Efficacy of Combined Visual-Olfactory Training With Patient-Preferred Scents as Treatment for Patients With COVID-19 Resultant Olfactory Loss: A Randomized Clinical Trial.

Importance: The number of olfactory dysfunction cases has increased dramatically because of the COVID-19 pandemic. Identifying therapies that aid and accelerate recovery is essential. Objective: To determine the efficacy of bimodal visual-olfactory training and patient-preferred scents vs unimodal olfactory training and physician-assigned scents in COVID-19 olfactory loss. Design, Setting, and Participants: This was a randomized, single-blinded trial with a 2-by-2 factorial design (bimodal, patient preferred; unimodal, physician assigned; bimodal, physician assigned; unimodal, patient preferred) and an independent control group. Enrollment occurred from February 1 to May 27, 2021. Participants were adults 18 to 71 years old with current olfactory loss defined as University of Pennsylvania Smell Identification Test (UPSIT) score less than 34 for men and less than 35 for women and duration of 3 months or longer. Olfactory loss was initially diagnosed within 2 weeks of COVID-19 infection. Interventions: Participants sniffed 4 essential oils for 15 seconds with a 30-second rest in between odors for 3 months. Participants in the physician-assigned odor arms trained with rose, lemon, eucalyptus, and clove. Participants randomized to the patient-preferred arms chose 4 of 24 available scents. If assigned to the bimodal arm, participants were shown digital images of the essential oil they were smelling. Main Outcomes and Measures: The primary end point was postintervention change in UPSIT score from baseline; measures used were the UPSIT (validated, objective psychometric test of olfaction), Clinical Global Impressions Impression-Improvement (CGI-I; self-report improvement scale), and Olfactory Dysfunction Outcomes Rating (ODOR; olfaction-related quality-of-life questionnaire). Results: Among the 275 enrolled participants, the mean (SD) age was 41 (12) years, and 236 (86%) were female. The change in UPSIT scores preintervention to postintervention was similar between the study arms. The marginal mean difference for change in UPSIT scores preintervention to postintervention between participants randomized to patient-preferred vs physician-assigned olfactory training was 0.73 (95% CI, -1.10 to 2.56), and between participants randomized to bimodal vs unimodal olfactory training was 1.10 (95% CI, -2.92 to 0.74). Five (24%) participants in the control arm had clinically important improvement on UPSIT compared with 18 (53%) in the bimodal, patient-preferred arm for a difference of 29% (95% CI, 4%-54%). Four (19%) participants in the control group self-reported improvement on CGI-I compared with 12 (35%) in the bimodal, patient-preferred arm for a difference of 16% (95% CI, -7% to 39%). The mean change in ODOR score preintervention to postintervention was 11.6 points (95% CI, 9.2-13.9), which was not deemed clinically important nor significantly different between arms. Conclusions and Relevance: Based on the change in UPSIT scores, this randomized clinical trial did not show any difference between intervention arms, but when exploring within-patient change in UPSIT as well as self-reported impression of improvement, active interventions were associated with larger improvement than controls with a potential advantage of bimodal intervention. While not definitive, these results suggest that patients with COVID-19 olfactory loss may benefit from bimodal visual-olfactory training with patient-preferred scents. Trial Registration: ClinicalTrials.gov Identifier: NCT04710394.

Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19-Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial.

Importance: Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic. Objective: To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19-related OD. Design, Setting, and Participants: This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021. Interventions: Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks. Main Outcomes and Measures: The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19-related questions. Results: A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, -13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, -1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, -2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, -4% to 52%) in favor of theophylline. Conclusions and Relevance: This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19-related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully. Trial Registration: ClinicalTrials.gov Identifier: NCT04789499.

Hearing and Quality-of-Life Outcomes After Cochlear Implantation in Adult Hearing Aid Users 65 Years or Older: A Secondary Analysis of a Nonrandomized Clinical Trial.

Importance: Hearing loss, especially moderate to severe forms, has the potential to negatively affect an individual's physical, social, emotional, and cognitive well-being. Moreover, having ineffective binaural hearing increases difficulty understanding speech in noise and leads to a greater degree of social isolation and loneliness and a reduced quality of life (QoL). Objective: To explore the audiometric and holistic effects of cochlear implantation in a group of adults 65 years or older compared with an optimized bilateral hearing aid condition. Design, Setting, and Participants: This ad hoc secondary analysis of a prospective, single-subject, repeated-measures nonrandomized clinical trial included 13 cochlear implantation centers across the United States. Participants 65 years or older with postlingual bilateral moderate-to-profound sensorineural hearing loss with aided Consonant-Vowel Nucleus-Consonant (CNC) word scores in quiet of 40% or less in the ear to undergo implantation and 50% or less in the contralateral ear were included in the analysis. Baseline QoL testing was performed after 1 month of optimized bilateral hearing aid use. Participants were enrolled from February 20, 2017, to May 3, 2018, and follow-up was completed December 21, 2018. Data were analyzed from March 25, 2019, to March 31, 2020. Interventions: Unilateral implantation with a slim, modiolar cochlear implant device. Hearing aid use in the contralateral ear was required through the 6-month primary end-point interval. Main Outcomes and Measures: The primary objective was to evaluate speech perception before and 6 months after activation of a new cochlear implant. Secondary objectives were QoL metrics in the everyday listening condition before and 6 months after implantation. Results: Seventy participants (51 men [73%]) with a median age of 74 (range, 65-91) years were included in the analysis. No major adverse events occurred. Mixed-model analysis with estimated marginal means and 95% CIs compared preimplantation baseline performance with 6-month postimplantation performance. A clinically important improvement in CNC words was shown in the bimodal condition, with a mean difference of 37.2% (95% CI, 32.0%-42.4%), and in the unilateral (cochlear implant only) condition, with a mean difference of 44.1% (95% CI, 39.0%-49.2%). A clinically important improvement in noise (AzBio sentences signal-to-noise ratio of +10 dB) was also shown, with a mean difference of 21.6% (95% CI, 15.7%-27.5%) in the bimodal condition and 24.5% (95% CI, 18.3%-30.7%) in the unilateral condition. The Health Utilities Index Mark 3 multiple-attribute score improved by 0.186 (95% CI, 0.136-0.234); the Speech, Spatial, and Qualities of Hearing Scale total score improved by 2.58 (95% CI, 2.18-2.99); and a novel Device Use Questionnaire reported 94% of participants were satisfied with overall hearing in the everyday listening condition. Conclusions and Relevance: This subgroup analysis of patients 65 years or older enrolled in a within-subject clinical trial of cochlear implantation demonstrated clinically meaningful audiometric and QoL benefit with an acceptable risk profile. These findings suggest that cochlear implantation in older adults may facilitate the concept of healthy aging. Trial Registration: ClinicalTrials.gov Identifier: NCT03007472.

Patient-defined duration of benefit from juvederm (hyaluronic acid) used in injection laryngoplasty.

OBJECTIVES/HYPOTHESIS: Injection laryngoplasty has become valuable in treating laryngologic disorders including vocal cord atrophy, paralysis, and paresis. Although materials such as carboxymethylcellulose and calcium hydroxylapatite are Food and Drug Administration (FDA) approved, they are not without limitations. Juvederm (hyaluronic acid) is an alternative treatment that is not FDA approved. Although studies have examined Juvederm's longevity in cutaneous injections, there are limited data examining durability of Juvederm used in laryngoplasty. We aimed to determine the longevity and effectiveness of Juvederm used in injection laryngoplasty. STUDY DESIGN: Retrospective cohort study. METHODS: Subjects who underwent injection laryngoplasty using Juvederm were reviewed. Longevity was defined as the time between injection and the date that a patient first noted subjective deterioration of their voice. All subjects were subsequently followed using videostroboscopy to evaluate for Juvederm resorption. Longevity was analyzed using a Kaplan-Meier survival model, and effectiveness of laryngoplasty was determined using the Voice-Related Quality of Life index scores and analyzed using a Wilcoxon signed ranks test. RESULTS: Fifty-nine subjects met inclusion criteria and underwent Juvederm injection laryngoplasty. Kaplan-Meier survival analysis revealed a mean longevity of 10.6 months (95% confidence interval: 9.1-12.0 months). Wilcoxon signed ranks analysis of the pre- and postinjection Voice Related Quality of Life (VRQOL) scores revealed improvement, with a mean preinjection VRQOL of 49.2 (standard deviation [SD] = 25.8) and mean postinjection VRQOL of 68.2 (SD = 27.5) (P < .001). CONCLUSIONS: Injection laryngoplasty using Juvederm is an effective treatment for vocal cord atrophy, paralysis, and paresis. Knowledge of the patient-defined duration of benefit following laryngoplasty using Juvederm plays an important role in counseling patients as well as in the planning of future interventions. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:2744-2747, 2019.

Heterogeneity in Definitions of High-risk Prostate Cancer and Varying Impact on Mortality Rates after Radical Prostatectomy.

BACKGROUND: Multiple definitions of high-risk prostate cancer (PC) exist in clinical practice. Prior studies have primarily evaluated the variability in prediction of biochemical recurrence. OBJECTIVE: To examine the impact of different definitions on mortality after radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of 6477 men with clinically localized disease undergoing RP at Barnes-Jewish Hospital (St. Louis, MO, USA) and Cleveland Clinic (Cleveland, OH, USA) between 1995 and 2007. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Seven pretreatment definitions of high-risk PC (prostate-specific antigen [PSA] ≥20ng/ml, biopsy Gleason score 8-10, clinical stage ≥T2c, cT3, D'Amico definition, National Comprehensive Cancer Network definition, Kattan nomogram) were evaluated. The Kaplan-Meier method was used to generate unadjusted survival estimates. Multivariable Cox proportional hazard regression models (controlling for age) were used to estimate the hazard ratio (HR) for PC-specific mortality (PCSM) and overall mortality (OM) in the high-risk group compared to men with lower risk not meeting that definition. RESULTS AND LIMITATIONS: 6477 men were treated with RP from 1995 to 2007 and were followed for a median of 67 mo. Depending on the definition, patients with high-risk PC comprised between 0.7% (when using cT3 as the criterion) and 8.2% (when using the D'Amico criterion) of the population. The 10-yr PC survival estimates varied from 89.7% (PSA ≥20ng/ml) to 69.7% (cT3) and overall survival ranged from 83.4% to 58.1%. On multivariable analysis, all high-risk definitions were associated with a higher risk of PCSM compared to lower risk (HR ranging from 4.38 for PSA ≥20ng/ml to 19.97 for cT3; all p<0.001). All definitions of high risk except for preoperative PSA ≥20ng/ml were associated with a higher risk of OM (HR 1.72 for D'Amico to 3.31 for cT3; all p<0.01). CONCLUSIONS: Heterogeneity in outcomes existed, depending on the pretreatment definition of high-risk PC. Clinical stage T3 and Gleason score 8-10 were most strongly associated with PCSM and OM. PATIENT SUMMARY: There is variability in prostate cancer outcomes after surgery, depending on the definition of pretreatment high-risk disease used. Clinical stage T3 and high Gleason score were most strongly associated with prostate cancer-specific mortality and overall mortality.

Evaluation of Quality Metrics for Surgically Treated Laryngeal Squamous Cell Carcinoma.

Importance: Quality metrics for patients with laryngeal squamous cell carcinoma (SCC) exist, but whether compliance with these metrics correlates with improved survival is unknown. Objective: To examine whether compliance with proposed quality metrics is associated with improved survival in patients with laryngeal SCC treated with surgery with or without adjuvant therapy. Design, Setting, and Participants: This retrospective cohort study included patients from a tertiary care academic medical center who had previously untreated laryngeal SCC and underwent surgery with or without adjuvant therapy from January 1, 2003, through December 31, 2012. Data analysis was performed from August 4, 2015, through December 13, 2015. Interventions: Surgery with or without adjuvant therapy. Main Outcomes and Measures: Compliance with quality metrics from the American Head and Neck Society (AHNS), National Comprehensive Cancer Network (NCCN) guidelines, and institutional metrics with face validity covering pretreatment evaluation, treatment, and posttreatment surveillance was evaluated. The association between compliance with the group of metrics and overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) was explored using Cox proportional hazards analysis. The association between compliance with individual metrics and survival was similarly determined. Results: A total of 243 patients (184 men and 59 women) were included in the study (median age, 62 years; age range, 23-87 years). No association was found between increasing levels of compliance with the AHNS or NCCN metrics and survival. The only AHNS or NCCN metric for which greater compliance correlated with improved survival on multivariable Cox proportional hazards analysis controlling for pT stage, pN stage, extracapsular spread, margin status, and comorbidity was pretreatment multidisciplinary evaluation for patients with stage cT3-4 or cN1-3 disease (OS adjusted hazard ratio [aHR], 0.47; 95% CI, 0.24-0.94; DFS aHR, 0.45; 95% CI, 0.23-0.85). For the institutional metrics, multidisciplinary evaluation for all patients (OS aHR, 0.51; 95% CI, 0.29-0.88; DFS aHR, 0.50, 95% CI, 0.32-0.80) and elective neck dissection yield of 18 lymph nodes or more (DFS aHR, 0.36; 95% CI, 0.14-0.99) were associated with improved survival on multivariable Cox proportional hazards analysis. Conclusions and Relevance: In this cohort of patients with surgically treated laryngeal SCC, multidisciplinary evaluation and elective neck dissection yield of 18 lymph nodes or more are associated with improved survival. Development of better quality metrics is necessary because increased compliance with metrics described by the AHNS and NCCN is not associated with improved survival. Previously described metrics for surgically treated oral cavity cancer are not prognostic for surgically treated laryngeal SCC. Future multi-institutional collaboration will be required to validate these findings, develop better quality metrics, and evaluate whether quality metrics for head and neck cancer are site specific.

Effects of mindfulness based stress reduction therapy on subjective bother and neural connectivity in chronic tinnitus.

OBJECTIVE: To evaluate the impact of a Mindfulness Based Stress Reduction (MBSR) program in patients with chronic bothersome tinnitus on the (1) severity of symptoms of tinnitus and (2) functional connectivity in neural attention networks. STUDY DESIGN: Open-label interventional pilot study. SETTING: Outpatient academic medical center. SUBJECTS: A total of 13 adult participants with a median age of 55 years, suffering from bothersome tinnitus. METHODS: An 8-week MBSR program was conducted by a trained MBSR instructor. The primary outcome measure was the difference in patient-reported tinnitus symptoms using the Tinnitus Handicap Index (THI) and Tinnitus Functional Index (TFI) between pre-intervention, post-MBSR, and 4-week post-MBSR assessments. Secondary outcomes included change in measurements of depression, anxiety, mindfulness, and cognitive abilities. Functional connectivity magnetic resonance imaging (MRI) was performed at pre- and post-MBSR intervention time points to serve as a neuroimaging biomarker of critical cortical networks. RESULTS: Scores on the THI and TFI showed statistically significant and clinically meaningful improvement over the course of the study with a median ΔTHI of -16 and median ΔTFI of -14.8 between baseline and 4-week follow-up scores. Except for depression, there was no significant change in any of the secondary outcome measures. Analysis of the resting state functional connectivity MRI (rs-fcMRI) data showed increased connectivity in the post-MBSR group in attention networks but not the default network. CONCLUSION: Participation in an MBSR program is associated with decreased severity in tinnitus symptoms and depression and connectivity changes in neural attention networks. MBSR is a promising treatment option for chronic bothersome tinnitus that is both noninvasive and inexpensive.

The role of postoperative chemoradiation for oropharynx carcinoma: a critical appraisal of the published literature and National Comprehensive Cancer Network guidelines.

The National Comprehensive Cancer Network (NCCN) describes the presence of extracapsular spread and/or positive margins in oropharynx cancer (OPC) as an indication for the addition of chemotherapy to postoperative radiation. The guideline's category 1 consensus is based on what they term high-level evidence. For this study, the authors performed a critical appraisal of the research upon which the NCCN guideline is based and assessed its relevance in the era of human papillomavirus (HPV)/p16-positive OPC. Multiple shortcomings were identified, including patient exclusion after randomization and the use of unplanned subgroup analyses without multivariate adjustment, which undermined internal validity. Indeterminate HPV/p16 status limited external validity. Given the unique biology of HPV/p16-positive tumors and the problems of internal and external validity, the authors concluded that the literature upon which the recommendation for the addition of chemotherapy to adjuvant radiation was based does not generate high-level evidence, and its relevance for the postoperative management of patients with HPV/p16-positive OPC remains unknown.

Functional connectivity during modulation of tinnitus with orofacial maneuvers.

OBJECTIVE: To determine changes in cortical neural networks as defined by resting-state functional connectivity magnetic resonance imaging during voluntary modulation of tinnitus with orofacial maneuvers. STUDY DESIGN: Cross-sectional study. SETTING: Academic medical center. SUBJECTS AND METHODS: Participants were scanned during the maneuver and also at baseline to serve as their own control. The authors chose, a priori, 58 seed regions to evaluate previously described cortical neural networks by computing temporal correlations between all seed region pairs. Seed regions whose correlations significantly differed between rest and maneuver (P < .05, uncorrected) entered into a second-stage analysis of computing the correlation coefficient between the seed region and time courses in each of the remaining brain voxels. A threshold-free cluster enhancement permutation analysis evaluated the distribution of these correlation coefficients after transformation to Fisher z scores and registration to a surface-based reconstruction using Freesurfer. RESULTS: The median age for the 16 subjects was 54 years (range, 27-72 years), and all had subjective, unilateral or bilateral, nonpulsatile tinnitus for 6 months or longer. In 9 subjects who could voluntarily increase the loudness of their tinnitus, there were no significant differences in functional connectivity in any cortical networks. A separate analysis evaluated results from 3 patients who decreased the loudness of their tinnitus. Four subjects were excluded because of excessive motion in the scanner. CONCLUSION: The absence of significant differences in functional connectivity due to voluntary orofacial maneuvers that increased tinnitus loudness failed to confirm prior reports of altered cerebral blood flows during somatomotor behaviors.