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Estrogens exert their function through genomic and non-genomic pathways mediated mainly by estrogen receptors. Estrogen signalling is highly complex and once activated initiates cancer cell proliferation and survival, playing a pivotal role in breast cancer development and progression. The identification of estrogen regulated genes is the first step towards elucidating the mechanisms of estrogen function. Although numerous studies have investigated the effect of estradiol at the mRNA level, assessment of global changes at the protein level has been limited mainly due to technological limitations. Here, we present the most extensive proteomic study in the quest of proteins whose expression is regulated or associated with estradiol action. To facilitate accurate quantification of proteins, we first developed and optimized a proteomic protocol for cell lysis and sample preparation, based on a mass spectrometry-compatible detergent. Following our protocol coupled to stable isotope labelling with amino acids in cell culture (SILAC) of MCF-7 breast cancer cells, we quantified approximately 4,000 proteins and identified 153 proteins differentially expressed upon estradiol stimulation. Notably, known estrogen regulated proteins such as trefoil 1 (TFF1) and progesterone receptor (PGR) showed a four- and three-fold increase respectively, at 48 hours after estradiol stimulation. Forty eight of 153 differentially expressed proteins have been found to contain estrogen receptor elements (EREs) indicating direct regulation by estradiol. Protein-protein network analysis (STRING) revealed an extensive protein network related to cell proliferation. Differential expression of proteins was verified in three estrogen receptor positive breast cancer cell lines (MCF-7, HCC-1428, BT-483) using a targeted mass spectrometry-based quantitative approach; selected reaction monitoring (SRM). A multiplex SRM assay was developed for the simultaneous quantification of 56 proteins. The same assay was utilized to study the kinetics of these proteins in time and in presence of inhibitors of estrogen receptor facilitating the distinction between direct and indirect protein targets. To our knowledge, such an extensive network of estrogen-regulated genes has never been previously studied at the protein level. Interestingly, numerous differentially expressed proteins identified in the present study have not been connected to estrogen signalling or breast cancer before. The role of these proteins in breast carcinogenesis and their potential as therapeutic targets warrants further investigation. [ABSTRACT FROM AUTHOR]

Breast cancer is a highly heterogeneous disease with different subtypes presenting distinct clinical characteristics. During the last decade has been shown that molecular classification of breast cancer holds the promise for the development of novel prognostic tools and the identification of novel treatment targets. However, proteins are the main mediators of biological processes and the molecular targets of the majority of drugs. Moreover, the proteome integrates the cellular genetic information and environmental influences. Hence coupling proteomic and transcriptomic studies may augment the development of targeted therapies and the identification of disease-relevant proteins networks. Here, we report an extensive mass spectrometry-based (MS) secretome analysis of eight breast cancer cell lines representing, the three main breast cancer subtypes (luminal, basal and HER2-neu amplified) in search of subtype-specific proteomic signatures. Following a bottom-up proteomic approach coupled to tandem mass spectrometry the conditioned media of 8 breast cancer cell lines were analyzed. More than 5,200 non-redundant proteins were identified in the conditioned media of the 8 cell lines with a false positive rate less than 1%. The mass spectrometry-based identification of 5 proteins was successfully verified by ELISA. For the generation of subtype-specific proteomic signatures, proteins common to all cell lines of the same subtype but not present in the other two subtypes were identified. Twenty -three, four and four proteins were found uniquely in basal, HER2-neu amplified and luminal breast cancer cells. Notably, ERBB2 was one of the proteins uniquely identified in the HER2-neu amplified subtype verifying the validity of our approach. Given that most of these proteins have no quantitative methods available at present, we opted to preliminarily examine the relationship of these candidates with breast cancer subtypes by using an in silico approach, based on transcriptomic data. We performed an in silico mRNA expression analysis using publicly available data from four independent experiments containing a total of 1039 patients with primary breast cancer. The expression profiles of 15 of 31 proteins investigated showed significant correlation with estrogen receptor expression and power to distinguish subtypes. The development of multiplex quantitative mass spectrometry-based assays for the quantification of the proteomic signatures in relevant biological specimens along with immunohistochemical studies for two of the 31 candidates are currently ongoing. The significance of these subtype-specific proteins in breast cancer prognosis and disease progression warrants further investigation. [ABSTRACT FROM AUTHOR]

Clinical suspicion, clinical presentation, and electrocardiogram can help clinicians diagnose flecainide toxicity. Currently, there are no guidelines for the management of patients with flecainide toxicity. Sodium bicarbonate, lipid emulsion therapy, and extracorporeal life support have been used in this setting. Amiodarone and lidocaine can be used for the management of wide QRS complex tachycardias in hemodynamically stable patients with flecainide toxicity., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Risk prediction models are routinely used to assist in clinical decision making. A small sample size for model development can compromise model performance when the model is applied to new patients. For binary outcomes, the calibration slope (CS) and the mean absolute prediction error (MAPE) are two key measures on which sample size calculations for the development of risk models have been based. CS quantifies the degree of model overfitting while MAPE assesses the accuracy of individual predictions., Methods: Recently, two formulae were proposed to calculate the sample size required, given anticipated features of the development data such as the outcome prevalence and c-statistic, to ensure that the expectation of the CS and MAPE (over repeated samples) in models fitted using MLE will meet prespecified target values. In this article, we use a simulation study to evaluate the performance of these formulae., Results: We found that both formulae work reasonably well when the anticipated model strength is not too high (c-statistic < 0.8), regardless of the outcome prevalence. However, for higher model strengths the CS formula underestimates the sample size substantially. For example, for c-statistic = 0.85 and 0.9, the sample size needed to be increased by at least 50% and 100%, respectively, to meet the target expected CS. On the other hand, the MAPE formula tends to overestimate the sample size for high model strengths. These conclusions were more pronounced for higher prevalence than for lower prevalence. Similar results were drawn when the outcome was time to event with censoring. Given these findings, we propose a simulation-based approach, implemented in the new R package 'samplesizedev', to correctly estimate the sample size even for high model strengths. The software can also calculate the variability in CS and MAPE, thus allowing for assessment of model stability., Conclusions: The calibration and MAPE formulae suggest sample sizes that are generally appropriate for use when the model strength is not too high. However, they tend to be biased for higher model strengths, which are not uncommon in clinical risk prediction studies. On those occasions, our proposed adjustments to the sample size calculations will be relevant., (© 2024. The Author(s).)

Regeneration of neurons has important implications for human health, and the retina provides an accessible system to study the potential of replacing neurons following injury. In previous work, we generated transgenic mice in which neurogenic transcription factors were expressed in Müller glia (MG) and showed that they stimulated neurogenesis following inner retinal damage. It was unknown, however, whether the timing or mode of injury mattered in this process. Here, we explored these parameters on induced neurogenesis from MG and show that MG expressing Ascl1 will generate new bipolar neurons with similar efficiency irrespective of injury mode or timing. However, MG that express Ascl1-Atoh1 produce a new type of retinal ganglion-like cell after outer retinal damage, which is absent with inner retinal damage. Our data suggest that although cell fate is primarily dictated by neurogenic transcription factors, the inflammatory state of MG relative to injury can influence the outcome of induced neurogenesis., Competing Interests: Declaration of interests Some of the findings in this report are part of a patent application that has been submitted by the University of Washington: patent application 63/362,361, filed January 4, 2022. The authors declare that they have no other competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Gain-of-function mutations in NOTCH1 are among the most frequent genetic alterations in T-cell acute lymphoblastic leukemia (T-ALL), highlighting the Notch signaling pathway as a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss of phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) causes resistance to Notch inhibition. PIK3R1 deficiency leads to increased PI3K/AKT signaling, which regulates cell cycle and the spliceosome machinery, both at the transcriptional and posttranslational level. Moreover, several therapeutic combinations have been identified, in which simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Close links exist between vestibular function and cognition. Dual-task (DT) tests may have ecological validity to assess the impact of daily life cognitive-motor demands in people with vestibular dysfunction (PwVD), functional gait and falls risk. The present paper aimed at building predictive models for functional gait under DT conditions, while clarifying the impact of vestibular dysfunction, individual characteristics, varying task types and motor-cognitive demands. Case-controlled observational study with 39 PwVD and 62 healthy participants. The Functional Gait Assessment (FGA), with and without an additional motor, numeracy, or literacy task, was completed. Multiple linear regression was used to fit models to predict FGA under single and DT performance. Dual task cost (DTC, %) was calculated to assess DT interference on FGA performance using the equation: 100*(single task score-dual task score)/single-task score. Following Bonferroni corrections for multiple comparisons (corrected alpha level of 0.003), PwVD had poorer performance than controls for all FGA conditions (p < 0.001), motor (- 3.94%; p = 0.002) and numeracy (- 22.77%; p = 0.001) DTCs and spatial working memory (p = 0.002). The literacy DTC was marginally significant (- 19.39% p = 0.005). FGA single and DT motor, numeracy, and literacy models explained 76%, 76%, 66% and 67% of the variance respectively for PwVD. Sustained attention, visual memory and sex contributed to all models; short-term visual recognition memory, balance confidence, and migraine contributed to some models. Cognitive performance is impaired in PwVD. Motor, numeracy and literacy tasks impair functional gait performance. Cognitive assessment and FGA with a numeracy or literacy cognitive component should be included within assessment protocols and considered in the provision of targeted interventions for PwVD., (© 2023. The Author(s).)

Dementia involves the loss of cognitive abilities and represents a decline from the prior level of function which impairs functional abilities in day-to-day life. No previous experimental research has been done to assess mental imagery (MI) effectiveness in the motor, cognitive and emotional status of individuals with early-stage dementia. One hundred and forty older individuals with early-stage dementia from the Day Care Centre of the Alzheimer Association in Athens will take part in this study. The sample will be randomly divided into three groups: MI and physical exercise (intervention group), only physical exercise (1 st control group), and neither MI nor physical exercise (2 nd control group). Assessment will be obtained one week prior to the program, in the middle of the program (6 th week of the intervention program) and after the end of the program (13 th week of the intervention program). Participants of the intervention group will perform a 30-minute MI programme after the end of every physiotherapy session. Reliable and valid instruments will be used to assess the primary outcomes, i.e., balance and functional status as well as the secondary outcomes i.e., cognitive ability, emotional state and quality of life. The two-way Mixed ANOVA with factors 'intervention' (between groups) and 'time' (within group) will be used as a statistical analysis. Approvals of clinical trial protocol: a) UNIWA Research Committee study protocol approval: 93292 - 26/10/2021. b) ClinicalTrials.gov: ID NCT05232526., (Copyright: © 2023 Hylonome Publications.)

Background: Institutions or clinicians (units) are often compared according to a performance indicator such as in-hospital mortality. Several approaches have been proposed for the detection of outlying units, whose performance deviates from the overall performance., Methods: We provide an overview of three approaches commonly used to monitor institutional performances for outlier detection. These are the common-mean model, the 'Normal-Poisson' random effects model and the 'Logistic' random effects model. For the latter we also propose a visualisation technique. The common-mean model assumes that the underlying true performance of all units is equal and that any observed variation between units is due to chance. Even after applying case-mix adjustment, this assumption is often violated due to overdispersion and a post-hoc correction may need to be applied. The random effects models relax this assumption and explicitly allow the true performance to differ between units, thus offering a more flexible approach. We discuss the strengths and weaknesses of each approach and illustrate their application using audit data from England and Wales on Adult Cardiac Surgery (ACS) and Percutaneous Coronary Intervention (PCI)., Results: In general, the overdispersion-corrected common-mean model and the random effects approaches produced similar p-values for the detection of outliers. For the ACS dataset (41 hospitals) three outliers were identified in total but only one was identified by all methods above. For the PCI dataset (88 hospitals), seven outliers were identified in total but only two were identified by all methods. The common-mean model uncorrected for overdispersion produced several more outliers. The reason for observing similar p-values for all three approaches could be attributed to the fact that the between-hospital variance was relatively small in both datasets, resulting only in a mild violation of the common-mean assumption; in this situation, the overdispersion correction worked well., Conclusion: If the common-mean assumption is likely to hold, all three methods are appropriate to use for outlier detection and their results should be similar. Random effect methods may be the preferred approach when the common-mean assumption is likely to be violated., (© 2023. The Author(s).)

Many neurodegenerative diseases cause degeneration of specific types of neurons. For example, glaucoma leads to death of retinal ganglion cells, leaving other neurons intact. Neurons are not regenerated in the adult mammalian central nervous system. However, in nonmammalian vertebrates, glial cells spontaneously reprogram into neural progenitors and replace neurons after injury. We have recently developed strategies to stimulate regeneration of functional neurons in the adult mouse retina by overexpressing the proneural factor Ascl1 in Müller glia. Here, we test additional transcription factors (TFs) for their ability to direct regeneration to particular types of retinal neurons. We engineered mice to express different combinations of TFs in Müller glia, including Ascl1, Pou4f2, Islet1, and Atoh1. Using immunohistochemistry, single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin sequencing, and electrophysiology, we find that retinal ganglion-like cells can be regenerated in the damaged adult mouse retina in vivo with targeted overexpression of developmental retinal ganglion cell TFs.

Background: Balance rehabilitation programs represent the most common treatments for balance disorders. Nonetheless, lack of resources and lack of highly expert physiotherapists are barriers for patients to undergo individualized rehabilitation sessions. Therefore, balance rehabilitation programs are often transferred to the home environment, with a considerable risk of the patient misperforming the exercises or failing to follow the program at all. Holobalance is a persuasive coaching system with the capacity to offer full-scale rehabilitation services at home. Holobalance involves several modules, from rehabilitation program management to augmented reality coach presentation., Objective: The aim of this study was to design, implement, test, and evaluate a scoring model for the accurate assessment of balance rehabilitation exercises, based on data-driven techniques., Methods: The data-driven scoring module is based on an extensive data set (approximately 1300 rehabilitation exercise sessions) collected during the Holobalance pilot study. It can be used as a training and testing data set for training machine learning (ML) models, which can infer the scoring components of all physical rehabilitation exercises. In that direction, for creating the data set, 2 independent experts monitored (in the clinic) 19 patients performing 1313 balance rehabilitation exercises and scored their performance based on a predefined scoring rubric. On the collected data, preprocessing, data cleansing, and normalization techniques were applied before deploying feature selection techniques. Finally, a wide set of ML algorithms, like random forests and neural networks, were used to identify the most suitable model for each scoring component., Results: The results of the trained model improved the performance of the scoring module in terms of more accurate assessment of a performed exercise, when compared with a rule-based scoring model deployed at an early phase of the system (k-statistic value of 15.9% for sitting exercises, 20.8% for standing exercises, and 26.8% for walking exercises). Finally, the resulting performance of the model resembled the threshold of the interobserver variability, enabling trustworthy usage of the scoring module in the closed-loop chain of the Holobalance coaching system., Conclusions: The proposed set of ML models can effectively score the balance rehabilitation exercises of the Holobalance system. The models had similar accuracy in terms of Cohen kappa analysis, with interobserver variability, enabling the scoring module to infer the score of an exercise based on the collected signals from sensing devices. More specifically, for sitting exercises, the scoring model had high classification accuracy, ranging from 0.86 to 0.90. Similarly, for standing exercises, the classification accuracy ranged from 0.85 to 0.92, while for walking exercises, it ranged from 0.81 to 0.90., Trial Registration: ClinicalTrials.gov NCT04053829; https://clinicaltrials.gov/ct2/show/NCT04053829., (©Vassilios Tsakanikas, Dimitris Gatsios, Athanasios Pardalis, Kostas M Tsiouris, Eleni Georga, Doris-Eva Bamiou, Marousa Pavlou, Christos Nikitas, Dimitrios Kikidis, Isabelle Walz, Christoph Maurer, Dimitrios Fotiadis. Originally published in JMIR Rehabilitation and Assistive Technology (https://rehab.jmir.org), 31.08.2022.)

Aims: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC)., Methods and Results: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function., Conclusion: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC., Competing Interests: Conflict of interest: P.M.E. declares consultancies for Pfizer, Sarepta. G.S. declares consultancies at Novartis, Bayer, Astrazeneca, Boston Scientific, Vifor Pharma, Menarini, Akcea Therapeutics. The other authors declare that there is no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

The emergence of efficient viral vectors derived from adeno-associated viruses (AAV) has led many groups to develop gene therapies for inherited monogenic diseases, such as retinal dystrophies. To evaluate the potency of new gene therapy vectors in a preclinical context, it is common to use animal models, such as gene-deficient or mutant animal models of a given human disease, and then assess vision restoration with functional or behavioral assays. While such animal models are invaluable to the preclinical testing process, they cannot be readily used as batch release tests during manufacturing or to validate biological activity at later stages of development. There is therefore a need for rapid and reliable in vitro models that can determine whether therapeutic vectors have delivered their cargo gene, and more importantly, whether this has resulted in the intended biological activity. Given our previous experience, we chose CNGA3-linked achromatopsia to develop a cell-based system to verify biological activity of AAV vectors designed to deliver a healthy CNGA3 gene copy into human cone photoreceptors. Our system is based on an immortalized cell line with high susceptibility to AAV transduction, i.e., HeLa cells, which we engineered to express a fungal rhodopsin guanylyl cyclase (RhGC) from Blastocladiella emersonii and a sensitive genetically encoded calcium indicator (GECI) under the control of a tetracycline operator. Using this system, we were able to confirm and quantify the function of the ion channel encoded by AAV/CNGA3 and differentiate between AAV vector potencies with a simple fluorometric assay. Finally, we show that this approach can be readily adapted for the assessment of phosphodiesterase function.

Background: Difficulties in discourse production are common in post-stroke chronic aphasia. Previous studies have found that speech and language therapy combined with transcranial direct-current stimulation (tDCS) may improve language skills like naming and enhance aphasia treatment outcomes. However, very few studies have investigated the effect of tDCS when combined with interventions for improving higher level language skills such as the Verb Network Strengthening Treatment (VNeST)., Aims: This study aimed to determine the feasibility of anodal tDCS as an adjunct to VNeST to improve discourse production in post-stroke chronic aphasia., Methods: Six people with post-stroke chronic aphasia took part in this double-blinded randomized feasibility study. Participants were randomly allocated to either the experimental group receiving a 6-week block of once weekly VNeST sessions combined with active tDCS over the left inferior frontal gyrus (LIFG) or a control group that received VNeST with sham stimulation. Feasibility outcomes included screening, eligibility, retention, and completion rates, and adverse events. Preliminary response to intervention was also examined using discourse production, functional communication, quality of life, psychological state, and cognition outcomes., Results: Overall 19 individuals were screened and ten met the inclusion criteria. Six individuals provided consent and participated in the study giving a consent rate of 60%. Participant retention and completion rates were 100% and no adverse effects were reported. Exploratory analyses revealed promising changes (i.e., estimated large effect size) in discourse production measures across discourse language tasks and functional communication for the active tDCS group., Conclusions: Our results support the feasibility of tDCS as an adjunct to VNeST. Preliminary findings provide motivation for future large-scale studies to better understand the potential of tDCS as a safe and economical tool for enhancing rehabilitation in chronic aphasia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Matar, Newton, Sorinola and Pavlou.)

Physical inactivity and sedentary time are associated with all-cause mortality, chronic non-communicable diseases and falls in the elderly. Objective of this review is to assess and summarize recommendations from clinical guidelines for physical activity (PA) of older adults in general and related to falls. A scoping review of the existing clinical guidelines was conducted. The included studies should have been developed under the auspices of a health organization and their methodology should be described in detail. Nine clinical guidelines providing specific recommendations for the elderly were identified. There was a strong agreement across the guidelines regarding goals, activities parameters, adverse effects of PA, in addition to reference for preventing falls. Keeping even the minimum of physical activity, introducing balance exercises and strengthening exercises for preventing falls, avoiding unexpected accelerations in the intensity of the activities, applying the necessary precautions and consulting a health professional are the main pillars of recommendations. Despite any deficiencies in definitions, monitoring and optimal dosage consistency of recommendations, is an ideal incentive for countries and organizations to adopt and enhance physical activity as an antidote to the degeneration of human's health and quality of life., (Copyright: © 2022 Hylonome Publications.)

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm 2 , LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care.Trial Registration ClinicalTrials.gov Identifier: NCT00930735 and ClinicalTrials.gov Identifier: NCT01755936., (© 2021. The Author(s).)

Background: Dizziness is a common complaint that often persists and leads to disability and distress. Several cognitive and behavioural responses may contribute to the neurobiological adaptations that maintain persistent vestibular symptoms. This paper will present the protocol of a two-arm parallel group feasibility randomised controlled trial designed to determine whether a fully powered efficacy trial is achievable by examining the feasibility of recruitment, acceptability and potential benefits of an integrated cognitive behavioural therapy and vestibular rehabilitation (CBT-VR) treatment for people with persistent dizziness., Methods: Forty adult patients will be recruited from a tertiary vestibular clinic with persistent movement-triggered dizziness for 3 months or longer who have moderate-high levels of dizziness handicap. Participants will be 1:1 randomised, using a minimisation procedure, to six sessions of either CBT-VR (intervention arm) or VR only (control arm). Measures will be collected at baseline and 4 months post randomisation. The primary feasibility outcomes include descriptive data on numbers meeting eligibility criteria, rates of recruitment, numbers retained post randomisation, treatment adherence and an acceptability questionnaire. Treatment effects on self-report outcomes will be estimated to determine that 95% confidence intervals for the effects are consistent with anticipated effects and minimum clinically important differences, and to provide information needed for the power calculation of an efficacy trial. A nested qualitative study will be conducted post-intervention (intervention group only) to explore the acceptability of the intervention and identify any areas in need of improvement., Discussion: If a trial of CBT-VR is feasible, acceptability data will be used to enhance the intervention if needed and refine the multicentre RCT protocol. Future studies will need to consider the training required for other physiotherapists to deliver the intervention., Trial Registration: ClinicalTrials.gov, ISRCTN 10420559., (© 2021. The Author(s).)