Faculty Bibliography

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.

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.

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.

OBJECTIVE:To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. METHODS:Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA). RESULTS:A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1β secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade. CONCLUSION/CONCLUSIONS:We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.

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.

BACKGROUND:Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described. OBJECTIVE:To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs. METHODS:An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model. RESULTS:A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P < .05) and a Ki-67 index > 15% (HR = 1.66, P < .03) negatively correlated with PFS. MMs (HR = 3.21, P < .05), increased age (HR = 1.04, P = .04), and reduced KPS (HR = 0.95, P = .04) were associated with shortened OS. Adjuvant versus salvage SRS did not impact PFS/OS. A shortened interval between surgery and SRS improved PFS for AMs (HR = 0.99, P = .02) on subgroup analysis. Radiation necrosis occurred in 34 (12.5%) patients. Five-year rates of repeat surgery/radiation were 33.8% and 60.4%, respectively. CONCLUSION/CONCLUSIONS:AM/MMs remain challenging tumors to treat. Elevated proliferative indices are associated with tumor recurrence, while MMs have worse survival. SRS can control AM/MMs in the short term, but the 5-yr PFS rates are low, underscoring the need for improved treatment options for these patients.

BACKGROUND:After head and neck cancer (HNC) treatment, dysgeusia may be a barrier to oral intake. In this exploratory study, we prospectively examined taste perception, clinician-rated (CRO) and patient-reported (PRO) taste changes and their effect on oral intake postradiotherapy. METHODS:Twenty-eight patients were assessed at baseline, treatment weeks 2 and 4, and 1, 3, and 6 months post-treatment using a whole-mouth taste test and associated CRO and subjective PRO measures. RESULTS:Greater taste impairment was reflected by subjective than by a whole-mouth taste test. The most significant and consistent decline occurred mid-treatment. The Chemotherapy-Induced Taste Alteration Scale (PRO) discomfort subscale correlated significantly with maintaining an oral diet, percent of oral intake, and appetite level from mid-treatment to 6 months post-treatment. CONCLUSIONS:PRO results indicated ongoing oral intake issues. Whole-mouth taste tests may fail to fully reflect functional taste-loss. Dysgeusia prevention and treatment methods are needed to improve patient outcomes.

PURPOSE/OBJECTIVE:To examine the role age plays in the treatment and prognosis of locally advanced head and neck cancer (LAHNC) treated definitively with radiation alone or combined modality therapy. METHODS:A retrospective analysis was performed of three NRG/RTOG trials examining either radiation alone or combined radiation and systemic therapy for LAHNC. The effect of age (≥70 yrs.) on cause-specific survival (CSS), overall survival (OS), and toxicity was evaluated. RESULTS:A total of 2688 patients were analyzed, of whom 309 patients (11.5%) were ≥ 70. For all studies combined, the hazard ratio (HR) for CSS for patients age ≥ 70 vs. those <70 was 1.33 (95%CI: 1.14-1.55, p < 0.001). For OS, the HR for patients age ≥ 70 vs. those <70 for all studies combined was 1.55 (95% CI 1.35-1.77, p < 0.001). After adjustment for all covariates, age ≥ 70 was associated with worse OS regardless of adjustment for smoking and p16 status. The survival difference was more pronounced in those receiving combined radiation and systemic therapy. Hematologic and renal toxicities were increased in combined modality trials in patients ≥70 years old. CONCLUSIONS:Patients age ≥ 70 with LAHNC were underrepresented in these clinical trials. Their CSS and OS proved inferior to patients <70 years old.

OBJECTIVE:To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to epilepsy control patients. METHODS:For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected post-mortem brain tissue of 12 SUDEP and 14 non-SUDEP epilepsy patients. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from mesial temporal lobe epilepsy (MTLE) patients: 6 low-risk and 8 high-risk SUDEP as determined by a short (< 50 seconds) or prolonged (≥ 50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. RESULTS:In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and non-SUDEP epilepsy patients, contrasting with our previously reported robust differences between epilepsy and non-epilepsy control patients. Transcriptomics in hippocampus and cortex from surgical epilepsy patients segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. CONCLUSION/CONCLUSIONS:The SUDEP proteome and high-risk SUDEP transcriptome were similar to other epilepsy patients in hippocampus and frontal cortex, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

This is a patient with multiple meningoencephaloceles which resulted in bacterial meningitis and subsequent status epilepticus. We identify impressive imaging findings demonstrating herniation of the meninges from nasal and bitemporal skull base defects possibly as a result of intracranial hypertension.