Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss.

Hearing loss is a significant public health concern, affecting over 250 million people worldwide. Both genetic and environmental etiologies are linked to hearing loss, but in many cases the underlying cellular pathophysiology is not well understood, highlighting the importance of further discovery. We found that inactivation of the gene Tmtc4 (transmembrane and tetratricopeptide repeat 4), which was broadly expressed in the mouse cochlea, caused acquired hearing loss in mice. Our data showed Tmtc4 enriched in the endoplasmic reticulum, and that it functioned by regulating Ca2+ dynamics and the unfolded protein response (UPR). Given this genetic linkage of the UPR to hearing loss, we demonstrated a direct link between the more common noise-induced hearing loss (NIHL) and the UPR. These experiments suggested a novel approach to treatment. We demonstrated that the small-molecule UPR and stress response modulator ISRIB (integrated stress response inhibitor), which activates eIF2B, prevented NIHL in a mouse model. Moreover, in an inverse genetic complementation approach, we demonstrated that mice with homozygous inactivation of both Tmtc4 and Chop had less hearing loss than knockout of Tmtc4 alone. This study implicated a novel mechanism for hearing impairment, highlighting a potential treatment approach for a broad range of human hearing loss disorders.

Long-term outcomes in unilateral vocal fold paralysis patients.

OBJECTIVES/HYPOTHESIS: At presentation, unilateral vocal fold paralysis (UVFP) patients have different treatment options, including conservative management (CM), injection laryngoplasty (IL) with a temporary agent, or permanent medialization (PM). This study evaluates long-term outcomes for UVFP patients relative to intervention. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review was performed of UVFP patients who presented to the University of California San Francisco Voice and Swallowing Center. Videolaryngostroboscopy examinations were reviewed. Maximum glottic closure was quantified with the normalized glottic gap area (NGGA). Perceptual voice analysis was performed using the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) at corresponding time points. RESULTS: Fifty-three patients met inclusion criteria. Six underwent CM only, 20 went on to require PM, 19 underwent IL only, and eight underwent IL and subsequent PM. NGGA at presentation was similar among groups; however, the CM group was noted to have more favorable CAPE-V scores for Breathiness (P = .007) and Loudness (P = .018). All groups had similar NGGA and CAPE-V scores at last follow-up. When compared to pooled data for patients who underwent PM, the IL group was noted to have similar NGGA and CAPE-V scores at presentation. Although improvements in both groups were noted following intervention, both groups appeared similar at last follow-up with the exception of Roughness, for which the IL group retained a slightly improved outcome (13.3 vs. 18.3, P = .03). CONCLUSIONS: At presentation, UVFP patients have similar NGGA. This finding suggests that treatment recommendations cannot be made on the size of the glottic gap alone. Furthermore, in many patients, IL results in long-term benefit with glottic closure and CAPE-V scores equivalent to that obtained with PM. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:430-436, 2018.

Clinical and quality-of-life outcomes following gland-preserving surgery for chronic sialadenitis.

OBJECTIVES/HYPOTHESIS: Gland-preserving salivary surgery utilizing salivary endoscopy has been proposed as a treatment alternative in the management of chronic sialadenitis. This study seeks to determine medium-term clinical and quality-of-life (QOL) outcomes following a gland-preserving approach for chronic sialadenitis. STUDY DESIGN: Cross-sectional survey with retrospective chart review. METHODS: All patients undergoing attempted gland-preserving salivary surgery with salivary endoscopy for chronic sialadenitis at a tertiary, academic salivary referral center between October 2008 and April 2013 were identified from a quality assurance database. A research database was constructed to examine clinical factors of interest. A clinical outcomes and QOL survey was mailed to all eligible patients in order to obtain long-term follow-up data. RESULTS: A total of 206 of 306 (67%) eligible patients returned the survey. The median length of follow-up was 17 months (3-54 months). The majority of patients (89%) endorsed symptom improvement after gland-preserving therapy. Surgical excision was performed on 8% of affected glands. Patients with chronic sialadenitis due to stones reported a greater incidence of symptom resolution (P = 0.0004) and more favorable QOL outcomes (P = 0.0001) than patients with nonstone etiologies. CONCLUSIONS: Patients undergoing gland-preserving salivary surgery with salivary endoscopy for chronic sialadenitis have favorable long-term symptom improvement and gland retention rates. Although patients with stones demonstrated the best outcomes, improvement was documented for all etiologies of chronic sialadenitis. LEVEL OF EVIDENCE: 4.