Investigating the optimal stimulus to evoke the binaural interaction component of the auditory brainstem response.

Objective assessment of spatial and binaural hearing deficits remains a major clinical challenge. The binaural interaction component (BIC) of the auditory brainstem response (ABR) holds promise as a non-invasive biomarker for diagnosing such deficits. However, while comparative studies have reported robust BIC in animal models, BIC in humans can sometimes be unreliably evoked even in subjects with normal hearing. Here we explore the hypothesis that the standard methodology for collecting monaural ABRs may not be ideal for electrophysiological assessment of binaural hearing. This study aims to improve ABR BIC measurements by determining more optimal stimuli to evoke it. Building on previous methodology demonstrated to enhance peak amplitude of monaural ABRs, we constructed a series of level-dependent chirp stimuli based on empirically derived latencies of monaural-evoked ABR waves I, IV and the binaural-evoked BIC DN1, the most prominent BIC peak, in a cohort of ten chinchillas. We hypothesized that chirps designed based on BIC DN1 latency would specifically enhance across-frequency temporal synchrony in the afferent inputs leading to the binaural circuits that produce the BIC and would thus produce a larger DN1 than either traditional clicks or chirps designed to optimize monaural ABRs. Compared to clicks, we found that level-specific chirp stimuli evoked significantly greater BIC DN1 amplitudes, and that this effect persisted across all stimulation levels tested. However, we found no significant differences between BICs resulting from chirps created using binaural-evoked BIC DN1 latencies and those using monaural-evoked ABR waves I or IV. These data indicate that existing level-specific, monaural-based chirp stimuli may improve BIC detectability and reduce variability in human BIC measurements.

A simplified methodology for the activation of organic charcoal.

One in three people globally are challenged to live on hazardous, unsanitary water, and this relates to higher risks of death and development of diseases. According to scientific research, activated charcoal can be used to clean water contaminants to help make water safer.•Carbonization: this study demonstrates an inexpensive method of producing activated charcoal that can be performed in any setting using locally available biomass materials.•Activation: thermal air oxidation between moderate temperatures of 450-550 °C. Our data indicate that this technique produces charcoal with an adsorptive capacity near to that of commercial-grade charcoal as demonstrated by spectrophotometric analysis. This simple approach to charcoal activation may benefit rural communities where sources of sanitary water are low or nonexistent.

Comparative morphology of the avian bony columella.

In birds, the columella is the only bony element of the sound conducting apparatus, conveying vibrations of the cartilaginous extracolumella to the fluid of the inner ear. Although avian columellar morphology has attracted some attention over the past century, it nonetheless remains poorly described in the literature. The few existing studies mostly focus on morphological descriptions in relatively few taxa, with no taxonomically broad surveys yet published. Here we use observations of columellae from 401 extant bird species to provide a comprehensive survey of columellar morphology in a phylogenetic context. We describe the columellae of several taxa for the first time and identify derived morphologies characterizing higher-level clades based on current phylogenies. In particular, we identify a derived columellar morphology diagnosing a major subclade of Accipitridae. Within Suliformes, we find that Fregatidae, Sulidae, and Phalacrocoracidae share a derived morphology that is absent in Anhingidae, suggesting a secondary reversal. Phylogenetically informed comparisons allow recognition of instances of homoplasy, including the distinctive bulbous columellae in suboscine passerines and taxa belonging to Eucavitaves, and bulging footplates that appear to have evolved at least twice independently in Strigiformes. We consider phylogenetic and functional factors influencing avian columellar morphology, finding that aquatic birds possess small footplates relative to columellar length, possibly related to hearing function in aquatic habitats. By contrast, the functional significance of the distinctive bulbous basal ends of the columellae of certain arboreal landbird taxa remains elusive.

Using Stapes Velocity to Estimate the Efficacy of Mechanical Stimulation of the Round Window With an Active Middle Ear Implant.

OBJECTIVE: To test a method to measure the efficacy of active middle ear implants when coupled to the round window. METHODS: Data previously published in Koka et al. ( Hear Res 2010;263:128-137) were used in this study. Simultaneous measurements of cochlear microphonics (CM) and stapes velocity in response to both acoustic stimulation (forward direction) and round window (RW) stimulation (reverse direction) with an active middle ear implant (AMEI) were made in seven ears in five chinchillas. For each stimulus frequency, the amplitude of the CM was measured separately as a function of intensity (dB SPL or dB mV). Equivalent vibrational input to the cochlea was determined by equating the acoustic and AMEI-generated CM amplitudes for a given intensity. In the condition of equivalent CM amplitude between acoustic and RW stimulation-generated output, we assume that the same vibrational input to the cochlea was present regardless of the route of stimulation. RESULTS: The measured stapes velocities for equivalent CM output from the two types of input were not significantly different for low and medium frequencies (0.25-4 kHz); however, the velocities for AMEI-RW drive were significantly lower for higher frequencies (4-14 kHz). Thus, for RM stimulation with an AMEI, stapes velocities can underestimate the mechanical input to the cochlea by ~20 dB for frequencies greater than ~4 kHz. CONCLUSIONS: This study confirms that stapes velocity (with the assumption of equivalent stapes velocity for forward and reverse stimulation) cannot be used as a proxy for effective input to the cochlea when it is stimulated in the reverse direction. Future research on application of intraoperative electrophysiological measurements during surgery (CM, compound action potential, or auditory brainstem response) for estimating efficacy and optimizing device coupling and performance is warranted.

The acoustical effect of the neck frill of the frill-necked lizard (Chlamydosaurus kingii).

Animals localise sound by making use of acoustical cues resulting from space and frequency dependent filtering of sound by the head and body. Sound arrives at each ear at different times, with different intensities, and with varying spectral content, all of which are affected by the animal's head and the relative sound source position. Location cues in mammals benefit from structures (pinnae) that modify these cues and provide information that helps resolve the cone of confusion and provide cues to sound source elevation. Animals without pinnae must rely on other mechanisms to solve localisation problems. Most non-mammals lack pinna-like structures, but some possess other anatomical features that could influence hearing. One such animal is the frill-necked lizard (Chlamydosaurus kingii). The species' elaborate neck frill has been speculated to act as an aid to hearing, but no acoustical measurements have been reported. In this study, we characterise the frill's influence on the acoustical information available to the animal. Results suggest that the change in binaural cues is not sufficiently large to impact localisation behavior within the species' likely audiometric range; however, the frill does increase gain for sounds directly in front of the animal similar to a directional microphone.

Auditory brainstem development of naked mole-rats (Heterocephalus glaber).

Life underground often leads to animals having specialized auditory systems to accommodate the constraints of acoustic transmission in tunnels. Despite living underground, naked mole-rats use a highly vocal communication system, implying that they rely on central auditory processing. However, little is known about these animals' central auditory system, and whether it follows a similar developmental time course as other rodents. Naked mole-rats show slowed development in the hippocampus suggesting they have altered brain development compared to other rodents. Here, we measured morphological characteristics and voltage-gated potassium channel Kv3.3 expression and protein levels at different key developmental time points (postnatal days 9, 14, 21 and adulthood) to determine whether the auditory brainstem (lateral superior olive and medial nucleus of the trapezoid body) develops similarly to two common auditory rodent model species: gerbils and mice. Additionally, we measured the hearing onset of naked mole-rats using auditory brainstem response recordings at the same developmental timepoints. In contrast with other work in naked mole-rats showing that they are highly divergent in many aspects of their physiology, we show that naked mole-rats have a similar hearing onset, between postnatal day (P) 9 and P14, to many other rodents. On the other hand, we show some developmental differences, such as a unique morphology and Kv3.3 protein levels in the brainstem.

What Next After MBSR/MBCT? An Open Trial of an 8-Week Follow-on Program Exploring Mindfulness of Feeling Tone (vedana).

Objectives: The effectiveness of mindfulness-based programs (MBPs) has been established in many randomized controlled trials. However, effect sizes are often modest, and there remains ample scope to improve their effectiveness. One approach to this challenge is to offer a "follow-on" course to people who have completed an MBP and are interested in further skill development. We developed and tested a new 8-week course for this purpose based on awareness of feeling tone (vedana), an understudied aspect of mindfulness in many current MBPs, incorporating new developments in neuroscience and trauma sensitivity. We examined its effectiveness and the frequency and severity of unpleasant experience and harm. Methods: In an open trial, 83 participants, 78 of whom had previously taken part in an MBP (majority MBSR or MBCT), completed the program in nine groups. Participants completed questionnaires before and after and gave qualitative written feedback at completion. Results: Participants reported significantly reduced depression (d = 0.56), stress (d = 0.36), and anxiety (d = 0.53) and increased well-being (d = 0.54) and mindfulness (d = 0.65) with 38% meeting criteria for reliable change on anxiety and depression. As expected, about three-quarters of participants reported some unpleasant experiences associated with mindfulness practice during the course, but none reported harm. Five participants showed "reliable deterioration" (an increase) in either depression or anxiety, but four of these five also gave anonymous qualitative feedback describing benefits of the course. Conclusions: Findings support the added value of a follow-on course based on the exploration of feeling tone for participants who have a range of previous mindfulness experience. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-01929-0.

The Binaural Interaction Component in Rhesus Macaques (Macaca mulatta).

The binaural interaction component (BIC) is a sound-evoked electrophysiological signature of binaural processing in the auditory brainstem that has received attention as a potential biomarker for spatial hearing deficits. Yet the number of trials necessary to evoke the BIC, or its measurability, seems to vary across species: while it is easily measured in small rodents, it has proven to be highly variable and less reliably measured in humans. This has hindered its potential use as a diagnostic tool. Further measurements of the BIC across a wide range of species could help us better understand its origin and the possible reasons for the variation in its measurability. Statistical analysis on the function relating BIC DN1 amplitude and the interaural time difference has been performed in only a few small rodent species, thus it remains to be shown how the results apply to more taxonomically diverse mammals, and those with larger heads. To fill this gap, we measured BICs in rhesus macaque. We show the overall behavior of the BIC is the same as in smaller rodents, suggesting that the brainstem circuit responsible for the BIC is conserved across a wider range of mammals. We suggest that differences in measurability are likely because of differences in head size.

Chest x-ray vs. computed tomography of the chest in pediatric blunt trauma.

INTRODUCTION: Chest x-ray (CXR) has been shown to be an effective detection tool for clinically significant trauma. We evaluated differences in findings between CXR and computed tomography of the chest (CCT), their impact on clinical management and the performance of the CXR. METHODS: This retrospective study examined children (less than 18 years) who received a CXR and CCT between 2009 and 2015. We compared characteristics of children by conducting univariate analysis, reporting the proportion of additional diagnoses captured by CCT, and using it to evaluate the sensitivity and specificity of the CXR. Outcome variables were diagnoses made by CCT as well as the ensuing changes in the clinical management attributable to the diagnoses reported by the CCT and not observed by the CXR. RESULTS: In 1235 children, CCT was associated with diagnosing higher proportions of contusion or atelectasis (60% vs 31%; p < .0001), pneumothorax (23% vs 9%; p < .0001), rib fracture (18% vs 7%; p < .0001), other fracture (20% vs 10%; p < .0001), diaphragm rupture (0.2% vs 0.1%; p = .002), and incidental findings (7% vs 2%; p < .0001) as compared to CXR. CCT findings changed the management of 107 children (8.7%) with 32 (2.6%) of the changes being surgical procedures. The overall sensitivity and specificity of the CXR were 57.9% (95% CI: 54.5-61.2) and 90.2% (95% CI: 86.8-93.1), respectively. The positive predictive value and negative predictive value were 93.1% and 48.6%, respectively. CONCLUSION: CXR is a useful initial screening tool to evaluate pediatric trauma patients along with clinical presentation in the Emergency Department in children. LEVEL OF EVIDENCE: Level III, diagnostic test.

A comparative study of avian middle ear mechanics.

Sound and hearing play an important role in the lives of many birds, and studies have been published on the acoustic habitat of various species, as well as on various aspects of their hearing system. However the function of the middle ear remains largely unexplored, with existing studies focusing on either single species, or a very narrow range of species. In this article we report measurements of the middle ear transfer function in 39 taxonomically diverse avian species. We used laser vibrometry to measure the vibrations of the columellar footplate in response to tones played in each animal's ear canal, and calculated the middle ear transfer functions. Transfer functions varied substantially across species, but appeared to follow common trends. Comparisons between the peak frequency in the transfer function and length/mass of the columella reveal a correlation between the three, however statistical analysis suggests that columellar length is a primary indicator of the peak frequency. These results provide a broad survey of avian middle ear function, and the observed trends provide a method with which to begin to predict the response of single ossicle middle ear systems.

Scaling of the avian middle ear.

This article presents a comparative study of morphology of the avian middle ear. The general morphology of the columella shows considerable variation across species, yet few studies have attempted to provide quantitative comparisons, and basic anatomical data has not been thoroughly reported. In this study, we examined the middle ear in 49 taxonomically diverse species of bird. We found significant correlations between measurements of several features (columellar length, mass, tympanic membrane area, footplate area) and interaural diameter. While scaling of columellar length with interaural diameter is consistent with isometry, masses and areas showed negative allometry, or a non-proportional scaling with interaural diameter. These observations remained true even for species with unusual middle ear morphology, such as Alcedinidae (Kingfishers) in which the basal struts of the columella form a structure almost resembling a mammalian stapes, or Tytonidae (Barn Owls) which have a highly bulbous footplate. It therefore appears that allometry cannot help explain the morphological variation in the columella.

Characterizing Insertion Pressure Profiles During Cochlear Implantation: Simultaneous Fluoroscopy and Intracochlear Pressure Measurements.

BACKGROUND: Combined electrical-acoustical stimulation (EAS) has gained popularity as patients with residual hearing are increasingly undergoing cochlear implantation. Preservation of residual hearing correlates with hearing outcomes, but loss of hearing occurs in a subset of these patients. Several mechanisms have been proposed as causing this hearing loss; we have previously described high amplitude pressure transients, equivalent to high-level noise exposures, in the inner ear during electrode insertion. The source of these transients has not been identified. METHODS: Cadaveric human heads were prepared with an extended facial recess. Fiber-optic pressure sensors were inserted into the scala vestibuli and scala tympani to measure intracochlear pressures. Two cochlear implant (CI) electrode styles (straight and perimodiolar) were inserted during time-synced intracochlear pressures and video fluoroscopy measurements. RESULTS: CI electrode insertions produced pressure transients in the cochlea up to 160 to 170 dB pSPL equivalent for both styles, consistent with previous results. However, the position of the electrode within the cochlea when transients were generated differed (particularly contact with the medial or lateral walls). CONCLUSIONS: These results begin to elucidate the insertion pressure profiles of CI electrodes, which can be used to improve CI electrode designs and facilitate "silent-insertions" to improve chances of hearing preservation.

Intracochlear pressure in response to high intensity, low frequency sounds in chinchilla.

Exposure to high intensity (blast) sounds can result in both conductive and sensorineural damage to hearing. This includes rupture of the tympanic membrane and dislocation of the middle ear ossicles, as well as damage to the inner and outer hair cells in the cochlea. A clearer understanding of how the hearing system responds to blast could help us better prevent auditory trauma, and support those who have been exposed to such sounds. Chinchillas are often used in studies of hearing due to the similarity between the chinchilla and human audiograms. The suitability of their use in research on auditory trauma from blast noise will depend on the extent to which cochlear pressures generated in chinchillas compare to those in humans. In order to gain a more detailed understanding of the response of the ear to high intensity sounds, a custom built sound concentrating horn was used to expose chinchilla cadaveric ears to a series of single frequency tones between 10 and 1280 Hz, with varying intensities from 90 to 194 dB SPL while intracochlear pressures were measured simultaneously in the scala vestibuli and scala tympani. These results were then compared to similar, previously published data from human cadavers. In both human and chinchillas, intracochlear pressures increased with applied sound pressure up to about 120 dB SPL, but began to saturate at higher intensities. The exact saturation point and the saturation pressures showed a strong frequency dependence. Intracochlear pressure magnitudes in chinchillas show some similarities with those measured in humans, but also significant differences, particularly at very high intensity levels such as those found in a blast. These differences should be taken into account when conducting blast studies in chinchillas.

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Intertumoral Heterogeneity within Medulloblastoma Subgroups.

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Spatial heterogeneity in medulloblastoma.

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Intraoperative assessment of ossicular fixation.

Determining the degree of ossicular fixation is a difficult task, with the final assessment often being made with manual palpation during exploratory tympanotomy. A more objective method to evaluate ossicular fixation would be valuable. In this paper we describe a new method which makes use of a magnet and coil to measure ossicular motion through the ear canal with an elevated tympanic membrane. We report measurements of the vibration response at the umbo, the tip of the incus long process and the lateral posterior crus of the stapes before and after artificially fixing the stapes footplate and anterior mallear ligament with luting cement. Results were obtained on temporal bones, but the practicality of the method allows easy clinical implementation. Velocity ratios between different measurement points along the ossicular chain may provide a quantitative indication of the degree of stapes fixation. Isolated anterior mallear ligament fixation was not distinguishable from the unfixed condition.

Divergent clonal selection dominates medulloblastoma at recurrence.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.