Interferon-Driven Immune Dysregulation in Common Variable Immunodeficiency-Associated Villous Atrophy and Norovirus Infection.

PURPOSE: About 15% of patients with common variable immunodeficiency (CVID) develop a small intestinal enteropathy, which resembles celiac disease with regard to histopathology but evolves from a distinct, poorly defined pathogenesis that has been linked in some cases to chronic norovirus (NV) infection. Interferon-driven inflammation is a prominent feature of CVID enteropathy, but it remains unknown how NV infection may contribute. METHODS: Duodenal biopsies of CVID patients, stratified according to the presence of villous atrophy (VA), IgA plasma cells (PCs), and chronic NV infection, were investigated by flow cytometry, multi-epitope-ligand cartography, bulk RNA-sequencing, and RT-qPCR of genes of interest. RESULTS: VA development was connected to the lack of intestinal (IgA+) PC, a T helper 1/T helper 17 cell imbalance, and increased recruitment of granzyme+CD8+ T cells and pro-inflammatory macrophages to the affected site. A mixed interferon type I/III and II signature occurred already in the absence of histopathological changes and increased with the severity of the disease and in the absence of (IgA+) PCs. Chronic NV infection exacerbated this signature when compared to stage-matched NV-negative samples. CONCLUSIONS: Our study suggests that increased IFN signaling and T-cell cytotoxicity are present already in mild and are aggravated in severe stages (VA) of CVID enteropathy. NV infection preempts local high IFN-driven inflammation, usually only seen in VA, at milder disease stages. Thus, revealing the impact of different drivers of the pathological mixed IFN type I/III and II signature may allow for more targeted treatment strategies in CVID enteropathy and supports the goal of viral elimination.

Slim Modiolar Electrode Placement in Candidates for Electroacoustic Stimulation.

OBJECTIVES: To determine rates of hearing preservation and performance in patients who met candidacy for electroacoustic stimulation (EAS) and were implanted with a slim modiolar electrode (CI532 or CI632). DESIGN: Adult patients meeting Food and Drug Administration criteria for electroacoustic stimulation (preoperative low-frequency pure-tone average [LFPTA] less than 60 dB at 125, 250, and 500 Hz and monosyllabic word scores between 10% and 60% in the ear to be implanted), who received a slim modiolar electrode were included. Main outcome measures included rates of hearing preservation, defined as a LFPTA ≤80 dB at 125, 250, and 500 Hz, as well as postoperative low-frequency pure-tone threshold shifts, consonant-Nucleus-Consonant (CNC) word scores and AzBio sentences in noise scores. RESULTS: Forty-six patients met inclusion criteria during a 4-year period. Mean (standard deviation) preoperative LFPTA was 34.5 (13.0) dB, and 71.7% had preserved hearing at initial activation. The mean LFPTA shift in patients who preserved hearing at initial activation was 19.7 (14.6) dB, compared with 62.6 (17.7) dB in patients who did not preserve hearing as per our definition. Perioperative steroid use was not different in patients with and without preserved hearing (X 2 (1, N = 46) = 0.19, p = .67, V = 0.06). One year after surgery, 57% of patients had a decline in LFPTA >80 dB and were no longer considered candidates for EAS, with 34.7% still retaining low-frequency thresholds ≤80 dB. CNC word scores at 1 year were 69.9% and 61.4% among individuals with and without preserved low-frequency hearing respectively, measured in their CI ear alone, in their regular listening condition of EAS or electric only ( t (32) = 1.13, p = 0.27, d = 0.39, 95% CI = -6.51, 22.86). Device use time did not differ between groups. Among adults with preserved residual hearing at 1 year (n = 16), 44% used EAS, although there was no significant difference in performance between EAS users and nonusers with preserved hearing. Loss of residual hearing over time did not result in a decline in speech perception performance. CONCLUSION: The present study demonstrated favorable early rates of hearing preservation with a slim modiolar array. Performance was not significantly different in individuals with and without preserved low-frequency acoustic hearing, independent of EAS use. Compared with reports of short electrode use, the loss of residual hearing in patients implanted with this array did not impact speech perception performance.

Distinct CD8 T Cell Populations with Differential Exhaustion Profiles Associate with Secondary Complications in Common Variable Immunodeficiency.

PURPOSE: Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency, with heterogeneous clinical presentation. Our goal was to analyze CD8 T cell homeostasis in patients with infection only CVID, compared to those additionally affected by dysregulatory and autoimmune phenomena. METHODS: We used flow and mass cytometry evaluation of peripheral blood of 40 patients with CVID and 17 healthy donors. RESULTS: CD8 T cells are skewed in patients with CVID, with loss of naïve and increase of effector memory stages, expansion of cell clusters with high functional exhaustion scores, and a highly activated population of cells with immunoregulatory features, producing IL-10. These findings correlate to clinically widely used B cell-based EURO classification. Features of exhaustion, including loss of CD127 and CD28, and expression of TIGIT and PD-1 in CD8 T cells are strongly associated with interstitial lung disease and autoimmune cytopenias, whereas CD8 T cell activation with elevated HLA-DR and CD38 expression predict non-infectious diarrhea. CONCLUSION: We demonstrate features of advanced differentiation, exhaustion, activation, and immunoregulatory capabilities within CD8 T cells of CVID patients. Assessment of CD8 T cell phenotype may allow risk assessment of CVID patients and provide new insights into CVID pathogenesis, including a better understanding of mechanisms underlying T cell exhaustion and regulation.

Acceptance and Benefits of Electro-Acoustic Stimulation for Conventional-Length Electrode Arrays.

BACKGROUND: Prior studies have shown an advantage for electro-acoustic stimulation (EAS) in cochlear implant (CI) patients with residual hearing, but the degree of benefit can vary. The objective was to explore which factors relate to performance with and acceptance of EAS for CI users with conventional-length electrodes. METHODS: A retrospective chart review was conducted for adults with an average threshold of 75 dB hearing loss or better across 250 and 500 Hz preoperatively (n = 83). All patients underwent cochlear implantation with a conventional-length electrode. Low-frequency audiometric thresholds were measured at initial activation as well as 3 and 12 months postoperatively to determine who met the criteria for EAS. Speech perception for CNC words and AzBio sentences in quiet and +10 dB SNR noise was evaluated 3 and 12 months after activation. RESULTS: Speech perception in quiet and noise was similar regardless of whether or not the patient was eligible for EAS. Less than half of the patients who met the EAS criteria chose to use it, citing reasons such as physical discomfort or lack of perceived benefit. EAS users performed better on CNC words but not sentence recognition than EAS nonusers. CONCLUSIONS: EAS use is dependent on audiologic and nonaudiologic issues. Hearing preservation is possible with conventional electrodes, but hearing preservation alone does not guarantee superior speech perception.

Assessing the Quality of Low-Frequency Acoustic Hearing: Implications for Combined Electroacoustic Stimulation With Cochlear Implants.

OBJECTIVES: There are many potential advantages to combined electric and acoustic stimulation (EAS) with a cochlear implant (CI), including benefits for hearing in noise, localization, frequency selectivity, and music enjoyment. However, performance on these outcome measures is variable, and the residual acoustic hearing may not be beneficial for all patients. As such, we propose a measure of spectral resolution that might be more predictive of the usefulness of the residual hearing than the audiogram alone. In the following experiments, we measured performance on spectral resolution and speech perception tasks in individuals with normal hearing (NH) using low-pass filters to simulate steeply sloping audiograms of typical EAS candidates and compared it with performance on these tasks for individuals with sensorineural hearing loss with similar audiometric configurations. Because listeners with NH had similar levels of audibility and bandwidth to listeners with hearing loss, differences between the groups could be attributed to distortions due to hearing loss. DESIGN: Listeners with NH (n = 12) and those with hearing loss (n = 23) with steeply sloping audiograms participated in this study. The group with hearing loss consisted of 7 EAS users, 14 hearing aid users, and 3 who did not use amplification in the test ear. Spectral resolution was measured with the spectral-temporal modulated ripple test (SMRT), and speech perception was measured with AzBio sentences in quiet and noise. Listeners with NH listened to stimuli through low-pass filters and at two levels (40 and 60 dBA) to simulate low and high audibility. Listeners with hearing loss listened to SMRT stimuli unaided at their most comfortable listening level and speech stimuli at 60 dBA. RESULTS: Results suggest that performance with SMRT is significantly worse for listeners with hearing loss than for listeners with NH and is not related to audibility. Performance on the speech perception task declined with decreasing frequency information for both listeners with NH and hearing loss. Significant correlations were observed between speech perception, SMRT scores, and mid-frequency audiometric thresholds for listeners with hearing loss. CONCLUSIONS: NH simulations describe a "best case scenario" for hearing loss where audibility is the only deficit. For listeners with hearing loss, the likely broadening of auditory filters, loss of cochlear nonlinearities, and possible cochlear dead regions may have contributed to distorted spectral resolution and thus deviations from the NH simulations. Measures of spectral resolution may capture an aspect of hearing loss not evident from the audiogram and be a useful tool for assessing the contributions of residual hearing post-cochlear implantation.

Force and pressure measurements in temporal bones.

PURPOSE: Some cochlear implant (CI) patients lose their residual hearing during surgery. Two factors that might play a role in residual hearing loss are the change in intracochlear hydraulic pressure and force on the cochlear wall during electrode insertion. The aim of this study is to investigate whether a difference in peak hydraulic pressure and peak force on the cochlear wall exists during a CI electrode insertion with different insertion techniques. MATERIALS AND METHODS: Twenty fresh frozen temporal bones were used. Hydraulic pressure and force on the cochlear wall were recorded during straight electrode insertions with 1) slow versus fast insertion speed, 2) manual versus automatic insertion method and 3) round window approach (RWA) versus extended RWA (ERWA). RESULTS: When inserting with a slow compared to a fast insertion speed, the peak hydraulic pressure is 239% (95% CI: 130-399%) higher with a RWA and 58% (95% CI: 6-137%) higher with an ERWA. However, the peak force on the cochlear wall is a factor 29% less (95% CI: 13-43%) with a slow insertion speed. No effect was found of opening and insertion method. CONCLUSIONS: As contradictory findings were found for hydraulic pressure and force on the cochlear wall on insertion speed, it remains unclear which insertion speed (slow versus fast) is less traumatic to inner ear structure.

T+ NK+ IL-2 Receptor γ Chain Mutation: a Challenging Diagnosis of Atypical Severe Combined Immunodeficiency.

PURPOSE: All reported patients with hypomorphic X-linked severe combined immunodeficiency (X-SCID) due to c.664C>T (p.R222C) mutations in the gene (IL2RG) encoding the common γ chain (γc) have presented with opportunistic infections within the first year of life, despite the presence of nearly normal NK and T cell numbers. Reporting five children of one extended family with hemizygous mutations in IL2RG, we explore potential diagnostic clues and extend our comprehension of the functional impact of this mutation. METHODS: Whole exome sequencing (WES); detailed immune phenotyping; cytokine-induced STAT phosphorylation; B, T, and NK cell activation; and quantification of sjTRECs in five Arab children with c.664C>T (p.R222C) IL2RG mutation. RESULTS: The mean age at clinical presentation with respiratory tract infection or diarrhea was 6.8 (range: 2-12) months. None of the children presented with opportunistic infections. Diagnostic clues were early onset in the first year of life, and a suggestive family history associated with reduced naïve CD4 T cells and absent switched memory B cells. Number and phenotype of NK cells and innate-like lymphocytes were normal. The diagnosis was made by WES and corroborated by absent STAT phosphorylation and reduced functional response after IL-2 and IL-21 stimulation. Four patients underwent successful hematopoietic stem cell transplantation. CONCLUSIONS: As early diagnosis and treatment are important, a high index of suspicion in the diagnosis of c.664C>T (p.R222C) X-SCID is needed. This requires prompt genetic testing by next generation sequencing in order to avoid unnecessary delays in the definite diagnosis since immunological work up may not be discriminating. Assays directly testing cytokine signaling or cytokine-dependent functions are helpful in confirming the functional impact of the identified hypomorphic variants.

Performance with an Auditory Brainstem Implant and Contralateral Cochlear Implant in Pediatric Patients.

OBJECTIVE: To assess bimodal auditory performance in children with a cochlear implant (CI) and contralateral auditory brainstem implant (ABI). METHODS: This is a retrospective case review performed at a tertiary referral center. Four patients with cochlear nerve deficiency initially underwent cochlear implantation but were not benefiting from their devices and underwent ABI in the contralateral ear. The main outcome measures included age-appropriate speech perception and production assessments. RESULTS: Three subjects performed better on their auditory perception assessments using both of their devices than with either device alone. One subject had only preliminary outcomes, but subjectively performed best with both devices. CONCLUSIONS: We observed continued improvement in CI performance over time, even if no benefit was evident before the decision for ABI. This could suggest that ABI and CI have a synergistic effect, or it could simply be the adaptive ability of the developing brain to utilize the signals coming from these devices. There is preliminary evidence to support choosing the ear contralateral to the CI for an ABI in a pediatric patient with bilateral cochlear nerve deficiency.

Preferential Reduction of Circulating Innate Lymphoid Cells Type 2 in Patients with Common Variable Immunodeficiency with Secondary Complications Is Part of a Broader Immune Dysregulation.

PURPOSE: Over a third of patients with common variable immunodeficiency (CVID) suffer from secondary complications like inflammatory organ disease, autoimmune manifestations, or lymphoproliferation contributing to increased morbidity and mortality in affected patients. Innate lymphoid cells (ILCs) have emerging roles in setting the milieu for physiological, but also pathological, immune responses and inflammation. We therefore sought to correlate the recently identified disturbed homeostasis of ILCs with alterations of the adaptive immune system in complex CVID patients (CVIDc). METHODS: We quantified peripheral blood ILC and T helper cell subsets of 58 CVID patients by flow cytometry and compared the results to the clinical and immunological phenotype. RESULTS: Total ILCs were significantly reduced in peripheral blood of CVIDc patients compared to healthy individuals, but not to CVID patients who suffered only from infections (CVIDio). This reduction was mainly due to a decrease in ILC2s, while ILC3s were relatively increased in CVIDc compared to CVIDio patients. This alteration in ILC phenotype was more prominent in patients with an expansion of CD21low B cells, but we could not detect an association of the altered ILC phenotype with a TH1-shift among circulating CD4 T cells, which was also prominent in CVIDc patients. CONCLUSION: We confirm a relative shift in ILCs of CVIDc patients towards ILC3s which was associated with the expansion of CD21low B cells, but not overtly with the relative expansion of TH1-like T cells. Given the relative abundance of TH1-like T cells compared to ILCs, these probably represent a more prominent source of the observed IFNγ-signature in CVIDc patients.

Structure of the α-tubulin acetyltransferase, αTAT1, and implications for tubulin-specific acetylation.

Protein acetylation is an important posttranslational modification with the recent identification of new substrates and enzymes, new links to disease, and modulators of protein acetylation for therapy. α-Tubulin acetyltransferase (αTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes. Here, we present the X-ray crystal structure of the human αTAT1/acetyl-CoA complex. Together with structure-based mutagenesis, enzymatic analysis, and functional studies in cells, we elucidate the catalytic mechanism and mode of tubulin-specific acetylation. We find that αTAT1 has an overall fold similar to the Gcn5 histone acetyltransferase but contains a relatively wide substrate binding groove and unique structural elements that play important roles in α-tubulin-specific acetylation. Conserved aspartic acid and cysteine residues play important catalytic roles through a ternary complex mechanism. αTAT1 mutations have analogous effects on tubulin acetylation in vitro and in cells, demonstrating that it is the central determining factor of α-tubulin K40 acetylation levels in vivo. Together, these studies provide general insights into distinguishing features between histone and tubulin acetyltransferases, and they have specific implications for understanding the molecular basis of tubulin acetylation and for developing small molecule modulators of microtubule acetylation for therapy.

Cochlear Implantation in Children Under 9 Months of Age: Safety and Efficacy.

OBJECTIVE: To assess the safety of cochlear implants (CIs) in children under 9 months of age to better understand expected postoperative complication rates, and to provide a preliminary look at efficacy. STUDY DESIGN: Single-center retrospective review. SETTING: Tertiary referral center. PATIENTS: Children 5 to 8 months of age who received a CI between 2011 and 2021. INTERVENTIONS: Therapeutic-CI. MAIN OUTCOME MEASURES: The primary outcome was 6-month postoperative complication rate. Secondary outcomes included length of stay, device explantation/reimplantation, rehabilitation supports, and hearing and language outcomes. Complications of children implanted under than 9 months of age was compared with a cohort of children implanted 9 to 18 months of age between the years 2011 and 2016 using a chi-squared test ( p < 0.05). RESULTS: One hundred six children under 9 months of age were implanted (204 CIs) at a mean age of 6.6 months (range: 5-8). Postoperative complications occurred in 28 patients (26%) and were often minor. There were no mortalities. There was no statistically significant difference in complications, including reimplantation rates, between patients implanted under 9 months of age and those implanted 9 to 18 months of age. Speech discrimination outcomes were excellent, and mean spoken language outcomes were near normative for typically developing children. CONCLUSIONS: Cochlear implantation can be a safe and effective treatment option for children 5 to 8 months of age. Early hearing screening and referral for infants to receive appropriate intervention will continue to play a critical role in optimizing speech and language outcomes.

Prevalence and Characteristics of Veterans with Severe Hearing Loss: A Descriptive Study.

Hearing loss is common among Veterans, and extensive hearing care resources are prioritized within the Veterans Administration (VA). Severe hearing loss poses unique communication challenges with speech understanding that may not be overcome with amplification. We analyzed data from the VA Audiometric Repository between 2005 and 2017 and the relationship between hearing loss severity with speech recognition scores. We hypothesized that a significant subset of Veterans with severe or worse hearing loss would have poor unaided speech perception outcomes even with adequate audibility. Sociodemographic characteristics and comorbidities were compiled using electronic medical records as was self-report measures of hearing disability. We identified a cohort of 137,500 unique Veterans with 232,789 audiograms demonstrating bilateral severe or worse hearing loss (four-frequency PTA > 70 dB HL). The median (IQR; range) age of Veterans at their first audiogram with severe or worse hearing loss was 81 years (74 to 87; 21-90+), and a majority were male (136,087 [99%]) and non-Hispanic white (107,798 [78.4%]). Among those with bilateral severe or worse hearing loss, 41,901 (30.5%) also had poor speech recognition scores (<50% words), with greater hearing loss severity correlating with worse speech perception. We observed variability in speech perception abilities in those with moderate-severe and greater levels of hearing loss who may derive limited benefit from amplification. Veterans with communication challenges may warrant alternative approaches and treatment strategies such as cochlear implants to support communication needs.

Facial Reanimation After Intratemporal Facial Nerve Schwannoma Resection: A Systematic Review.

Objective: To systematically analyze the outcomes of reanimation techniques that have been described for patients undergoing non-fascicle sparing resection of intratemporal facial schwannomas. Methods: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines of the PubMed, MEDLINE, and Cochrane Central Register of Controlled Trials databases. Results: Eight hundred forty studies were screened with 22 meeting inclusion criteria comprising 266 patients. Most facial nerve reanimations (81.2%) were performed using an interposition nerve graft. The remaining patients underwent hypoglossal-facial nerve transposition (13.9%), primary anastomosis (3.4%), and free muscle transfer (0.1%). Of the reported interposition grafts, the two most utilized were the great auricular (113/199) and sural (86/199) nerves. Interposition nerve grafts resulted in significantly better outcomes in facial nerve function postoperatively than hypoglossal-facial transposition (3.48 vs. 3.92; p < 0.01). There was no difference between interposition grafts. Conclusion: This study systematically reports that interposition nerve grafts, after resection of intratemporal facial schwannoma, result in superior outcomes than hypoglossal-facial nerve transposition in these patients.

Characterizing Cochlear Implant Trans-Impedance Matrix Heatmaps in Patients With Abnormal Anatomy.

OBJECTIVE: To characterize transimpedance matrix (TIM) heatmap patterns in patients at risk of labyrinthine abnormality to better understand accuracy and possible TIM limitations. STUDY DESIGN: Retrospective review of TIM patterns, preoperative, and postoperative imaging. SETTING: Tertiary referral center. PATIENTS: Patients undergoing cochlear implantation with risk of labyrinthine abnormality. INTERVENTION: None. RESULTS: Seventy-seven patients were evaluated. Twenty-five percent (n = 19) of patients had a TIM pattern variant identified. These variants were separated into 10 novel categories. Overall, 9% (n = 6) of electrodes were malpositioned on intraoperative x-ray, of which 50% (n = 3) were underinserted, 17% (n = 1) were overinserted, 17% (n = 1) had a tip foldover, and 17% (n = 1) had a coiled electrode. The number of patients with a variant TIM pattern and normal x-ray was 18% (n = 14), and the number of patients with normal TIM pattern and malposition noted on x-ray was 3% (n = 2; both were electrode underinsertions that were recognized due to open circuits and surgical visualization).A newly defined skip heat pattern was identified in patients with IP2/Mondini malformation and interscalar septum width <0.5 mm at the cochlear pars ascendens of the basal turn. CONCLUSIONS: This study defines novel patterns for TIM heatmap characterization to facilitate collaborative and comparative research moving forward. In doing so, it highlights a new pattern termed skip heat, which corresponds with a deficient interscalar septum of the cochlea pars ascendens of the basal turn in patients with IP2 malformation. Overall, the data assist the surgeon in better understanding the implications and limitations of TIM patterns within groups of patients with risk of labyrinthine abnormalities.

Cochlear Apex Triangulation Utilizing Ct Measures And Middle Ear Landmarks.

Objective: To better characterize the cochlear apex in relation to surgically relevant landmarks to guide surgeons and improve procedural success of apical electrode placement. Study Design: Retrospective image analysis. Setting: Tertiary referral center. Patients: Cochlear implant recipients with available preoperative computed tomography (CT) imaging. Intervention: None. Main Outcome Measure: Cochlear dimensions and cochlear apex distance measures to surgically relevant middle ear landmarks and critical structures. Results: Eighty-two temporal bone CT scans were analyzed utilizing multiplanar reformats. The average lateral width of promontory bone over the cochlear apex was 1.2 mm (standard deviation [SD], 0.3). The anteroposterior distance from the round window (avg, 4.2 mm; SD, 0.5), oval window (avg, 3.3 mm; SD, 0.3), cochleariform process (avg, 2.3; SD, 0.5), and superior-inferior distance from the cochleariform process (avg, -0.9; SD, 0.8) to the cochlear apex were measured. The relationship of the cochlear apex to critical structures was highly variable.A newly developed stapes vector was created and found to mark the posterior/superior boundary of the apex in 94% of patients. When a vector parallel to the stapes vector was drawn through the round window, it marked the anterior/inferior boundary of the cochlear apex in 89% of patients. Conclusions: This study assists in characterizing cochlear apex anatomy and its relation to surrounding structures as a means of improving procedural accuracy and reducing trauma during apical cochleostomy. Understanding both distance relationships and expected boundaries of the apex could help to inform future surgical approaches.

Performance After Cochlear Reimplantation Using a Different Manufacturer.

OBJECTIVE: To better understand cochlear implant (CI) performance after reimplantation with a different device manufacturer. STUDY DESIGN: Multisite retrospective review. SETTING: Tertiary referral centers. PATIENTS: Patients older than 4 years who received a CI and subsequently underwent CI reimplantation with a different manufacturer over a 20-year period. INTERVENTION: Reimplantation. MAIN OUTCOME MEASURE: The primary outcome was difference in the best CNC score obtained with the primary CI, compared with the most recent CNC score obtained after reimplantation. RESULTS: Twenty-nine patients met the criteria at three centers. The best average CNC score achieved by adult patients after primary cochlear implantation was 46.2% (n = 16), measured an average of 14 months (range: 3-36 mo) postoperatively. When looking at the most recent CNC score of adult patients before undergoing reimplantation, the average CNC score dropped to 19.2% (n = 17). After reimplantation, the average 3- to 6-month CNC score was 48.3% (n = 12), with most recent average CNC score being 44.4% (n = 17) measured an average of 19 months (range: 3-46 mo) postoperatively. There was no statistically significant difference (p = 0.321; t11 = 0.48) identified in performance between the best CNC score achieved by adult patients after primary cochlear implantation, and the most recent score achieved after reimplantation (n = 12). Analysis of prerevision and postrevision speech performance was not possible in pediatric patients (<18 yr old) because of differences in tests administered. CONCLUSION: Patients undergoing reimplantation with a different manufacturer achieved CNC score performance comparable to their best performance with their original device.

Characterization of CSL (CBF-1, Su(H), Lag-1) mutants reveals differences in signaling mediated by Notch1 and Notch2.

Notch is a conserved signaling pathway that plays essential roles during embryonic development and postnatally in adult tissues; misregulated signaling results in human disease. Notch receptor-ligand interactions trigger cleavage of the Notch receptor and release of its intracellular domain (NICD) from the membrane. NICD localizes to the nucleus where it forms a transcriptionally active complex with the DNA-binding protein CSL and the coactivator Mastermind (MAM) to up-regulate transcription from Notch target genes. Previous studies have determined the structure of the CSL-NICD-MAM ternary complex and characterized mutations that affect complex assembly in functional assays. However, as CSL is expressed in all cell types, these studies have been limited to analyzing mutations in NICD and MAM. Here, we describe a novel set of cellular reagents to characterize how mutations in CSL affect its function as a transcriptional activator. Using retrovirally transduced embryonic fibroblasts from a CSL-null mouse, we generated cell lines that express either wild-type or mutant CSL molecules. We then analyzed these mutants for defects in Notch1- (NICD1) or Notch2 (NICD2)-mediated activation from two different transcriptional reporters (HES-1 or 4×CBS). Our results show that mutations targeted to the different domains of CSL display significant differences in their ability to adversely affect transcription from the two reporters. Additionally, a subset of CSL mutants is sensitive to whether NICD1 or NICD2 was used to activate the reporter. Taken together, these studies provide important molecular insights into how Notch transcription complexes assemble at different target genes and promoter arrangements in vivo.

HiRes ultra series cochlear implant field recall: failure rates and early outcomes.

OBJECTIVE: Evaluate rates of Advanced Bionics Ultra 3D/Ultra cochlear implant failure in the setting of a worldwide device recall and report surgical and auditory outcomes after revision. METHODS: Retrospective chart review was performed for adult and pediatric patients implanted with at risk devices at our center from 2016 to 2020. Device failure rates, surgical, and auditory outcomes were recorded and analyzed. RESULTS: Of 113 at-risk devices, 20 devices (17.7%) in 18 patients (two bilaterally implanted) were identified as failures. All devices were with mid-scala electrodes. Eleven patients (61.1%) were children and 7 (38.9%) adults. Twelve patients were found to have failing devices after reporting subjective performance decline; the remainder were prompted by manufacturer notification. All were revised, with the majority (83.3%) choosing the same manufacturer. All had uncomplicated original and revision insertions. Among adults, average word scores on the revised side were stable pre- to post-revision (P = 0.95). DISCUSSION: Patients with device failure due to this field action performed well after revision implantation. Patients with bilateral at-risk devices but evidence of unilateral failure may elect to undergo simultaneous empiric revision of the contralateral device. Three patients who elected to change device manufacturers on revision have variable results that require further investigation. CONCLUSIONS: Patients requiring revision for a device field action overall perform well. At-risk devices continue to require monitoring as a growing number are likely to fail over time.

Bilateral cochlear implantation after immunotherapy-related profound hearing loss: A case report.

OBJECTIVES: Immune-checkpoint inhibitors (ICI) are being utilized with increasing frequency and may be linked to neurologic and audiovestibular toxicities. This report aimed to describe a case of ICI-induced sensorineural hearing loss ultimately requiring bilateral cochlear implantation. METHODS: A 42-year-old female with stage IV metastatic melanoma of the perianal skin was treated with ipilimumab (blocker of cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) and nivolumab (anti-programmed cell death protein 1 [PD1]). After 21 weeks of therapy, she developed sudden vertigo and bilateral hearing loss. A full workup including MRI and lumbar puncture ruled out intracranial parenchymal metastases, leptomeningeal metastases, stroke and intracranial infection. ICI-associated aseptic meningoencephalitis was therefore diagnosed. The patient received systemic steroids as well as intratympanic steroids, which temporarily improved hearing, but eventually developed permanent, bilateral profound sensorineural hearing loss. RESULTS: The patient received bilateral cochlear implants and has demonstrated good performance one year after implantation. DISCUSSION: ICI are being increasingly used to treat a variety of advanced malignancies. This is the first report of bilateral cochlear implants in the context of profound hearing loss after an immunotherapy induced meningoencephalitis. CONCLUSION: ICI carries the risk of potential ototoxicity, including profound SNHL as depicted in our case. Cochlear implantation proved to be beneficial and may be considered in patients with ICI-related hearing loss.