Faculty Bibliography

OBJECTIVE:The purpose of this study was to evaluate the feasibility of intraoperative navigation (ION) using adhesive fiducials and high-resolution computed tomography (HRCT) of the temporal bone in pediatric patients undergoing atresiaplasty for congenital aural atresia (CAA). METHODS:From June 2018 to August 2019, a retrospective review was performed on pediatric patients with unilateral or bilateral CAA who underwent atresiaplasty with or without concurrent bone anchored implant (BAI) placement. Single stage atresiaplasty was performed at a tertiary referral center with ION linked to image-guidance compatible HRCT non-contrast temporal bone images. Up to six adhesive fiducials were placed for navigation. Patient demographics were collected including Schuknecht classification type and Jahrsdoerfer score. Main outcome measures included the number of useable adhesive fiducials for navigation, navigation system registration accuracy, operative time, intraoperative complications, and postoperative outcomes including facial nerve function, surgical site infection rate, restenosis rate, and audiometric data. RESULTS:Five patients (3 male, 1 AU atresia, 2 AS atresia, all Schuknecht type C) with an average age of 9.2 years (range 6.8-11.8 years) underwent single sided atresiaplasty with ION. Two patients underwent concurrent BAI placement. Average Jahrsdoerfer score was 8.6 (range 7-10). Preoperative audiogram demonstrated a mean air-bone gap (ABG) of 45 dB (range 35-54 dB). The navigation system registration accuracy ranged from 0.08 to 1.80 mm (mean 1.00 mm). Mean operative time was 268 min (range 217-307 min). There were no intraoperative complications. At an average follow up of 7.2 months (range 2-15 months), postoperative facial nerve function was normal in all patients and no patients developed postoperative stenosis or surgical site infections. Four patients underwent postoperative audiogram at an average of 4 months after surgery (range 2-5 months) and all demonstrated an ABG of less than 30 dB (mean 20 dB, range 15-26 dB) with an average improvement in ABG of 23 dB (range 11-39 dB). The one patient who did not undergo postoperative pure tone audiometry underwent AzBio speech perception testing and demonstrated an improvement from 81% to 89%. CONCLUSIONS:The use of ION in otologic surgery is uncommon. Inherent aberrant temporal bone anatomy in CAA makes this a unique population to study the value of this technology. The use of adhesive fiducials is feasible, with navigation registration accuracy and surgical outcomes comparable to those in the literature. More data is necessary regarding the impact of ION on long-term surgical and audiometric outcomes.

Core auditory cortex (AC) neurons encode slow fluctuations of acoustic stimuli with temporally patterned activity. However, whether temporal encoding is necessary to explain auditory perceptual skills remains uncertain. Here, we recorded from gerbil AC neurons while they discriminated between a 4-Hz amplitude modulation (AM) broadband noise and AM rates >4 Hz. We found a proportion of neurons possessed neural thresholds based on spike pattern or spike count that were better than the recorded session's behavioral threshold, suggesting that spike count could provide sufficient information for this perceptual task. A population decoder that relied on temporal information outperformed a decoder that relied on spike count alone, but the spike count decoder still remained sufficient to explain average behavioral performance. This leaves open the possibility that more demanding perceptual judgments require temporal information. Thus, we asked whether accurate classification of different AM rates between 4 and 12 Hz required the information contained in AC temporal discharge patterns. Indeed, accurate classification of these AM stimuli depended on the inclusion of temporal information rather than spike count alone. Overall, our results compare two different representations of time-varying acoustic features that can be accessed by downstream circuits required for perceptual judgments.

INTRODUCTION/BACKGROUND:Cochlear implantation (CI) is a reliable and safe means by which sensorineural hearing loss can be ameliorated in the elderly population. However, a high degree of variation exists in postimplantation hearing outcomes for which some modifiable factors of the daily natural auditory environment may be contributory. In this study, we analyze the relationship between cochlear implant patient age, natural auditory environment, and postimplantation speech perception among older adults. METHODS:Data log from automatic environment classification enabled sound processors of postlingually deafened CI recipients ≥50 years old (n = 115) were obtained retrospectively and analyzed for time spent (hours per day) in listening environment and loudness (SPL dB). Speech perception testing was assessed in a subset of patients (n = 27) using open-set word recognition in quiet Consonant-Nucleus-Consonant in the short and intermediate postoperative period. RESULTS:The mean subject age was 70 years (range, 53-99 years). Average daily implant use was 10.8 h and was not significantly correlated with age (p = 0.23, Spearman's rho). Age was positively correlated with the percentage of hours spent at <40 and 40-50 dB and negatively correlated to proportional CI use at higher volume (60-70, 70-80, and >80 dB; rs = 0.21, 0.20, -0.20, -0.35, -0.43; p = 0.021, 0.036, 0.033, <0.001, <0.001, respectively). Age was positively correlated with CI use in the quiet scene (rs = 0.26, p = 0.006) and negatively correlated with scenes containing speech and noise (rs = -0.19, -0.25; p = 0.046, 0.007). Total hours of device use and time spent at <40, 40-50 dB, and quiet environments were significantly correlated with improved CNC word scores (rs = 0.48, 0.48, 0.51; p = 0.01, 0.01, <0.01, Spearman's rho). While all speech (speech in noise + speech) was not significantly correlated to improvements in speech perception, a medium effect size was observed (rs = 0.37, p = 0.057). DISCUSSION/CONCLUSION/CONCLUSIONS:This study supports a relationship between auditory environment and age, with older CI recipients spending a greater proportion of time in quiet. Older CI users demonstrated greater improvements in speech perception with longer daily device use. Additional examination of the relationship between auditory environment and speech perception is necessary to conclusively guide future auditory rehabilitation efforts.

Erythropoiesis involves complex interrelated molecular signals influencing cell survival, differentiation, and enucleation. Diseases associated with ineffective erythropoiesis, such as β-thalassemias, exhibit erythroid expansion and defective enucleation. Clear mechanistic determinants of what make erythropoiesis effective are lacking. We previously demonstrated that exogenous transferrin ameliorates ineffective erythropoiesis in β-thalassemic mice. In the current work, we utilize transferrin treatment to elucidate a molecular signature of ineffective erythropoiesis in β-thalassemia. We hypothesize that compensatory mechanisms are required in β-thalassemic erythropoiesis to prevent apoptosis and enhance enucleation. We identify pleckstrin-2-a STAT5-dependent lipid binding protein downstream of erythropoietin-as an important regulatory node. We demonstrate that partial loss of pleckstrin-2 leads to worsening ineffective erythropoiesis and pleckstrin-2 knockout leads to embryonic lethality in β-thalassemic mice. In addition, the membrane-associated active form of pleckstrin-2 occurs at an earlier stage during β-thalassemic erythropoiesis. Furthermore, membrane-associated activated pleckstrin-2 decreases cofilin mitochondrial localization in β-thalassemic erythroblasts and pleckstrin-2 knockdown in vitro induces cofilin-mediated apoptosis in β-thalassemic erythroblasts. Lastly, pleckstrin-2 enhances enucleation by interacting with and activating RacGTPases in β-thalassemic erythroblasts. This data elucidates the important compensatory role of pleckstrin-2 in β-thalassemia and provides support for the development of targeted therapeutics in diseases of ineffective erythropoiesis.

PURPOSE/OBJECTIVE:Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the maximum tolerated dose (MTD)/Recommended phase 2 Dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection. EXPERIMENTAL DESIGN/METHODS:) for 7-10 days pre-operatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts. RESULTS:for 21 and 28 days, respectively. Steady state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations and CSF samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range: 2.22- 53.4). CONCLUSIONS:Ribociclib and everolimus were well tolerated and demonstrated similar pharmacokinetic properties as in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.

Although malpositioning of the cochlear implant (CI) electrode array is rare in patients with normal anatomy, when occurring it may result in reduced hearing outcome. In addition to intraoperative electrophysiologic tests, imaging is an important modality to assess correct electrode array placement. The purpose of this report was to assess the incidence and describe cases in which intraoperative plain radiographs detected a malpositioned array. Intraoperative anti-Stenver"™s view plain X-rays are conducted routinely in all CI surgeries in our tertiary center before awakening the patient and breaking the sterile field. Data of patients undergoing 399 CI surgeries were retrospectively analyzed. A total of 355 had normal inner ear and temporal bone anatomy. Patients with intra or extracochlear malpositioned electrode arrays demonstrated in the intraoperative X-ray were described. There were four cases of electrode array malposition out of 355 implantations with normal anatomy (1.1%): two tip fold-overs, one extracochlear placement and one partial insertion. All electrodes were reinserted immediately; repeated radiographs were normal and the patients achieved good hearing function. Intraoperative plain anti-Stenver"™s view X-rays are valuable to confirm electrode array location, allowing correction before the conclusion of surgery. These radiographs are cheaper, faster, and emit much less radiation than other imaging options, making them a viable cost-effective tool in patients with normal anatomy.

Purpose: This research aimed to perform an overview on adjuvant vaginal brachytherapy (VBT) in stage I to II endometrial carcinoma (EC) according to ESMO-ESGO-ESTRO risk group consensus in China from multi-institutional analysis.Materials and Methods: We retrospectively analyze patients with stage I to II EC at 13 institutions in China treated between 2003 and 2015. All patients underwent adjuvant radiotherapy and were divided into low-risk (LR), intermediate-risk (IR), high-intermediate risk (HIR) and high-risk (HR) groups according to ESMO-ESGO-ESTRO risk group consensus. XXResult(s): A total of 1048 cases were included. Stage I disease accounted for 85.9% of the cohort. Proportion of HR disease was 27.6%, HIR 17.7%, IR 27.7% and LR 27.1%. Patients received adjuvant VBT alone (n = 474), pelvic external beam radiotherapy (EBRT) alone (n = 116) or combined EBRT with VBT (n = 458). An increasing trend was found toward referrals for VBT alone. Historical data demonstrate that the clinical practice of adjuvant VBT alone increased significantly in the LR to HIR groups over the past 13 years. However, in the HR group, the proportion of VBT alone or as a boost after EBRT stayed stable in the corresponding period.All institutions commonly use High-dose-rate VBT prescribed to 0.5-cm depth from the vaginal surface with 14 and 17 different dose-fractionation schedules for VBT alone and VBT boost, respectively. The most common fractionation for VBT alone is 5 Gy in six fraction (407/474) and the most common fractionation for VBT as a boost after EBRT is 5 Gy in two fractions (178/458). Proximal 2-3 cm vagina was the most often irradiated vaginal target (61.3%). The most commonly used applicators were the multichannel vaginal cylinder (79.6%). The median follow-up time was 56 months. For LR to HIR patients, VBT alone achieved comparable survival to EBRT. Compared to EBRT, patients receiving VBT had significantly decreased incidence of grade 1-2 early and late gastrointestinal and urinary reactions, and the rate of grade 3-4 acute hematological toxicity. XXConclusion(s): There is remarkable heterogeneity among VBT dose-fractionation schedules. An increasing trend was found toward referrals for VBT alone. The clinical practice of adjuvant VBT alone increased significantly in LR to HIR groups over the past 13 years. In LR to HIR group, VBT alone achieved comparable survival to EBRT.XXCopyright

Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.

OBJECTIVE:To characterize a series of patients with MRI evidence of spontaneous vestibular schwannoma (VS) regression. STUDY DESIGN/METHODS:Retrospective case series. METHODS:Retrospective review between 2012 and 2020 from a single, tertiary-care center of all patients with an untreated, sporadic VS and spontaneous regression in volumetric tumor size over the course of observation. The main outcome measures included VS size and location, presenting symptoms, medication use, changes in pure-tone averages and word recognition scores. RESULTS:/yr). Five patients were classified as having major regression, defined by a relative decrease in volume of >40%, while eight patients had minor regression (<40% relative volume reduction). No significant differences in initial tumor size, rate of regression, or audiometric changes were observed between the major and minor regression cohorts. CONCLUSIONS:Patients with evidence of a spontaneously shrinking VS have a heterogeneous presentation. Due to the scarcity of this phenomenon, predicting which tumors will eventually undergo regression remains unclear. Employing volumetric measurements to compare serial MRI scans may improve the accuracy of detecting shrinking tumors. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 2020.

Captive breeding is vital for primate conservation, with modern zoos serving a crucial role in breeding populations of threatened species and educating the general public. However, captive populations can experience welfare issues that may also undermine their reproductive success. To enhance the wellbeing of endangered zoo primates, we conducted a study to assess the effects of a new scent enrichment program on captive red-ruffed lemurs (Varecia rubra), black howler monkeys (Alouatta caraya), siamangs (Symphalangus syndactylus), lar gibbons (Hylobates lar) and orangutans (Pongo pygmaeus pygmaeus). We combined behavioral observations and fecal endocrinology analyses to evaluate the effects of a series of essential oils (benzoin, lavender, lemongrass) on five captive troops (N = 19) housed at Dudley Zoo & Castle and Twycross Zoo (UK). We recorded observations of natural species-specific and abnormal stress-related behaviors for 480 h using instantaneous scan sampling. We collected 189 fecal samples and measured the fecal cortisol concentrations using radioimmunoassay. We found a significant effect of the scent enrichment on behaviors, with red-ruffed lemurs and black howler monkeys reducing their social interactions, as well as red-ruffed lemurs and lar gibbons decreasing their stress-related behaviors after they were exposed to the series of essential oils. We also found that red-ruffed lemurs displayed a significant increase in fecal glucocorticoids following exposure to essential oils. Our contradictory findings suggest that the effects of this series of essential oils may change depending on the species-specific social lives and olfactory repertoires of primates. In conclusion, we cannot recommend using these essential oils widely with zoo primates without additional evaluation.