Posture, Gait, Quality of Life, and Hearing with a Vestibular Implant.

BACKGROUND: Bilateral vestibular hypofunction is associated with chronic disequilibrium, postural instability, and unsteady gait owing to failure of vestibular reflexes that stabilize the eyes, head, and body. A vestibular implant may be effective in alleviating symptoms. METHODS: Persons who had had ototoxic (7 participants) or idiopathic (1 participant) bilateral vestibular hypofunction for 2 to 23 years underwent unilateral implantation of a prosthesis that electrically stimulates the three semicircular canal branches of the vestibular nerve. Clinical outcomes included the score on the Bruininks-Oseretsky Test of Motor Proficiency balance subtest (range, 0 to 36, with higher scores indicating better balance), time to failure on the modified Romberg test (range, 0 to 30 seconds), score on the Dynamic Gait Index (range, 0 to 24, with higher scores indicating better gait performance), time needed to complete the Timed Up and Go test, gait speed, pure-tone auditory detection thresholds, speech discrimination scores, and quality of life. We compared participants' results at baseline (before implantation) with those at 6 months (8 participants) and at 1 year (6 participants) with the device set in its usual treatment mode (varying stimulus pulse rate and amplitude to represent rotational head motion) and in a placebo mode (holding pulse rate and amplitude constant). RESULTS: The median scores at baseline and at 6 months on the Bruininks-Oseretsky test were 17.5 and 21.0, respectively (median within-participant difference, 5.5 points; 95% confidence interval [CI], 0 to 10.0); the median times on the modified Romberg test were 3.6 seconds and 8.3 seconds (difference, 5.1; 95% CI, 1.5 to 27.6); the median scores on the Dynamic Gait Index were 12.5 and 22.5 (difference, 10.5 points; 95% CI, 1.5 to 12.0); the median times on the Timed Up and Go test were 11.0 seconds and 8.7 seconds (difference, 2.3; 95% CI, -1.7 to 5.0); and the median speeds on the gait-speed test were 1.03 m per second and 1.10 m per second (difference, 0.13; 95% CI, -0.25 to 0.30). Placebo-mode testing confirmed that improvements were due to treatment-mode stimulation. Among the 6 participants who were also assessed at 1 year, the median within-participant changes from baseline to 1 year were generally consistent with results at 6 months. Implantation caused ipsilateral hearing loss, with the air-conducted pure-tone average detection threshold at 6 months increasing by 3 to 16 dB in 5 participants and by 74 to 104 dB in 3 participants. Changes in participant-reported disability and quality of life paralleled changes in posture and gait. CONCLUSIONS: Six months and 1 year after unilateral implantation of a vestibular prosthesis for bilateral vestibular hypofunction, measures of posture, gait, and quality of life were generally in the direction of improvement from baseline, but hearing was reduced in the ear with the implant in all but 1 participant. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02725463.).

Sex and Race Representation in Temporal Bone Histopathology Studies in the United States: A Systematic Review.

OBJECTIVES: The author's objective was to evaluate sex and race representation in temporal bone histopathology studies. DESIGN: PubMed, Embase, Cochrane, Web of Science, and Scopus were searched for studies written in English examining temporal bone histopathology specimens from U.S.-based institutions from January 1, 1947, to September 1, 2021. Two authors then performed "snowballing" by reviewing references from the initial search and included the studies that fulfilled the inclusion criteria. For each study, the following information was collected: publication details, study design, funding, institution from where temporal bone specimens were procured, number of study specimens, and donor demographical information. RESULTS: The authors found that out of 300 studies, 166 (55%) report sex while only 15 (5%) reported race information. Over the past 70 years, the ratio of studies reporting sex to those that do not has increased from 1.00 to 2.19 and the number of female temporal bone histopathology subjects relative to male has increased from 0.67 to 0.75. Over 90% of studies that do report this information feature participant racial compositions that do not reflect the diversity of the U.S. population. CONCLUSIONS: Studies of temporal bone histopathology often do not report participant sex or race. The reporting of participant sex and the inclusion of specimens from female donors have both increased over time. However, temporal bone histopathology study cohorts are not representative of the racial diversity of the U.S. population. The otolaryngology community must strive to build temporal bone histopathology libraries that are representative of the diverse U.S. population.

Three-Dimensional High-Resolution Temporal Bone Histopathology Identifies Areas of Vascular Vulnerability in the Inner Ear.

OBJECTIVES: Hypothesized causes of vestibular neuritis/labyrinthitis include neuroinflammatory or vascular disorders, yet vascular disorders of the inner ear are poorly understood. Guided by known microvascular diseases of the retina, we developed 2 hypotheses: (1) there exist vascular vulnerabilities of artery channels in cases of hypothetical nerve swelling for the superior, inferior, and vestibulocochlear artery and (2) there are arteriovenous crossings that could compromise vascular flow in disease states. METHODS: Two fully mounted and stained temporal bones were used to render three-dimensional reconstructions of the labyrinth blood supply. Using these maps, areas of potential vascular compression were quantified in 50 human temporal bones. RESULTS: Although inner ear arteries and veins mostly travel within their own bony channels, they may be exposed (1) at the entrance into the otic capsule, and (2) where the superior vestibular vein crosses the inferior vestibular artery. At the entry into the otic capsule, the ratio of the soft tissue to total space for the superior vestibular artery was significantly greater than the inferior vestibular artery/cochleovestibular artery (median 44, interquartile range 34-55 vs. 14 [9-17], p < 0.0001). CONCLUSIONS: Three-dimensional reconstruction of human temporal bone histopathology can guide vascular studies of the human inner ear. Studies of retinal microvascular disease helped identify areas of vascular vulnerability in cases of hypothetical nerve swelling at the entrance into the otic capsule and at an arteriovenous crossing near the saccular macula. These data may help explain patterns of clinical findings in peripheral vestibular lesions.

Medical interventions for chronic rhinosinusitis in cystic fibrosis.

BACKGROUND: Chronic rhinosinusitis frequently occurs in people with cystic fibrosis. Several medical interventions are available for treating chronic rhinosinusitis in people with cystic fibrosis; for example, different concentrations of nasal saline irrigations, topical or oral corticosteroids, antibiotics - including nebulized antibiotics - dornase alfa and modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) (such as lumacaftor, ivacaftor or tezacaftor). However, the efficacy of these interventions is unclear. This is an update of a previously published review. OBJECTIVES: The objective of this review is to compare the effects of different medical interventions in people diagnosed with cystic fibrosis and chronic rhinosinusitis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search of trials register: 09 September 2021. We also searched ongoing trials databases, other medical databases and the reference lists of relevant articles and reviews. Date of latest additional searches: 22 November 2021. SELECTION CRITERIA: Randomized and quasi-randomized trials of different medical interventions compared to each other or to no intervention or to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials identified for potential inclusion in the review. We planned to conduct data collection and analysis in accordance with Cochrane methods and to independently rate the quality of the evidence for each outcome using the GRADE guidelines. MAIN RESULTS: We identified no trials that met the pre-defined inclusion criteria. The most recent searches identified 44 new references, none of which were eligible for inclusion in the current version of this review; 12 studies are listed as excluded and one as ongoing. AUTHORS' CONCLUSIONS: We identified no eligible trials assessing the medical interventions in people with cystic fibrosis and chronic rhinosinusitis. High-quality trials are needed which should assess the efficacy of different treatment options detailed above for managing chronic rhinosinusitis, preventing pulmonary exacerbations and improving quality of life in people with cystic fibrosis.

Functional Analysis of Calcium-Sensing Receptor Variants Identified in Families Provisionally Diagnosed with Familial Hypocalciuric Hypercalcaemia.

Identification of variants in the calcium-sensing receptor (CASR) gene is an important means of distinguishing between familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism. However, identification and bioinformatics analysis of genetic variants alone is now considered insufficient as definitive proof; additional functional assessment is required to diagnose FHH with certainty. We identified two novel variants, D433Y and C739Y, and one previously reported variant G509R in the CASR of four kindreds provisionally diagnosed with FHH and aimed to functionally characterise these variants to confirm the diagnosis. Variant receptors were cloned as FLAG-tagged constructs into the mammalian expression vector, pcDNA3.1. Wild type and variant receptor constructs were expressed in HEK293 cells and their expression assessed by Western blot analysis and their functionality analysed using an IP-One assay which measures myo-inositol 1-phosphate accumulation following CaSR activation. Western blot analysis showed that the D433Y receptor had diminished mature glycosylated receptor compared with wild type CaSR whereas the G509R receptor had a complete lack of mature receptor. The C739Y receptor was consistently overexpressed. Functional assessment showed the D433Y receptor to be mildly inactivating at physiological calcium concentrations whereas the G509R receptor was inactive at all calcium concentrations. By contrast, the C739Y variant was activating compared to wild type receptor which is inconsistent with it causing FHH. We conclude that functional assessment of CaSR variants using the IP-One assay was useful in the investigation of suspected FHH probands, confirming the D433Y and G509R variants as likely pathogenic/pathogenic, but dismissing the C739Y variant as causing FHH.

A decade of magnetic vestibular stimulation: from serendipity to physics to the clinic.

For many years, people working near strong static magnetic fields of magnetic resonance imaging (MRI) machines have reported dizziness and sensations of vertigo. The discovery a decade ago that a sustained nystagmus can be observed in all humans with an intact labyrinth inside MRI machines led to a possible mechanism: a Lorentz force occurring in the labyrinth from the interactions of normal inner ear ionic currents and the strong static magnetic fields of the MRI machine. Inside an MRI, the Lorentz force acts to induce a constant deflection of the semicircular canal cupula of the superior and lateral semicircular canals. This inner ear stimulation creates a sensation of rotation, and a constant horizontal/torsional nystagmus that can only be observed when visual fixation is removed. Over time, the brain adapts to both the perception of rotation and the nystagmus, with the perception usually diminishing over a few minutes, and the nystagmus persisting at a reduced level for hours. This observation has led to discoveries about how the central vestibular mechanisms adapt to a constant vestibular asymmetry and is a useful model of set-point adaptation or how homeostasis is maintained in response to changes in the internal milieu or the external environment. We review what is known about the effects of stimulation of the vestibular system with high-strength magnetic fields and how the understanding of the mechanism has been refined since it was first proposed. We suggest future ways that magnetic vestibular stimulation might be used to understand vestibular disease and how it might be treated.

Medical interventions for chronic rhinosinusitis in cystic fibrosis.

BACKGROUND: Chronic rhinosinusitis frequently occurs in people with cystic fibrosis. Several medical interventions are available for treating chronic rhinosinusitis in people with cystic fibrosis; for example, different concentrations of nasal saline irrigations, topical or oral corticosteroids, antibiotics - including nebulized antibiotics, dornase alfa and modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) (such as lumacaftor, ivacaftor or tezacaftor). However, the efficacy of these interventions is unclear. OBJECTIVES: The objective of this review is to compare the effects of different medical interventions in people diagnosed with cystic fibrosis and chronic rhinosinusitis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search of trials register: 22 May 2019.We also searched ongoing trials databases, other medical databases and the reference lists of relevant articles and reviews. Date of latest additional searches: 20 May 2019. SELECTION CRITERIA: Randomized and quasi-randomized trials of different medical interventions compared to each other or to no intervention or to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials identified for potential inclusion in the review. We planned to conduct data collection and analysis in accordance with Cochrane methods and to independently rate the quality of the evidence for each outcome using the GRADE guidelines. MAIN RESULTS: We identified no trials that met the pre-defined inclusion criteria. The searches identified 47 trials, none of which were eligible for inclusion in the current version of this review. AUTHORS' CONCLUSIONS: We identified no eligible trials assessing the medical interventions in people with cystic fibrosis and chronic rhinosinusitis. High-quality trials are needed which should assess the efficacy of different treatment options detailed above for managing chronic rhinosinusitis, preventing pulmonary exacerbations and improving quality of life in people with cystic fibrosis.

The endoplasmic reticulum-associated protein, OS-9, behaves as a lectin in targeting the immature calcium-sensing receptor.

The mechanisms responsible for the processing and quality control of the calcium-sensing receptor (CaSR) in the endoplasmic reticulum (ER) are largely unknown. In a yeast two-hybrid screen of the CaSR C-terminal tail (residues 865-1078), we identified osteosarcoma-9 (OS-9) protein as a binding partner. OS-9 is an ER-resident lectin that targets misfolded glycoproteins to the ER-associated degradation (ERAD) pathway through recognition of specific N-glycans by its mannose-6-phosphate receptor homology (MRH) domain. We show by confocal microscopy that the CaSR and OS-9 co-localize in the ER in COS-1 cells. In immunoprecipitation studies with co-expressed OS-9 and CaSR, OS-9 specifically bound the immature form of wild-type CaSR in the ER. OS-9 also bound the immature forms of a CaSR C-terminal deletion mutant and a C677A mutant that remains trapped in the ER, although binding to neither mutant was favored over wild-type receptor. OS-9 binding to immature CaSR required the MRH domain of OS-9 indicating that OS-9 acts as a lectin most likely to target misfolded CaSR to ERAD. Our results also identify two distinct binding interactions between OS-9 and the CaSR, one involving both C-terminal domains of the two proteins and the other involving both N-terminal domains. This suggests the possibility of more than one functional interaction between OS-9 and the CaSR. When we investigated the functional consequences of altered OS-9 expression, neither knockdown nor overexpression of OS-9 was found to have a significant effect on CaSR cell surface expression or CaSR-mediated ERK1/2 phosphorylation.

Gravity dependence of the effect of optokinetic stimulation on the subjective visual vertical.

Accurate and precise estimates of direction of gravity are essential for spatial orientation. According to Bayesian theory, multisensory vestibular, visual, and proprioceptive input is centrally integrated in a weighted fashion based on the reliability of the component sensory signals. For otolithic input, a decreasing signal-to-noise ratio was demonstrated with increasing roll angle. We hypothesized that the weights of vestibular (otolithic) and extravestibular (visual/proprioceptive) sensors are roll-angle dependent and predicted an increased weight of extravestibular cues with increasing roll angle, potentially following the Bayesian hypothesis. To probe this concept, the subjective visual vertical (SVV) was assessed in different roll positions (≤ ± 120°, steps = 30°, n = 10) with/without presenting an optokinetic stimulus (velocity = ± 60°/s). The optokinetic stimulus biased the SVV toward the direction of stimulus rotation for roll angles ≥ ± 30° (P < 0.005). Offsets grew from 3.9 ± 1.8° (upright) to 22.1 ± 11.8° (±120° roll tilt, P < 0.001). Trial-to-trial variability increased with roll angle, demonstrating a nonsignificant increase when providing optokinetic stimulation. Variability and optokinetic bias were correlated (R2 = 0.71, slope = 0.71, 95% confidence interval = 0.57-0.86). An optimal-observer model combining an optokinetic bias with vestibular input reproduced measured errors closely. These findings support the hypothesis of a weighted multisensory integration when estimating direction of gravity with optokinetic stimulation. Visual input was weighted more when vestibular input became less reliable, i.e., at larger roll-tilt angles. However, according to Bayesian theory, the variability of combined cues is always lower than the variability of each source cue. If the observed increase in variability, although nonsignificant, is true, either it must depend on an additional source of variability, added after SVV computation, or it would conflict with the Bayesian hypothesis.NEW & NOTEWORTHY Applying a rotating optokinetic stimulus while recording the subjective visual vertical in different whole body roll angles, we noted the optokinetic-induced bias to correlate with the roll angle. These findings allow the hypothesis that the established optimal weighting of single-sensory cues depending on their reliability to estimate direction of gravity could be extended to a bias caused by visual self-motion stimuli.

Epidemiology of Dizziness and Balance Problems in Children in the United States: A Population-Based Study.

OBJECTIVE: To study national prevalence of dizziness and balance problems in US children and explore associated risk factors and patterns of healthcare utilization. STUDY DESIGN: A multistage, nationally representative, probability sample of children (n = 10,954; aged 3-17 years) was examined based on the 2012 National Health Interview Survey Child Balance Supplement. Parents were asked if during the past year their child was bothered by symptoms of dizziness and balance problems: vertigo (motion sensation), light-headedness/fainting, clumsiness/poor coordination, poor balance/unsteadiness when standing-up or walking, frequent falls, or other dizziness and balance problems. Logistic regression was used to examine associations with sociodemographic information, birth weight, developmental delays, and significant health conditions. RESULTS: Prevalence of dizziness and balance problems was 5.3% (3.3 million US children); females, 5.7%, males, 5.0%. Non-Hispanic white (6.1%) had increased prevalence compared with Hispanic (4.6%) and non-Hispanic black (4.3%) children, P = .01. Prevalence increased with age, from 4.1% for children aged 3-5 years to 7.5% for children aged 15-17 years, P < .001. Even though the majority had symptoms rated as "no problem" or "a small problem," 18.6% (600,000 US children) had symptoms rated as "moderate," "big," or "very big" problems. Overall, 36.0% of children with dizziness and balance problems were seen by healthcare professionals during the past year and 29.9% received treatment. Among children with dizziness and balance problems rated as moderate/big/very big problems, 71.6% had seen healthcare professionals and 62.4% received treatment for dizziness and balance problems. CONCLUSIONS: The risk factors identified provide useful epidemiologic information about dizziness and balance problems in children and will be used in tracking the Healthy People 2020 goal to increase utilization of healthcare services for these children.

Popularizing Surgical Cures: Walter Dandy and the Vestibular Neurectomy for Menière's Disease at the Johns Hopkins Hospital.

OBJECTIVES: To uncover the context that allowed for the vestibular neurectomy to grow in favor and practice at the Johns Hopkins Hospital in the early 20th century, and the reasons for its broad abandonment since. METHODS: The Walter E. Dandy (1905-1946) and Samuel J. Crowe collections (1905-1920) at the Alan Mason Chesney Medical Archives were reviewed, as well as the Samuel J. Crowe and Stacy Guild Temporal Bone Collection. RESULTS: Speculation on the etiology of Menière's disease (MD) has been countless, as have the medical and surgical interventions aimed at treating it. At the Johns Hopkins Hospital, Walter Dandy popularized the neurectomy for MD and performed 692 procedures from 1924 to 1946, believing it to be a curative therapy for vertigo. When he later modified the procedure from a total cranial nerve section to a partial vestibular neurectomy preserving auditory function, surgical candidacy expanded to include nearly any patient with vestibular symptoms. After his passing, trainees' attention shifted to traumatic injuries, likely influenced by WWII. This left the procedure scarcely used until third parties rekindled interest decades later. CONCLUSIONS: Neurectomy as the preferential treatment for MD at the Johns Hopkins Hospital was not driven by pure scientific reasoning but was rather contingent on historical context and sponsorship by a prominent figure like Walter Dandy. Appreciation of MD's natural history has since curtailed the favorability of destructive procedures in preference for conservative management.

Historical Therapies for Suspected Autonomic Dysregulation in Meniere's Disease.

OBJECTIVE: This narrative review examines how speculative belief that the autonomic nervous system causes Meniere's Disease (MD) led otolaryngologists to adopt invasive surgical procedures and medical treatments still offered today. DATA SOURCES: Google Scholar, PubMed. REVIEW METHODS: A comprehensive literature review (1860-2022) was performed using the terms "Meniere AND (sympathetic OR sympathectomy OR vasomotor OR cervical ganglion)," returning 5360 items. All abstracts were briefly reviewed, relevant publications selected for further study, and key articles discussed by all authors. As it became clear that betahistine was related to the historical narrative, an additional search was performed using "Betahistine AND Meniere AND (vasomotor OR sympathetic OR sympathectomy OR cervical ganglion OR autonomic)," which yielded 336 results. RESULTS: In the 19th and 20th centuries, growing knowledge of human anatomy led the scientific community to speculate that autonomic dysregulation caused many medical conditions. Excessive sympathetic mediated vasomotor changes were thought to cause hypertension, ischemia, and tissue damage. Clinicians applied the hypothesis to MD, assigning the sympathetic nervous system responsible for vertigo secondary to paroxysmal vasospasm and for hearing loss to poor cochlear nutrition. Despite limited animal experiments and isolated clinical observations, otolaryngologists performed sympathectomies, and, in the 1970s, replaced the procedure with betahistine as an alternative medical treatment. CONCLUSION: Premature excitement about a plausible hypothesis led to unnecessary and unwarranted operations. Despite absent evidence of sympathetic overactivation in MD, surgeons eagerly adopted sympathectomies, and later betahistine. Rigorous evaluation of the validity of these treatment practices is needed. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:535-542, 2024.

Patterns of Signal Intensity in CISS MRI of the Inner Ear and Eye.

BACKGROUND: Constructive interference in steady state (CISS) is a gradient echo magnetic resonance imaging (MRI) pulse sequence that provides excellent contrast between cerebrospinal fluid and adjacent structures but is prone to banding artifacts due to magnetic field inhomogeneities. We aimed to characterize artifacts in the inner ear and eye. METHODS: In 30 patients (60 ears/eyes) undergoing CISS sequence MRI, nine low-signal intensity regions were identified in the inner ear and compared to temporal bone histopathology. The number and angle of bands across the eye were examined. RESULTS: In the cochlea, all ears had regions of low signal corresponding to anatomy (modiolus (all), spiral lamina (n = 59, 98.3%), and interscalar septa (n = 50, 83.3%)). In the labyrinth, the lateral semicircular canal crista (n = 42, 70%) and utricular macula (n = 47, 78.3%) were seen. Areas of low signal in the vestibule seen in all ears may represent the walls of the membranous utricle. Zero to three banding artifacts were seen in both eyes (right: 96.7%, mean 1.5; left: 93.3%, mean 1.3). CONCLUSION: Low signal regions in the inner ear on CISS sequences are common and have consistent patterns; most in the inner ear represent anatomy, appearing blurred due to partial volume averaging. Banding artifacts in the eye are more variable.

Superior Canal Dehiscence and the Risk of Additional Dehiscences: A Retrospective CT Cohort Study.

OBJECTIVE: Determine if superior canal dehiscence (SCD) found on flat-panel CT increases the risk for other defects in the otic capsule. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care center. PATIENTS: One hundred ears (50 with SCD and 50 matched controls without SCD). INTERVENTIONS: Flat-panel CT imaging. MAIN OUTCOME MEASURES: (1) Prevalence of other dehiscences in SCD ears, (2) dehiscences in controls, and (3) otic capsule thickness in other reported dehiscence locations (cochlea-carotid, lateral semicircular canal [SCC] and mastoid, facial nerve-lateral SCC, vestibular aqueduct, posterior SCC-jugular bulb, posterior SCC-posterior fossa). Between-group comparisons were considered significant at p < 0.007 after applying the Bonferroni correction for multiple comparisons. RESULTS: Not including the SCD, there was a mean of 0.04 additional dehiscences in the SCD group (n = 2/50, 4%) and 0.04 non-SCD dehiscences in the controls (n = 2/50, 4%, p > 0.007). In the SCD group, there was one dehiscence between the cochlea and carotid artery and one between the posterior SCC and posterior fossa. The control group had one enlarged vestibular aqueduct and one dehiscence between the facial nerve and lateral SCC. As a group, SCD ears had wider vestibular aqueducts (0.68 ± 0.20 vs 0.51 ± 0.30 mm, p < 0.007) and thinner bone between the posterior SCC and posterior fossa (3.12 ± 1.43 vs 4.34 ± 1.67 mm, p < 0.007). The bone between the facial nerve and lateral SCC was thicker in SCD ears (0.77 ± 0.23 vs 0.55 ± 0.27 mm, p < 0.007) and no different for cochlea-carotid, and lateral SCC and mastoid (p > 0.007). CONCLUSIONS: SCD does not increase the likelihood of a second dehiscence in the same otic capsule. SCD patients may have congenitally thinner otic capsule bones compared to controls, particularly near the posterior SCC, where the vestibular aqueduct may be enlarged.

Reconstruction of the External Auditory Canal for Spontaneous Temporomandibular Joint Herniation.

Spontaneous herniation of the temporomandibular joint into the external auditory canal is rare and generally results from inflammation or trauma but is rarely documented as a result of osteoradionecrosis. We report the novel surgical management of TMJ herniation by reconstructing the anterior EAC using conchal cartilage and a vascularized pedicled muscle flap in two patients. At follow-up, both had healing of the ear canal and TM without any evidence of joint herniation, with improved QOL and hearing. TMJ herniation due to an anterior EAC defect from osteoradionecrosis or trauma can be reconstructed with a cartilage graft and vascularized fascia flap. Laryngoscope, 2024.

SVPath: A Deep Learning Tool for Analysis of Stria Vascularis from Histology Slides.

INTRODUCTION: The stria vascularis (SV) may have a significant role in various otologic pathologies. Currently, researchers manually segment and analyze the stria vascularis to measure structural atrophy. Our group developed a tool, SVPath, that uses deep learning to extract and analyze the stria vascularis and its associated capillary bed from whole temporal bone histopathology slides (TBS). METHODS: This study used an internal dataset of 203 digitized hematoxylin and eosin-stained sections from a normal macaque ear and a separate external validation set of 10 sections from another normal macaque ear. SVPath employed deep learning methods YOLOv8 and nnUnet to detect and segment the SV features from TBS, respectively. The results from this process were analyzed with the SV Analysis Tool (SVAT) to measure SV capillaries and features related to SV morphology, including width, area, and cell count. Once the model was developed, both YOLOv8 and nnUnet were validated on external and internal datasets. RESULTS: YOLOv8 implementation achieved over 90% accuracy for cochlea and SV detection. nnUnet SV segmentation achieved a DICE score of 0.84-0.95; the capillary bed DICE score was 0.75-0.88. SVAT was applied to compare both the ears used in the study. There was no statistical difference in SV width, SV area, and average area of capillary between the two ears. There was a statistical difference between the two ears for the cell count per SV. CONCLUSION: The proposed method accurately and efficiently analyzes the SV from temporal histopathology bone slides, creating a platform for researchers to understand the function of the SV further.

Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.

Background: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion: This study shows the importance of examining patient's family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister's unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.

Rapid imaging of intravenous gadolinium-based contrast agent (GBCA) entering ventricular cerebrospinal fluid (CSF) through the choroid plexus in healthy human subjects.

BACKGROUND: Pathways for intravenously administered gadolinium-based-contrast-agents (GBCAs) entering cerebrospinal-fluid (CSF) circulation in the human brain are not well-understood. The blood-CSF-barrier (BCSFB) in choroid-plexus (CP) has long been hypothesized to be a main entry-point for intravenous-GBCAs into CSF. Most existing studies on this topic were performed in animals and human patients with various diseases. Results in healthy human subjects are limited. Besides, most studies were performed using MRI methods with limited temporal resolution and significant partial-volume effects from blood and CSF. METHODS: This study employs the recently developed dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI approach to measure GBCA-distribution in the CSF immediately and 4 h after intravenous-GBCA administration in healthy subjects. With a temporal resolution of 10 s, cDSC MRI can track GBCA-induced CSF signal changes during the bolus phase, which has not been investigated previously. It employs a long echo-time (TE = 1347 ms) to suppress tissue and blood signals so that pure CSF signal is detected with minimal partial-volume effects. GBCA concentration in the CSF can be estimated from cDSC MRI. In this study, cDSC and FLAIR MRI were performed immediately and 4 h after intravenous GBCA administration in 25 healthy volunteers (age 48.9 ± 19.5 years; 14 females). Paired t-tests were used to compare pre-GBCA and post-GBCA signal changes, and their correlations with age were evaluated using Pearson-correlation-coefficients. RESULTS: At ~ 20 s post-GBCA, GBCA-induced cDSC signal changes were detected in the CSF around CP (ΔS/S = - 2.40 ± 0.30%; P < .001) but not in the rest of lateral ventricle (LV). At 4 h, significant GBCA-induced cDSC signal changes were observed in the entire LV (ΔS/S = - 7.58 ± 3.90%; P = .002). FLAIR MRI showed a similar trend. GBCA-induced CSF signal changes did not correlate with age. CONCLUSIONS: These results provided direct imaging evidence that GBCAs can pass the BCSFB in the CP and enter ventricular CSF immediately after intravenous administration in healthy human brains. Besides, our results in healthy subjects established a basis for clinical studies in brain diseases exploiting GBCA-enhanced MRI to detect BCSFB dysfunction.

A Deep Learning Framework for Analysis of the Eustachian Tube and the Internal Carotid Artery.

OBJECTIVE: Obtaining automated, objective 3-dimensional (3D) models of the Eustachian tube (ET) and the internal carotid artery (ICA) from computed tomography (CT) scans could provide useful navigational and diagnostic information for ET pathologies and interventions. We aim to develop a deep learning (DL) pipeline to automatically segment the ET and ICA and use these segmentations to compute distances between these structures. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center. METHODS: From a database of 30 CT scans, 60 ET and ICA pairs were manually segmented and used to train an nnU-Net model, a DL segmentation framework. These segmentations were also used to develop a quantitative tool to capture the magnitude and location of the minimum distance point (MDP) between ET and ICA. Performance metrics for the nnU-Net automated segmentations were calculated via the average Hausdorff distance (AHD) and dice similarity coefficient (DSC). RESULTS: The AHD for the ET and ICA were 0.922 and 0.246 mm, respectively. Similarly, the DSC values for the ET and ICA were 0.578 and 0.884. The mean MDP from ET to ICA in the cartilaginous region was 2.6 mm (0.7-5.3 mm) and was located on average 1.9 mm caudal from the bony cartilaginous junction. CONCLUSION: This study describes the first end-to-end DL pipeline for automated ET and ICA segmentation and analyzes distances between these structures. In addition to helping to ensure the safe selection of patients for ET dilation, this method can facilitate large-scale studies exploring the relationship between ET pathologies and the 3D shape of the ET.

The adaptor protein 14-3-3 binds to the calcium-sensing receptor and attenuates receptor-mediated Rho kinase signalling.

A yeast two-hybrid screen performed to identify binding partners of the CaR (calcium-sensing receptor) intracellular tail identified the adaptor protein 14-3-3θ as a novel binding partner that bound to the proximal membrane region important for CaR expression and signalling. The 14-3-3θ protein directly interacted with the CaR tail in pull-down studies and FLAG-tagged CaR co-immunoprecipitated with EGFP (enhanced green fluorescent protein)-tagged 14-3-3θ when co-expressed in HEK (human embryonic kidney)-293 or COS-1 cells. The interaction between the CaR and 14-3-3θ did not require a putative binding site in the membrane-proximal region of the CaR tail and was independent of PKC (protein kinase C) phosphorylation. Confocal microscopy demonstrated co-localization of the CaR and EGFP-14-3-3θ in the ER (endoplasmic reticulum) of HEK-293 cells that stably expressed the CaR (HEK-293/CaR cells), but 14-3-3θ overexpression had no effect on membrane expression of the CaR. Overexpression of 14-3-3θ in HEK-293/CaR cells attenuated CaR-mediated Rho signalling, but had no effect on ERK (extracellular-signal-regulated kinase) 1/2 signalling. Another isoform identified from the library, 14-3-3ζ, exhibited similar behaviour to that of 14-3-3θ with respect to CaR tail binding, cellular co-localization and impact on receptor-mediated signalling. However, unlike 14-3-3θ, this isoform, when overexpressed, significantly reduced CaR plasma membrane expression. Results indicate that 14-3-3 proteins mediate CaR-dependent Rho signalling and may modulate the plasma membrane expression of the CaR.