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Background: An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects., Objectives: We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention., Search Methods: We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors., Selection Criteria: We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm., Data Collection and Analysis: We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes., Main Results: We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I 2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect., Authors' Conclusions: We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: Electrocochleography (ECochG) is increasingly being used during cochlear implant (CI) surgery to detect and mitigate insertion-related intracochlear trauma, where a drop in ECochG signal has been shown to correlate with a decline in hearing outcomes. In this study, an ECochG-guided robotics-assisted CI insertion system was developed and characterized that provides controlled and consistent electrode array insertions while monitoring and adapting to real-time ECochG signals., Study Design: Experimental research., Setting: A research laboratory and animal testing facility., Methods: A proof-of-concept benchtop study evaluated the ability of the system to detect simulated ECochG signal changes and robotically adapt the insertion. Additionally, the ECochG-guided insertion system was evaluated in a pilot in vivo sheep study to characterize the signal-to-noise ratio and amplitude of ECochG recordings during robotics-assisted insertions. The system comprises an electrode array insertion drive unit, an extracochlear recording electrode module, and a control console that interfaces with both components and the surgeon., Results: The system exhibited a microvolt signal resolution and a response time <100 milliseconds after signal change detection, indicating that the system can detect changes and respond faster than a human. Additionally, animal results demonstrated that the system was capable of recording ECochG signals with a high signal-to-noise ratio and sufficient amplitude., Conclusion: An ECochG-guided robotics-assisted CI insertion system can detect real-time drops in ECochG signals during electrode array insertions and immediately alter the insertion motion. The system may provide a surgeon the means to monitor and reduce CI insertion-related trauma beyond manual insertion techniques for improved CI hearing outcomes.

Understanding genetic causes of hearing loss can determine the pattern and course of a patient's hearing loss and may also predict outcomes after cochlear implantation. Our goal in this study was to evaluate genetic causes of hearing loss in a large cohort of adults and children with cochlear implants. We performed comprehensive genetic testing on all patients undergoing cochlear implantation. Of the 459 patients included in the study, 128 (28%) had positive genetic testing. In total, 44 genes were identified as causative. The top 5 genes implicated were GJB2 (20, 16%), TMPRSS3 (13, 10%), SLC26A4 (10, 8%), MYO7A (9, 7%), and MT-RNR1 (7, 5%). Pediatric patients had a higher diagnostic rate. This study lays the groundwork for future studies evaluating the relationship between genetic variation and cochlear implant performance.

Purpose: In pharmacoepidemiological studies, the precision of effect estimates usually depends on the lowest number in the underlying two by two table. We denote this the "bottleneck count" (BNC). We describe how to translate the BNC into an achievable precision and provide empirical examples., Methods: First, we derive a theoretical prediction of the precision in a study where only the BNC determines precision. As an illustration, we calculated the expected precision of a null-effect study on retinoids and peptic ulcer bleeding, expressed as the upper/lower confidence limit ratio (ULCLR). Finally, we reviewed 126 effect estimates from the literature, analyzing the relationship between the predicted and achieved precision., Results: The log-log transformed ULCLR was shown to be a simple linear function of log(BNC). The expected annual number of retinoid-users experiencing a peptic ulcer bleeding was 9.8, yielding an estimated ULCLR for a 1-year study of 3.84. The literature review showed an inverse linear relationship between the logarithmic BNC and the log-log transformed ULCLR, which was largely independent of study design, effect measure and category of BNC. Achieved precision deviated little from predictions but was usually lower than predicted, particularly with low BNC., Conclusion: The precision of a study can be predicted simply and with good accuracy from the BNC, which is useful for determining whether a study is worth pursuing or not., (© 2021 John Wiley & Sons Ltd.)

Objective: Radiation therapy is a mainstay in the treatment of numerous neoplasms. Numerous publications have reported good clinical outcomes for primary radiation therapy for Vestibular Schwannomas (VS). However, there are relatively few pathologic specimens of VSs available to evaluate post-radiation, which has led to a relative dearth in research on the cellular mechanisms underlying the effects of radiation therapy on VSs., Methods: Here we review the latest literature on the complex biological effects of radiation therapy on these benign tumors-including resistance to oxidative stress, mechanisms of DNA damage repair, alterations in normal growth factor pathways, changes in surrounding vasculature, and alterations in immune responses following radiation., Results: Although VSs are highly radioresistant, radiotherapy is often successful in arresting their growth., Conclusion: By better understanding the mechanisms underlying these effects, we could potentially harness such mechanisms in the future to potentiate the clinical effects of radiotherapy on VSs., Level of Evidence: N/A., Competing Interests: The authors report no conflicts of interest relating to the current work., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Objective: To study the relationship between various electrodiagnostic modalities in acute facial palsy., Setting: Academic tertiary care center., Patients: One-hundred and six patients who presented with traumatic or non-traumatic acute facial paralysis (House-Brackmann, HB, grade 6/6) between 2008 and 2017 and underwent acute electrodiagnostic testing., Intervention: Electroneurography (ENoG) using nasolabial fold (NLF) or nasalis muscle (NM) methods, and volitional electromyography (EMG) in all patients., Main Outcome Measures: Percent degeneration of ipsilateral facial nerve compound muscle action potentials (CMAP) on NLF- and NM-ENoG, presence or absence of muscle unit potentials (MUPs) on EMG., Results: Extent of facial nerve degeneration measured by NLF- and NM-ENoG were highly correlated ( r = 0.85, P  < .01) on each test and on serial testing. NLF- and NM-ENoG concordantly diagnosed ≥90% degeneration in 44 patients (80%), of whom 32 patients were diagnosed to have 100% degeneration by both methodologies. Absence of MUPs on EMG was 63% sensitive and 92% specific for ≥90% degeneration on ENoG, with a positive predictive value of 90%. For patients with Bell's palsy, percent degeneration on ENoG was also correlated to HB score at 1 year. Surgical decompression resulted in mean HB scores of 2.2 and 3.0 for patients with Bell's palsy and trauma, respectively., Conclusions: NM-ENoG may be a valid and comparable method to NLF-ENoG for predicting the recovery of facial nerve function in acute paralysis. Absence of MUPs on EMG is a specific measure of severe degeneration and highly predictive of candidacy for surgical decompression., Level of Evidence: Level 3., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Objective: To report current knowledge on the topic of intracochlear fibrosis and the foreign body response following cochlear implantation (CI)., Methods: A literature search was performed in PubMed to identify peer-reviewed articles. Search components included "cochlear implant," "Foreign body response (FBR)," and "fibrosis." Original studies and review articles relevant to the topic were included., Results: Ninety peer-reviewed articles describing the foreign body response or intracochlear fibrosis following CI were included., Conclusions: Intracochlear fibrosis following CI represents a significant limiting factor for the success of CI users. Several strategies have been employed to mitigate the foreign body response within the cochlea including drug delivery systems and modifications in surgical technique and electrode design. A better understanding of the FBR has the potential to improve CI outcomes and the next generation of cochlear prostheses., Competing Interests: Dr Hansen is a co‐founder and Chief Medical Officer of Iotamotion, Inc. All other authors of this work declare no conflict of interest., (© 2019 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals, Inc. on behalf of The Triological Society.)

Background and Purpose: Multiple sclerosis (MS) clinical management is based upon lesion characterization from 2-dimensional (2D) magnetic resonance imaging (MRI) views. Such views fail to convey the lesion-phenotype (ie, shape and surface texture) complexity, underlying metabolic alterations, and remyelination potential. We utilized a 3-dimensional (3D) lesion phenotyping approach coupled with imaging to study physiologic profiles within and around MS lesions and their impacts on lesion phenotypes., Methods: Lesions were identified in 3T T 2 -FLAIR images and segmented using geodesic active contouring. A calibrated fMRI sequence permitted measurement of cerebral blood flow (CBF), blood-oxygen-level-dependent signal (BOLD), and cerebral metabolic rate of oxygen (CMRO 2 ). These metrics were measured within lesions and surrounding tissue in concentric layers exact to the 3D-lesion shape. BOLD slope was calculated as BOLD changes from a lesion to its surrounding perimeters. White matter integrity was measured using diffusion kurtosis imaging. Associations between these metrics and 3D-lesion phenotypes were studied., Results: One hundred nine lesions from 23 MS patients were analyzed. We identified a noninvasive biomarker, BOLD slope, to metabolically characterize lesions. Positive BOLD slope lesions were metabolically active with higher CMRO 2 and CBF compared to negative BOLD slope or inactive lesions. Metabolically active lesions with more intact white matter integrity had more symmetrical shapes and more complex surface textures compared to inactive lesions with less intact white matter integrity., Conclusion: The association of lesion phenotypes with their metabolic signatures suggests the prospect for translation of such data to clinical management by providing information related to metabolic activity, lesion age, and risk for disease reactivation and self-repair. Our findings also provide a platform for disease surveillance and outcome quantification involving myelin repair therapeutics., (© 2019 by the American Society of Neuroimaging.)

Cochlear implantation has become the standard-of-care for adults and children with severe to profound hearing loss. There is growing evidence that qualitative as well as quantitative deficits in the auditory nerve may affect cochlear implant (CI) outcomes. Auditory neuropathy spectrum disorder (ANSD) is characterized by dysfunctional transmission of sound from the cochlea to the brain due to defective synaptic function or neural conduction. In this review, we examine the precise mechanisms of genetic lesions causing ANSD and the effect of these lesions on CI outcomes. Reviewed data show that individuals with lesions that primarily affect the cochlear sensory system and the synapse, which are bypassed by the CI, have optimal CI outcomes. Individuals with lesions that affect the auditory nerve show poor performance with CIs, likely because neural transmission of the electrical signal from the CI is affected. We put forth a nuanced molecular classification of ANSD that has implications for preoperative counseling for patients with this disorder prior to cochlear implantation. We propose that description of ANSD patients should be based on the molecular site of lesion typically derived from genetic evaluation (synaptopathy vs. neuropathy) as this has implications for expected CI outcomes. Improvements in our understanding of genetic site of lesions and their effects on CI function should lead to better CI outcomes, not just for individuals with auditory neuropathy, but all individuals with hearing loss.

Purpose: Standard Kaplan-Meier (KM) survival analysis is often used to study treatment persistence estimating the proportion of patients who have not yet experienced a treatment break by a given day after treatment initiation. This method only allows patients to be studied until their first treatment break. The "proportion of patients covered" (PPC) method is another approach to study treatment persistence. It measures the proportion of live patients currently covered by treatment. We aimed to describe the PPC method, show how the KM survival analysis and the PPC method can describe treatment persistence, and discuss the interpretation/application of the methods., Methods: We identified new users of statins, selective serotonin reuptake inhibitors, hormone replacement therapy, and ibuprofen. We used KM estimates and the PPC to describe persistence in the 3 years post treatment initiation, using a grace period of 90 days to define a treatment break., Results: Three years after statin initiation, approximately 40% of patients were still in continuous treatment (KM survival) and 60% of patients still alive were in current treatment (PPC). Corresponding numbers were 12% and 25% for selective serotonin reuptake inhibitors and 9% and 29% for hormone replacement therapy. At 1 year, numbers were 5% and 10% for ibuprofen. The PPC showed markedly less variability than the KM survival analysis with different choices of grace periods., Conclusions: The KM survival analysis and the PPC method can be used to study different aspects of treatment persistence. Together, they provide a more complete picture of treatment persistence and drug use patterns., (© 2018 John Wiley & Sons, Ltd.)

Background: Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug-drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values., Methods: The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test., Results: We identified 305 warfarin users initiating treatment with PPIs. The median age was 71 years (interquartile range 63-78 years), and 64% were men. The mean INR in the 70 days prior to PPI initiation was 2.6 (95%CI 2.5-2.8) and 2.6 (95%CI 2.5-2.7) in the period 1-3 weeks after PPI initiation (p = 0.67). Further, neither mean warfarin dose nor the dose/INR ratios were significantly different before and after PPI initiation. Sensitivity analyses revealed no differences among individual PPIs., Conclusions: We found no evidence of a clinically meaningful drug-drug interaction between PPIs and warfarin in a Northern European patient population of unselected patients from an everyday outpatient and primary care clinical setting. Thus, we do not support the recommendation to "cautiously monitor" users of warfarin initiating PPI treatment., (Copyright © 2015 John Wiley & Sons, Ltd.)