within the organ of Corti sharpen frequency selectivity by defining which OHCs enhance the vibration of the basilar membrane, thereby tuning the gain of cochlear amplification. SIGNIFICANCE STATEMENT: Outer hair cells amplify the traveling wave within the mammalian cochlea. The resultant gain and frequency sharpening are necessary for speech discrimination, particularly in the presence of background noise. Here we measured the 2-D motion of the organ of Corti in mice and found that the structures that stimulate the outer hair cell stereocilia, the tectorial membrane and reticular lamina, were sharply tuned in the radial direction. Radial tuning was similar in dead mice and in mice lacking a tectorial membrane. This suggests that radial tuning comes from passive mechanics within the hair cell epithelium, and that these mechanics, at least in part, may tune the gain of cochlear amplification.

Vibration of the organ of Corti within the cochlear apex in mice.

The tonotopic map of the mammalian cochlea is commonly thought to be determined by the passive mechanical properties of the basilar membrane. The other tissues and cells that make up the organ of Corti also have passive mechanical properties; however, their roles are less well understood. In addition, active forces produced by outer hair cells (OHCs) enhance the vibration of the basilar membrane, termed cochlear amplification. Here, we studied how these biomechanical components interact using optical coherence tomography, which permits vibratory measurements within tissue. We measured not only classical basilar membrane tuning curves, but also vibratory responses from the rest of the organ of Corti within the mouse cochlear apex in vivo. As expected, basilar membrane tuning was sharp in live mice and broad in dead mice. Interestingly, the vibratory response of the region lateral to the OHCs, the "lateral compartment," demonstrated frequency-dependent phase differences relative to the basilar membrane. This was sharply tuned in both live and dead mice. We then measured basilar membrane and lateral compartment vibration in transgenic mice with targeted alterations in cochlear mechanics. Prestin(499/499), Prestin(-/-), and Tecta(C1509G/C1509G) mice demonstrated no cochlear amplification but maintained the lateral compartment phase difference. In contrast, Sfswap(Tg/Tg) mice maintained cochlear amplification but did not demonstrate the lateral compartment phase difference. These data indicate that the organ of Corti has complex micromechanical vibratory characteristics, with passive, yet sharply tuned, vibratory characteristics associated with the supporting cells. These characteristics may tune OHC force generation to produce the sharp frequency selectivity of mammalian hearing.

Quantitative imaging of cochlear soft tissues in wild-type and hearing-impaired transgenic mice by spectral domain optical coherence tomography.

Human hearing loss often occurs as a result of damage or malformations to the functional soft tissues within the cochlea, but these changes are not appreciable with current medical imaging modalities. We sought to determine whether optical coherence tomography (OCT) could assess the soft tissue structures relevant to hearing using mouse models. We imaged excised cochleae with an altered tectorial membrane and during normal development. The soft tissue structures and expected anatomical variations were visible using OCT, and quantitative measurements confirmed the ability to detect critical changes relevant to hearing.

[Cost-effectiveness study of internist joint practices]. / Kosten- und Ertragsanalyse internistischer Gemeinschaftspraxen.

BACKGROUND AND PURPOSE: Practicing doctors are managers of their own practice. A doctor, who manages his practice besides his technical qualification, considering business aspects, enables a solid economic base. The objective of this article is to point out key starting points for an effective management of internist doctors' practices. MATERIAL AND METHODS: Within the article it has particularly been analyzed, to what extent cooperations make an impact on the return and cost structure. For this purpose, a total of 495 business assessments from the DATEV eG of internist doctors' practices have been analyzed. RESULTS: The percental returns of smaller internistic joint practices (averaged turnover: 573,071 Euros) is about 6% higher than the percental returns of internistic doctors' practices (averaged turnover: 384,049 Euros). This result shows that small internistic joint practices work more efficiently. In contrast to this result bigger joint practices (averaged turnover: 1,618,608 Euros) gain an about 6% lower percental return than internistic doctors' practices. The reasons for this result are, compared to the internistic doctors' practices, the higher consumption of materials (+7%), the higher personnel costs (+3.5%), and the higher occupancy costs (+0.2%). On the basis of these results it can be concluded, that medium-sized internistic joint practices work more efficiently than internistic doctors' practices as well as large internistic joint practices. CONCLUSION: On the basis of the results it can be concluded, that internist cooperations can make good economic sense. However, the extent of cost efficiency and profit increase is particularly dependent on the size of the practice, the offered service portfolio, and the human resource management.

ELHnet: a convolutional neural network for classifying cochlear endolymphatic hydrops imaged with optical coherence tomography.

Detection of endolymphatic hydrops is important for diagnosing Meniere's disease, and can be performed non-invasively using optical coherence tomography (OCT) in animal models as well as potentially in the clinic. Here, we developed ELHnet, a convolutional neural network to classify endolymphatic hydrops in a mouse model using learned features from OCT images of mice cochleae. We trained ELHnet on 2159 training and validation images from 17 mice, using only the image pixels and observer-determined labels of endolymphatic hydrops as the inputs. We tested ELHnet on 37 images from 37 mice that were previously not used, and found that the neural network correctly classified 34 of the 37 mice. This demonstrates an improvement in performance from previous work on computer-aided classification of endolymphatic hydrops. To the best of our knowledge, this is the first deep CNN designed for endolymphatic hydrops classification.

High-speed spectral calibration by complex FIR filter in phase-sensitive optical coherence tomography.

Swept-laser sources offer a number of advantages for Phase-sensitive Optical Coherence Tomography (PhOCT). However, inter- and intra-sweep variability leads to calibration errors that adversely affect phase sensitivity. While there are several approaches to overcoming this problem, our preferred method is to simply calibrate every sweep of the laser. This approach offers high accuracy and phase stability at the expense of a substantial processing burden. In this approach, the Hilbert phase of the interferogram from a reference interferometer provides the instantaneous wavenumber of the laser, but is computationally expensive. Fortunately, the Hilbert transform may be approximated by a Finite Impulse-Response (FIR) filter. Here we explore the use of several FIR filter based Hilbert transforms for calibration, explicitly considering the impact of filter choice on phase sensitivity and OCT image quality. Our results indicate that the complex FIR filter approach is the most robust and accurate among those considered. It provides similar image quality and slightly better phase sensitivity than the traditional FFT-IFFT based Hilbert transform while consuming fewer resources in an FPGA implementation. We also explored utilizing the Hilbert magnitude of the reference interferogram to calculate an ideal window function for spectral amplitude calibration. The ideal window function is designed to carefully control sidelobes on the axial point spread function. We found that after a simple chromatic correction, calculating the window function using the complex FIR filter and the reference interferometer gave similar results to window functions calculated using a mirror sample and the FFT-IFFT Hilbert transform. Hence, the complex FIR filter can enable accurate and high-speed calibration of the magnitude and phase of spectral interferograms.

Hair cell force generation does not amplify or tune vibrations within the chicken basilar papilla.

Frequency tuning within the auditory papilla of most non-mammalian species is electrical, deriving from ion-channel resonance within their sensory hair cells. In contrast, tuning within the mammalian cochlea is mechanical, stemming from active mechanisms within outer hair cells that amplify the basilar membrane travelling wave. Interestingly, hair cells in the avian basilar papilla demonstrate both electrical resonance and force-generation, making it unclear which mechanism creates sharp frequency tuning. Here, we measured sound-induced vibrations within the apical half of the chicken basilar papilla in vivo and found broadly-tuned travelling waves that were not amplified. However, distortion products were found in live but not dead chickens. These findings support the idea that avian hair cells do produce force, but that their effects on vibration are small and do not sharpen tuning. Therefore, frequency tuning within the apical avian basilar papilla is not mechanical, and likely derives from hair cell electrical resonance.

In vivo vibrometry inside the apex of the mouse cochlea using spectral domain optical coherence tomography.

Sound transduction within the auditory portion of the inner ear, the cochlea, is a complex nonlinear process. The study of cochlear mechanics in large rodents has provided important insights into cochlear function. However, technological and experimental limitations have restricted studies in mice due to their smaller cochlea. These challenges are important to overcome because of the wide variety of transgenic mouse strains with hearing loss mutations that are available for study. To accomplish this goal, we used spectral domain optical coherence tomography to visualize and measure sound-induced vibrations of intracochlear tissues. We present, to our knowledge, the first vibration measurements from the apex of an unopened mouse cochlea.

Prestin regulation and function in residual outer hair cells after noise-induced hearing loss.

The outer hair cell (OHC) motor protein prestin is necessary for electromotility, which drives cochlear amplification and produces exquisitely sharp frequency tuning. Tecta(C1509G) transgenic mice have hearing loss, and surprisingly have increased OHC prestin levels. We hypothesized, therefore, that prestin up-regulation may represent a generalized response to compensate for a state of hearing loss. In the present study, we sought to determine the effects of noise-induced hearing loss on prestin expression. After noise exposure, we performed cytocochleograms and observed OHC loss only in the basal region of the cochlea. Next, we patch clamped OHCs from the apical turn (9-12 kHz region), where no OHCs were lost, in noise-exposed and age-matched control mice. The non-linear capacitance was significantly higher in noise-exposed mice, consistent with higher functional prestin levels. We then measured prestin protein and mRNA levels in whole-cochlea specimens. Both Western blot and qPCR studies demonstrated increased prestin expression after noise exposure. Finally, we examined the effect of the prestin increase in vivo following noise damage. Immediately after noise exposure, ABR and DPOAE thresholds were elevated by 30-40 dB. While most of the temporary threshold shifts recovered within 3 days, there were additional improvements over the next month. However, DPOAE magnitudes, basilar membrane vibration, and CAP tuning curve measurements from the 9-12 kHz cochlear region demonstrated no differences between noise-exposed mice and control mice. Taken together, these data indicate that prestin is up-regulated by 32-58% in residual OHCs after noise exposure and that the prestin is functional. These findings are consistent with the notion that prestin increases in an attempt to partially compensate for reduced force production because of missing OHCs. However, in regions where there is no OHC loss, the cochlea is able to compensate for the excess prestin in order to maintain stable auditory thresholds and frequency discrimination.

Mechanisms of hearing loss after blast injury to the ear.

Given the frequent use of improvised explosive devices (IEDs) around the world, the study of traumatic blast injuries is of increasing interest. The ear is the most common organ affected by blast injury because it is the body's most sensitive pressure transducer. We fabricated a blast chamber to re-create blast profiles similar to that of IEDs and used it to develop a reproducible mouse model to study blast-induced hearing loss. The tympanic membrane was perforated in all mice after blast exposure and found to heal spontaneously. Micro-computed tomography demonstrated no evidence for middle ear or otic capsule injuries; however, the healed tympanic membrane was thickened. Auditory brainstem response and distortion product otoacoustic emission threshold shifts were found to be correlated with blast intensity. As well, these threshold shifts were larger than those found in control mice that underwent surgical perforation of their tympanic membranes, indicating cochlear trauma. Histological studies one week and three months after the blast demonstrated no disruption or damage to the intra-cochlear membranes. However, there was loss of outer hair cells (OHCs) within the basal turn of the cochlea and decreased spiral ganglion neurons (SGNs) and afferent nerve synapses. Using our mouse model that recapitulates human IED exposure, our results identify that the mechanisms underlying blast-induced hearing loss does not include gross membranous rupture as is commonly believed. Instead, there is both OHC and SGN loss that produce auditory dysfunction.