Betahistine for tinnitus (Protocol)

Background: Tinnitus describes 'ringing', 'whooshing' or 'hissing' sounds that are heard in the absence of any corresponding external sound. Between 5% and 43% of people experience this symptom and for some it has a significant negative impact on their quality of life. Tinnitus can be managed through education and advice, prescription devices that improve hearing, over-the-counter devices that generate background sounds, psychological therapy and relaxation therapy. Drug therapies are used to manage complaints associated with tinnitus such as sleep difficulties, anxiety or depression. No drug therapies exist that manage the tinnitus itself. Nonetheless, betahistine is often prescribed for tinnitus. The purpose of this review is to evaluate the evidence from high-quality clinical trials to work out the effect of betahistine on people's tinnitus. We particularly wanted to look at the effect of betahistine on tinnitus loudness and the side effects of betahistine.Study characteristics: Our review identified five randomised controlled trials with a total of 303 to 305 participants who suffered from tinnitus. These studies compared participants receiving betahistine to those receiving a placebo. Four study designs allocated participants into parallel groups. In one study, participants consented to take all study medications in a pre-defined sequence. The outcomes that we evaluated included tinnitus loudness and intrusiveness, tinnitus symptoms and side effects.Key results: The included studies did not show differences in tinnitus loudness, severity of tinnitus symptoms or side effects between participants receiving betahistine and participants receiving a placebo. No significant side effects were reported. We had planned to evaluate changes in tinnitus intrusiveness, depression and anxiety and quality of life, but these were not measured. The evidence suggests that betahistine is generally well tolerated with a similar risk of side effects to placebo.Quality of the evidence: The quality of the evidence ranged from moderate to very low. The risk of bias in all of the included studies was unclear. The results were drawn from one or two studies only. In some studies, the participants that were included did not fully represent the entire population of people with tinnitus and so we cannot draw general conclusions

Effect of electrical stimulation with a cochlear implant on tinnitus impact: protocol of an individual patient data meta-analysis

INTRODUCTION: Tinnitus is the perception of sound without an external stimulus, often experienced as a ringing, buzzing sound. While several studies have shown a reduction in tinnitus distress following cochlear implantation, others showed an increase or no change after implantation. At this stage, clinicians have little certainty when counselling their patients prior to implantation regarding tinnitus post-implantation. To help clinicians to counsel cochlear implant (CI) candidates on the risk of developing or improving tinnitus after implantation, we aim to assess the effect of electrical stimulation with a CI on tinnitus impact for individual adult patients with tinnitus. We will also apply prediction models to individual patient data (IPD) of clinical trials to find predictive factors of the effect of electrical stimulation on tinnitus impact. METHOD AND ANALYSIS: The IPD meta-analysis is a follow-up project of the systematic review on cochlear implantation in patients with tinnitus as a primary complaint. First, the systematic searches will be updated to date. Methodological quality of eligible studies will be assessed using the Risk of Bias In Non-randomised Studies of Intervention tool (ROBINS-I). Based on a data-sharing agreement, authors of the eligible studies will be invited to share their deidentified and complete IPD. The primary outcome is the effect of electrical stimulation with a CI on tinnitus impact 1 month or more post-implantation. IPD meta-analysis will be used to assess the primary outcome, while differentiating the tinnitus impact questionnaires. Second, linear regression analyses will be used to model the effect of electrical stimulation on tinnitus impact based on relevant predictors. ETHICS AND DISSEMINATION: The Medical Research Involving Human Subject Act does not apply, and ethical approval is not required. The study results will be made accessible to the public in a peer-review open access journal. PROSPERO REGISTRATION NUMBER: CRD42022319367, review ongoing

Cochlear Implant Awareness: Development and Validation of a Patient Reported Outcome Measure

BACKGROUND: Surgical success of cochlear implantation is usually measured through speech perception and quality of life questionnaires. Although these questionnaires cover a broad spectrum of domains, they do not evaluate the consciousness of wearing a cochlear implant (CI) and how this impacts the daily life of patients. To evaluate this concept we aimed to develop and validate a standardized patient reported outcome measure (PROM) for use in cochlear implant users. METHODS: Development and evaluation of the COchlear iMPlant AwareneSS (COMPASS) questionnaire was realized following the COSMIN guidelines in three phases: (1) item generation, (2) qualitative pilot study to ensure relevance, comprehensiveness, comprehensibility, and face validity, and (3) quantitative survey study for the assessment of reliability (test-retest) with 54 participants. RESULTS: Nine domains of CI awareness were identified through literature research and interviews with experts and patients. These resulted in the formulation of 18 items which were tested with a pilot study, after which 3 items were deleted. The final 15-item COMPASS questionnaire proved to have good validity and satisfactory reliability. The intraclass correlation coefficient calculated for items with continuous variables ranged from 0.66 to 0.89 with seven out of eight items scoring above the acceptable level of 0.7. The Cohen's kappa calculated for items with nominal variables ranged from -0.4 to 0.78 with 11 (sub)items out of 15 scoring above fair to good agreement. Measurement error analysis for items with continuous variables showed a mean difference of -2.18 to 0.22. The calculated 95% limits of agreement for these items revealed no statistically significant difference between the two administered questionnaires. For items with nominal variables, the percentages of agreement calculated, ranged between 0 and 95%, and 83.3 and 96.6% for positive and negative agreement, respectively. CONCLUSION: The COMPASS questionnaire is a valid and reliable PROM for evaluating the cochlear implant awareness, and it can be easily used in routine clinical practice

Diagnostic accuracy of the screenings Sniffin' Sticks Test (SST-12) in COVID-19 induced olfactory disorders

Objective olfactory function can be assessed using validated olfactory tests like the Sniffin' Sticks Test (SST). However, their extensive nature makes them less suitable for clinical practice. To address this, shorter olfactory tests like the screenings Sniffin' Sticks Test (SST-12) can be used for screening purposes and reduce testing time. The SST-12 serves as a diagnostic tool for screening olfaction in cases unrelated to COVID-19. However, these screening tests are uncertain regarding their accuracy in detecting olfactory dysfunction in patients with COVID-19 as the plausible cause. We aim to determine the diagnostic accuracy of the SST-12 in adults with post-COVID-19 olfactory dysfunction. We performed a diagnostic accuracy study with data from 113 consecutive COVID-19 diagnosed patients who experienced objectified smell loss ever since. At approximately 6 months after their diagnosis, all participants underwent the SST (reference standard), part of the SST was the SST-12 (index test). Diagnostic accuracy of the SST-12 is measured as negative predictive value (NPV), positive predictive value (PPV), sensitivity, and specificity. The SST-12 detected smell loss in 85 patients among 91 patients with smell loss and ruled out smell loss in 15 patients among the 22 patients without smell loss based on the reference standard. Making sensitivity 93.4% (CI 0.87-0.97), and specificity 68.2% (CI 0.48-0.85). Out of the 92 patients with a positive test result on SST-12, 85 patients had indeed smell loss (PPV 92.4% CI 0.86-0.97), and out of the 21 patients with a negative test result, 15 patients had no smell loss regarding the reference standard (NPV 71.4% CI 0.50-0.88). The findings suggest that the SST-12 holds promise as a useful tool for identifying individuals with smell loss, also in individuals with COVID-19 as cause, but it is important to have a good understanding of the interpretation of the results of the SST-12 when considering its implementation in clinical practice

The chemical defensome of five model teleost fish

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Eide, M., Zhang, X., Karlsen, O. A., Goldstone, J., Stegeman, J., Jonassen, I., & Goksoyr, A. The chemical defensome of five model teleost fish. Scientific Reports, 11(1), (2021): 10546, https://doi.org/10.1038/s41598-021-89948-0.How an organism copes with chemicals is largely determined by the genes and proteins that collectively function to defend against, detoxify and eliminate chemical stressors. This integrative network includes receptors and transcription factors, biotransformation enzymes, transporters, antioxidants, and metal- and heat-responsive genes, and is collectively known as the chemical defensome. Teleost fish is the largest group of vertebrate species and can provide valuable insights into the evolution and functional diversity of defensome genes. We have previously shown that the xenosensing pregnane x receptor (pxr, nr1i2) is lost in many teleost species, including Atlantic cod (Gadus morhua) and three-spined stickleback (Gasterosteus aculeatus), but it is not known if compensatory mechanisms or signaling pathways have evolved in its absence. In this study, we compared the genes comprising the chemical defensome of five fish species that span the teleosteii evolutionary branch often used as model species in toxicological studies and environmental monitoring programs: zebrafish (Danio rerio), medaka (Oryzias latipes), Atlantic killifish (Fundulus heteroclitus), Atlantic cod, and three-spined stickleback. Genome mining revealed evolved differences in the number and composition of defensome genes that can have implication for how these species sense and respond to environmental pollutants, but we did not observe any candidates of compensatory mechanisms or pathways in cod and stickleback in the absence of pxr. The results indicate that knowledge regarding the diversity and function of the defensome will be important for toxicological testing and risk assessment studies.The work was supported by the Norwegian Research Council as part of the iCOD and iCOD 2.0 projects (Grant Nos. 192441/I30 and 244654/E40), and the dCod 1.0 project (Grant No. 248840) which is part of Centre for Digital Life Norway. The American collaborators were funded by the National Institute of Health (USA) NIH P42ES007381 (Boston University Superfund Center to JJS and JVG), NIH R21HD073805 (JVG) and NHI R01ES029917 (JVG) grants. The Ocean Outlook exchange program funded the trans-Atlantic collaboration

Treatment of Tinnitus in Children-A Systematic Review

Objectives: To systematically review studies on the effect of treatment of subjective tinnitus in children. Data Sources: We searched for studies in MEDLINE and EMBASE databases, after which additional studies were hand searched using Scopus databases. The methods are described in the study protocol, which has been registered in the PROSPERO register. PRISMA guidelines were followed in the reporting of this study. Eligibility Criteria: We considered for inclusion randomized controlled trials (RCTs), observational studies, case reports, and case series, with tinnitus as primary outcome in children (0-18 years old) with acute or chronic subjective tinnitus. We excluded studies in which both children and adults participated but outcomes were not specifically reported for children, as well as animal studies, studies with a non-original study design and studies about children with pulsatile or objective tinnitus. Data Selection: Two reviewers independently assessed studies for eligibility and quality, collected and extracted data. Statistical analyses were performed in case of homogeneous outcomes. Results: The search yielded a total of 4,447 studies. Of these, 147 eligible studies were selected. One case report and five observational studies met the eligibility criteria. Three studies applied counseling and (simplified-)TRT and reported improvement in tinnitus outcome in 68 out of 82 children after 3-6 months of treatment. Two studies used pharmacological treatments and reported improvement in 74 out of 86 patients after 10 days to 3 months of treatment. One study reported the outcome of biofeedback therapy, describing an improvement in tinnitus loudness and annoyance after 2 months of treatment. Conclusion: Due to the high risk of bias of the included studies, we cannot determine the effectiveness of the treatment of subjective tinnitus in children. Also, owing to brief follow-up periods, it is not possible to draw conclusions regarding long-term effects. Randomized controlled trials with longer follow-up periods are necessary to provide substantial evidence of the effects of therapies for children affected by tinnitus. https://www.crd.york.ac.uk/prospero/ Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier [CRD42020178134]

Coping in Chronic Tinnitus Patients

Background: Tinnitus is the perception of sound without an external stimulus. A large part of the adult population experiences this symptom but never seeks professional help, where others have devastating complaints in daily life. This suggests that the impact of tinnitus varies among patients and may be influenced by coping strategies and multiple psychological factors. Method: Cross- sectional study of patients visiting the tertiary tinnitus referral center of the University Medical Center Utrecht, the Netherlands. Three hundred and twenty-one consecutive chronic tinnitus patients were evaluated by the tinnitus care group Utrecht from 6-2007 till 11-2012 of which 308 patients were included. Patients completed two tinnitus distress questionnaires (THI, TQ), a coping questionnaire (CISS) as well as a psychopathological questionnaire (SCL-90-R). Results: Emotional-orientated coping and distraction-orientated coping strategies were significantly correlated with the experienced tinnitus burden. Also a significant negative correlation with task orientated coping was found. The effect size was small. Tinnitus distress also had a significant positive correlation with anxiety, agoraphobia, depression, insufficiency of handling, distrust & personal sensitivity, hostility and sleeping problems. Conclusion: Patients with higher tinnitus handicap scores demonstrated the use different coping strategies than the patients with lower distress scores. This insight in coping strategies in a group of patients with high tinnitus burden is useful for counseling patients. As tinnitus coping strategy might be related to the extent and success of habituation, this outcome could be of interest to optimize tinnitus treatments in the near future

Correlation Between Chronic Tinnitus Distress and Symptoms of Depression: A Systematic Review

OBJECTIVES: In this systematic review, we aim to evaluate the evidence regarding the correlation between tinnitus distress and the severity of depressive symptoms in patients with chronic tinnitus. Also, the prevalence of clinically relevant depressive symptoms scores in patients with chronic tinnitus was evaluated. METHODS: We performed a systematic review in PubMed, EMBASE, and the Cochrane library in June 2021 using the terms "depression" and "tinnitus," and their synonyms, following PRISMA guidelines. Studies were selected on relevance and critically appraised regarding risk of bias using the Newcastle-Ottowa Quality Assessment Scale. RESULTS: A total of 1,912 articles were screened on title and abstract after the removal of the duplicates. Eventually, 33 (1.5%) articles were included for the final analysis. Only cross-sectional cohort studies and case-control studies with a low level of evidence and a high risk of bias due to the study design and patient selection were found. Statistically significant correlations between the experienced tinnitus distress and depressive symptoms were reported in 31 out of 33 studies. Clinically relevant depression scores had a prevalence of 4.6-41.7%. CONCLUSIONS: In this systematic review, in which mostly cross-sectional studies were included, a statistically significant correlation was found between the experienced tinnitus distress and the reported severity of symptoms of depression in patients with chronic tinnitus. A wide range of clinically relevant depression scores were reported in included studies. Due to the high risk of bias of included studies it is not possible to provide a definite answer on the existence of this relationship. Future population-based studies are necessary to provide more clarity

A monocenter, patient-blinded, randomized, parallel-group, non-inferiority study to compare cochlear implant receiver/stimulator device fixation techniques (COMFIT) with and without drilling in adults eligible for primary cochlear implantation

Background: During the cochlear implantation procedure, the receiver/stimulator (R/S) part of the implant is fixated to prevent postoperative device migration, which could have an adverse effect on the position of the electrode array in the cochlea. We aim to compare the migration rates of two fixation techniques, the bony recess versus the subperiosteal tight pocket without bony sutures. Methods and analysis: This single-blind randomized controlled trial will recruit a total of 112 primary cochlear implantation adult patients, eligible for implantation according to the current standard of practice. Randomization will be performed by an electronic data capture system Castor EDC, with participants block randomized to either bony recess or standard subperiosteal tight pocket in a 1:1 ratio, stratified by age. The primary outcome of this study is the R/S device migration rate; secondary outcomes include patient-experienced burden using the validated COMPASS questionnaire, electrode migration rate, electrode impedance values, speech perception scores, correlation between R/S migration, electrode array migration and patient complaints, assessment of complication rates, and validation of an implant position measurement method. Data will be collected at baseline, 1 week, 4 weeks, 8 weeks, 3 months, and 12 months after surgery. All data analyses will be conducted according to the intention-to-treat principle. Discussion: Cochlear implantation by means of creating a tight subperiosteal pocket without drilling a bony seat is a minimally invasive fixation technique with many advantages. However, the safety of this technique has not yet been proven with certainty. This is the first randomized controlled trial that directly compares the minimally invasive technique with the conventional method of drilling a bony seat. Trial registration: Netherlands Trial Register NL9698. Registered on 31 August 2021

Genetic outcomes in children with developmental language disorder: a systematic review

IntroductionDevelopmental language disorder (DLD) is a common childhood condition negatively influencing communication and psychosocial development. An increasing number of pathogenic variants or chromosomal anomalies possibly related to DLD have been identified. To provide a base for accurate clinical genetic diagnostic work-up for DLD patients, understanding the specific genetic background is crucial. This study aims to give a systematic literature overview of pathogenic variants or chromosomal anomalies causative for DLD in children.MethodsWe conducted a systematic search in PubMed and Embase on available literature related to the genetic background of diagnosed DLD in children. Included papers were critically appraised before data extraction. An additional search in OMIM was performed to see if the described DLD genes are associated with a broader clinical spectrum.ResultsThe search resulted in 15,842 papers. After assessing eligibility, 47 studies remained, of which 25 studies related to sex chromosome aneuploidies and 15 papers concerned other chromosomal anomalies (SCAs) and/or Copy Number Variants (CNVs), including del15q13.1–13.3 and del16p11.2. The remaining 7 studies displayed a variety of gene variants. 45 (candidate) genes related to language development, including FOXP2, GRIN2A, ERC1, and ATP2C2. After an additional search in the OMIM database, 22 of these genes were associated with a genetic disorder with a broader clinical spectrum, including intellectual disability, epilepsy, and/or autism.ConclusionOur study illustrates that DLD can be related to SCAs and specific CNV's. The reported (candidate) genes (n = 45) in the latter category reflect the genetic heterogeneity and support DLD without any comorbidities and syndromic language disorder have an overlapping genetic etiology