Hyperacusis Diagnosis and Management in the United States: Clinical Audiology Practice Patterns.

PURPOSE: Hyperacusis often leads to debilitating psychosocial consequences, but there is no standard protocol for its diagnosis and management in the United States. In this study, we surveyed U.S. clinical audiologists to understand their education and clinical practices surrounding the evaluation and treatment of hyperacusis. METHOD: An online survey was distributed to clinical audiologists across the United States. Survey responses were quantified using descriptive statistics and inductive content analysis. RESULTS: Hyperacusis definitions and clinical practice patterns varied widely across the 102 respondents. Respondents cited a lack of education and training as the primary barrier to effective audiological diagnosis and management of hyperacusis, with most respondents reporting ≤ 5 hr of hyperacusis education. Other primary barriers to effective audiological management of hyperacusis included time constraints, reimbursement, poor sensitivity and specificity of available diagnostic tools, and poor efficacy of available treatments and management strategies. Most respondents (82.5%) agreed that audiologists are the primary professionals who are responsible for implementing hyperacusis interventions. However, 63.3% of respondents reported that their clinic does not have a hyperacusis management protocol, and 80.0% routinely recommend treatment that is outside their scope of practice to implement (cognitive behavioral therapy). CONCLUSIONS: Clinical audiologists in the United States do not receive uniform education on hyperacusis, and they report multiple barriers to its evidence-based diagnosis and management. Effective hyperacusis management necessitates a multidisciplinary approach. The information obtained via this survey will pave the way toward the refinement of interprofessional education programs and the development of systematic, evidence-based clinical protocols for hyperacusis. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24431188.

Pilot study on the role of somatic modulation in hyperacusis.

BACKGROUND: Hyperacusis is a reduced tolerance to sounds that often co-occurs with tinnitus. Both symptoms have convergent as well as divergent characteristics. Somatic modulation, changes in pitch or loudness during certain movements, is common in patients with a primary complaint of tinnitus. However, thus far, this is not documented in patients with hyperacusis. OBJECTIVES: This study aimed to examine the influence of somatic manoeuvres on the perception of external sounds in patients with a primary complaint of hyperacusis. METHODOLOGY: In this prospective cross-sectional pilot study, 18 patients with a primary complaint of hyperacusis were recruited at the Tinnitus Treatment and Research Center Antwerp (TINTRA). While patients listened to a 1 kHz broadband noise of 30 dB sensation level, six neck manoeuvres (flexion, extension, lateroflexion left/right, traction and compression), three jaw manoeuvres (protrusion, laterotrusion left/right) and one placebo manoeuvre (hand on head) were performed. The primary outcome measure was the change in the perception of the presented sound in terms of loudness and intrusiveness between baseline and each modulation measured by a visual analogue scale (VAS). RESULTS: No overall significant changes were found; however, individual results indicated that five patients presented a clinically relevant change of more than three points out of ten on VAS in terms of hyperacusis after at least one of the executed somatic manoeuvres. CONCLUSIONS: This pilot study did not demonstrate an overall significant change in hyperacusis after somatic manoeuvres but does not rule out the possibility of somatic modulation in some hyperacusis patients. TRIAL REGISTRATION: The protocol of this prospective cross-sectional pilot study was registered on clinicaltrials.gov with registration number NCT04693819.

Clinical and investigational tools for monitoring noise-induced hyperacusis.

Hyperacusis is a recognized perceptual consequence of acoustic overexposure that can lead to debilitating psychosocial effects. Despite the profound impact of hyperacusis on quality of life, clinicians and researchers lack objective biomarkers and standardized protocols for its assessment. Outcomes of conventional audiologic tests are highly variable in the hyperacusis population and do not adequately capture the multifaceted nature of the condition on an individual level. This presents challenges for the differential diagnosis of hyperacusis, its clinical surveillance, and evaluation of new treatment options. Multiple behavioral and objective assays are emerging as contenders for inclusion in hyperacusis assessment protocols but most still await rigorous validation. There remains a pressing need to develop tools to quantify common nonauditory symptoms, including annoyance, fear, and pain. This review describes the current literature on clinical and investigational tools that have been used to diagnose and monitor hyperacusis, as well as those that hold promise for inclusion in future trials.

Sound Tolerance Conditions (Hyperacusis, Misophonia, Noise Sensitivity, and Phonophobia): Definitions and Clinical Management.

Purpose: For some people, exposure to everyday sounds presents a significant problem. The purpose of this tutorial was to define and differentiate between the various sound tolerance conditions and to review some options for their clinical management. METHOD: We informally reviewed the literature regarding sound tolerance conditions. The terminology and definitions provided are mostly consistent with how these terms are defined. However, many inconsistencies are noted. Methods of assessment and treatment also differ, and different methodologies are briefly described. RESULTS: Hyperacusis describes physical discomfort or pain when any sound reaches a certain level of loudness that would be tolerable for most people. Misophonia refers to intense emotional reactions to certain sounds (often body sounds such as chewing and sniffing) that are not influenced by the perceived loudness of those sounds. Noise sensitivity refers to increased reactivity to sounds that may include general discomfort (annoyance or feeling overwhelmed) due to a perceived noisy environment, regardless of its loudness. Phonophobia, as addressed in the audiology profession, describes anticipatory fear of sound. Phonophobia is an emotional response such as anxiety and avoidance of sound due to the "fear" that sound(s) may occur that will cause a comorbid condition to get worse (e.g., tinnitus) or the sound itself will result in discomfort or pain. (Note that phonophobia is a term used by neurologists to describe "migraineur phonophobia"-a different condition not addressed herein.) Conclusions: The literature addresses sound tolerance conditions but reveals many inconsistencies, indicating lack of consensus in the field. When doing an assessment for decreased sound tolerance, it is important to define any terms used so that the patient and all health care professionals involved in the care of the patient are aligned with the goals of the treatment plan. Treatment generally involves gradual and systematic sound desensitization and counseling. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.20164130.

Tinnitus suppression with electrical stimulation in adults: long-term follow-up.

Objectives: To investigate the long-term effects of cochlear implants as a treatment for patients with severe to profound neurosensory loss associated with severe tinnitus. Methods: Prospective study in 17 adult patients with severe to profound sensorineural hearing loss associated with severe tinnitus, indicated with a Tinnitus Handicap Inventory (THI) score ≥ 58%, and hyperacusis. Measures were made on hearing, tinnitus, hyperacusis and quality of life up to 5 years after activation of the sound processor of the cochlear implant. It was evaluated by using the disyllabic test, THI, visual analogue scale and Glasgow Benefit Inventory questionnaire. Results: 60 months after cochlear implantation, improvements in loudness and discomfort of tinnitus, speech discrimination and hyperacusis were observed. Subjects perceive an important subjective benefit upon receiving the cochlear implant. Conclusions: Cochlear implants can be used as treatment for patients with severe to profound sensorineural hearing loss associated with severe tinnitus and hyperacusis with long-term benefits on quality of life and lasting relief of tinnitus.

The reliability and validity of decreased sound tolerance scale-screening.

OBJECTIVES: Decreased Sound Tolerance (DST) is a negative reaction to a sound that does not cause any reaction in an individual with normal hearing. DST's subclasses include hyperacusis, phonophobia, and misophonia, which are distinct and have therapy variations. There is no diagnostic method or scale that distinguishes them in the literature. This study's purpose was to develop a screening scale that distinguishes these three DSTs. METHODS: The study comprised 257 willing participants with normal hearing. Cronbach alpha coefficient, item-total correlation, and item differentiation of the Decreased Sound Tolerance Scale-Screening (DSTS-S) were evaluated. Structural validity of DSTS-S was performed by Varimax rotation with Kaiser normalization using Explanatory Factor Analysis (EFA), and Confirmatory Factor Analysis (CFA) was performed to assess its structural compatibility. The scale's total scores from each section were compared using the Mann-Whitney U test in symptom (+) and symptom (-) participants. RESULTS: The Cronbach alpha value for hyperacusis, phonophobia, and misophonia sections of DSTS-S was calculated as 0.881, 0.775, and 0.938, respectively. The difference between the independent samplet-test and the variables was statistically significant (p < 0.01). The Mann-Whitney U test showed a significant difference between the median values of the total groups' scores with and without hyperacusis, phonophobia, and misophonia (HTS, PTS, and MTS, respectively) (p < 0.05). Evaluation by ROC analysis showed that hyperacusis was useful in predicting the presence of hyperacusis, phonophobia was useful in predicting the presence of phonophobia, and misophonia was useful in predicting the presence of misophonia (p < 0.001). Hyperacusis and misophonia sections showed high reliability, and phonophobia section showed a moderately reliable level. The Kappa test showed that the compatibility between test-retest for the total scores was statistically significant (p < 0.001). CONCLUSION: The study's results indicated that DSTS-S is a valid and reliable scale for identifying subtypes/problems/classes of decreased sound tolerance.

Modulation of hyperacusis and tinnitus loudness in tinnitus patients with and without hearing loss following 3 weeks of acoustic stimulation: A proof-of-concept study.

Tinnitus and hyperacusis are two debilitating conditions that are highly comorbid. It has been postulated that they may originate from similar pathophysiological mechanisms such as an increase in central gain. Interestingly, sound stimulation has been shown to reduce central gain and is currently used for the treatment of both conditions. This study investigates the effect of sound stimulation on both tinnitus and hyperacusis in the same patients. Two distinct series of tinnitus participants were tested: one with normal or near-normal hearing (n=16) and one with hearing loss (n=14). A broadband noise shaped to cover most of the tinnitus frequency spectrum was delivered through hearing aids using the noise generator feature (no amplification) and verified through real-ear measurements. Participants received sound stimulation for 3 weeks and were tested before (at baseline), then after 1 week and at the end of the 3 weeks of sound stimulation. There was also a 1-month follow-up after the end of the stimulation protocol. The measurements included self-reported measures of tinnitus and hyperacusis (VAS), validated questionnaires (THI, HQ) and psychoacoustic measurements (tinnitus battery and loudness functions). On both self-assessment (VAS of sound tolerance and tinnitus loudness) and psychoacoustic measures (loudness function and tinnitus loudness in dB), about 50% of tinnitus participants had a synchronous (either a decrease or an increase) modulation of hyperacusis and tinnitus loudness after 1 week and 3 weeks of acoustic stimulation and up to about 70% of participants at 1-M follow-up. The decrease of hyperacusis and tinnitus loudness was more prevalent in normal-hearing participants. There was a significant increase in tinnitus loudness during and following the stimulation in the group with hearing loss. Hyperacusis improvement as assessed by loudness function was significantly correlated with the intensity level of the acoustic stimulation (dB level of the noise produced by the noise generator) in tinnitus participants with normal/near-normal hearing thresholds. Our study partly supports the central gain hypothesis by showing synchronous modulation of hyperacusis and tinnitus loudness. It also shows beneficial effects of acoustic stimulation in some tinnitus individuals, in particular those with normal or near-normal hearing, while highlighting the importance of a careful fitting of sound generators to prevent increase. Since the amplification feature was not turned on in our study, future work should determine whether amplification alone, or in addition to acoustic stimulation (sound generators), would benefit to those with hearing loss.

Assessment and Treatment of Noise Hypersensitivity in a Teenager with Autism Spectrum Disorder: A Case Study.

Noise hypersensitivity is a poorly understood symptom of Autism Spectrum Disorder (ASD). For some, problem behaviors co-occur with the aversive noise. Limited literature exists on treating noise hypersensitivity; however, noise hypersensitivity may be related to a specific phobia. This case study utilizes modified Cognitive Behavioral Therapy (CBT) to address anxiety, avoidance, and problem behaviors evoked by noise in a teen with ASD and mild Intellectual Disability (ID). Using multi-method assessment and individualized treatment, problem behaviors reduced, and independent coping strategies use occurred. Successful desensitization supports the efficacy of modified CBT as a treatment for noise-related anxiety and problem behaviors in individuals with ASD and ID. Outcomes are discussed considering intervention difficulties for noise hypersensitivity in a complex and diverse population.

Hyperacusis in children: a scoping review.

BACKGROUND: Hyperacusis is a chronic condition commonly defined as a lowered tolerance or increased sensitivity to everyday environmental sounds. It has been viewed as a paediatric disorder which can cause significant impairment to a child's normal functioning. Although clinical guidance highlights the importance of identifying whether the child has intolerance to loud sounds and managing this appropriately, there are currently no assessment or treatment methods that have been designed and tested for use with children with hyperacusis. A review is therefore indicated to consider the profile of children with hyperacusis as a basis for future research into their assessment and treatment. METHOD: A scoping review methodology was followed with literature searches conducted in Embase, PsychINFO, PubMed CENTRAL, Scopus, Web of Science and Google Scholar. Research articles were included if they reported on research studies describing children diagnosed with hyperacusis, providing clinical profile information, and/or reporting on an assessment or management method for children with a primary complaint of hyperacusis. Data were charted on Excel and verified by a second researcher. Twenty-one research articles were included. RESULTS: Children with hyperacusis are typically described in terms of age at presentation, troublesome sounds, physical sensation, behavioural reactions, coping strategies, comorbid conditions and impact on daily life. Methods of assessing the children include semi-structured interviews, questionnaires, neurological assessment, observation and uncomfortable loudness levels. Management methods include psychological therapy, sound therapy, tinnitus retraining therapy, medication and neuro-rehabilitation. CONCLUSION: The information we catalogued on various elements of clinical profile, assessment and management can serve as a stepping stone in future research developing questionnaires for clinical measurement of the impact of hyperacusis on children, and the measurement of treatment related change in clinic and in trials. Positive outcomes were noted by the authors following all of the above treatments; future research must compare these and specify the parameters for optimal results.

A review of auditory gain, low-level noise and sound therapy for tinnitus and hyperacusis.

Objective: This article reviews: (1) the evidence related to enhanced central gain as a potential mechanism for the generation of tinnitus and hyperacusis, (2) the neuroplastic changes induced by prolonged, low-level sound stimulation and (3) the clinical effectiveness of various sound therapies and amplification for the treatment of tinnitus and hyperacusis.Design: General literature review.Study sample: Peer-reviewed articles related to auditory neural gain, prolonged low-level noise exposure and effectiveness of sound therapy.Results: A large body of literature exists supporting the enhanced neural gain model of tinnitus and hyperacusis. Neuroplastic changes associated with prolonged low-level noise show evidence of reversing enhanced neural gain, which should theoretically reduce percepts of tinnitus and/or hyperacusis. However, the available clinical evidence assessing the efficacy of sound therapy to reduce tinnitus or hyperacusis lacks controlled clinical trials to accurately assess the effectiveness of sound therapy.Conclusions: The available literature from basic science studies supports the neural gain model of tinnitus and hyperacusis, which conceivably should be effectively managed with sound therapy. However, well-controlled clinical trials are needed before conclusions can be made on the effectiveness of sound therapy for tinnitus and hyperacusis.

Misophonia: A scoping review of research.

OBJECTIVE: To scope the literature describing misophonia populations, management, and research opportunities. METHOD: Literature searches for research studies describing patients diagnosed with misophonia, defining a patient profile, or outlining development or testing of an intervention for misophonia. A data extraction form was developed and piloted before data from each article were independently charted by two researchers. Researchers then agreed on a final data set for each article. RESULTS: Thirty-one records were included. The misophonia population was described in terms of onset age, triggers, reaction, coping strategies, and comorbid conditions. We identified nine outcome measures. Case studies on treatments included cognitive behavioral therapy, counterconditioning, mindfulness and acceptance, dialectical behavioral therapy, and pharmaceuticals. Future research priorities identified included clarifying the phenomenology and prevalence of misophonia, and randomized controlled trials of treatments. CONCLUSION: Misophonia is under-researched but there are strong foundations for future research to finalize diagnostic criteria, validate outcome measures, and trial treatments.

Long-Term Efficacy of Audiologist-Guided Internet-Based Cognitive Behavior Therapy for Tinnitus.

PURPOSE: The purpose of this study was to investigate the long-term outcomes 1 year after undertaking an audiologist-guided Internet-based cognitive behavioral therapy (iCBT) intervention for tinnitus. Secondary aims were to identify any predictors of outcome and whether there were any unwanted events related to undertaking iCBT for tinnitus. METHOD: Participants who had previously undertaken a randomized iCBT efficacy trial for tinnitus were invited to participate. Of the 146 who were initially randomized for the efficacy trial, 104 participants completed the 1-year postintervention assessment measures. The primary outcome was a change in tinnitus distress as assessed by the Tinnitus Functional Index. Secondary assessment measures were included for insomnia, anxiety, depression, hearing handicap, hyperacusis, cognitive failures, and satisfaction with life. An intention-to-treat analysis using repeated-measures analysis of variance and hierarchical multiple regression was used for statistical analysis. Unwanted effects were categorized according to the unwanted events checklist. RESULTS: Undertaking iCBT for tinnitus led to significant improvements 1 year postintervention for tinnitus and related difficulties, for example, insomnia, anxiety, depression, hearing handicap, hyperacusis, and life satisfaction. The best predictors of improving tinnitus severity at 1-year postintervention were greater baseline tinnitus severity scores, reading more of the modules, and higher satisfaction with the intervention. Unwanted events were reported by 11% of the participants and were more likely to be reported by women than men. These events were related to worsening of symptoms, the emergence of new symptoms, negative well-being, and prolongation of treatment. CONCLUSIONS: The clinical benefits of audiologist-guided iCBT for tinnitus and tinnitus-related difficulties were sustained 1 year postintervention. Predictors of outcome indicated that the intervention is applicable to a wide range of participants regardless of their demographic backgrounds. Attempts should be made to minimize unwanted events in subsequent trials.

The association of auditory integration training in children with autism spectrum disorders among Chinese: a meta-analysis.

Randomized controlled trials (RCTs) have reported an inconsistent relationship about the auditory integration training (AIT) in children with autism spectrum disorders (ASD) among Chinese. The current study was to investigate the efficacy of AIT for children with ASD compared with those in control group by using meta-analysis. Relevant trials published were identified by an electronic search of PubMed, CENTRAL, EMBASE, WanFang, CNKI, and SinoMed databases up to December 31, 2017. Outcome of interest included childhood autism rating scale (CARS), autism behavior checklist (ABC), intelligence quotient (IQ), and autism treatment evaluation checklist (ATEC). Standardized mean difference (SMD) with 95% confidence intervals (CIs) was calculated using a random-effect model. Thirteen RCTs with 976 children with ASD were included for analysis. The pooled SMD showed that children with ASD had significantly lower ABC scores [summary SMD = -0.58, 95%CI = -0.79 to -0.38] and ATEC scores [summary SMD = -0.75, 95%CI = -1.05 to -0.45] in AIT group compared with that in control group. The analysis of pooled statistics put forward AIT could increase the IQ score when compared with that in control group [summary SMD = 0.59, 95%CI = 0.41-0.77]. A negative association was found about CARS scores between AIT group and control group. No publication bias was found and no single study had essential effect on the pooled results. In conclusions, AIT can reduce the score of ABC and ATEC and can increase the IQ score among children with ASD in Chinese. Therefore, it is recommended for Chinese children with ASD to receive AIT.

Insights from the third international conference on hyperacusis: causes, evaluation, diagnosis, and treatment.

BACKGROUND: Hyperacusis is intolerance of certain everyday sounds that causes significant distress and impairment in social, occupational, recreational, and other day-to-day activities. OBJECTIVE: The aim of this report is to summarize the key findings and conclusions from the Third International Conference on Hyperacusis. TOPICS COVERED: The main topics discussed comprise (1) diagnosis of hyperacusis and audiological evaluations, (2) neurobiological aspect of hyperacusis, (3) misophonia, (4) hyperacusis in autism spectrum disorder, (5) noise sensitivity, (6) hyperacusis-related distress and comorbid psychiatric illness, and (7) audiologist-delivered cognitive behavioral therapy for hyperacusis. CONCLUSIONS: Implications for research and clinical practice are summarised.

Hyperacusis in children: The Edinburgh experience.

OBJECTIVES: This study aimed to determine the factors associated with hyperacusis in children referred to an audiology-led paediatric hyperacusis clinic in a Paediatric tertiary centre. It also aimed to identify current management strategies in paediatric hyperacusis and their outcomes. METHODS: Retrospective cohort study conducted by case note and AuditBase® review over a 5-year period (March 2010 to March 2015) in a tertiary Paediatric ENT and Audiology service. RESULTS: 412 children were referred with hyperacusis during the 5-year period. All children were assessed and managed within a dedicated Paediatric hyperacusis clinic. Median age at referral was 7 years. 76% were boys (n = 313). On average, children were sensitive to 6 identifiable sound stimuli at presentation (range 1-20). 82% complained of sensitivity to noise from household appliances and hand dryers. 60% had a background history of autistic spectrum disorder (ASD), followed by attention deficit hyperactivity disorder (ADHD) and other neurodevelopmental problems. In 91% management comprised behavioural therapy and provision of a 'sound-ball' (Wellcare® Naturcare Relaxation Therapy Ball) to take home. Of these, 25% did not attend their first review appointment. A further 25% were considered to have sufficient symptom improvement to permit discharge after a single clinic review. Only 2% of children required more than 3 review sessions before achieving resolution of symptoms. CONCLUSIONS: In our paediatric cohort, hyperacusis is more common in boys and in those children with ASD. A combined treatment approach with behavioural therapy and the provision of a sound-ball has a very high success rate in our experience.

Hyperacusis: major research questions.

BACKGROUND: Hyperacusis is a troublesome symptom that can have a marked negative impact on quality of life. OBJECTIVES: To identify major research questions in hyperacusis. MATERIALS AND METHODS: Review of gaps in knowledge regarding hyperacusis, and where opportunities may lie to address these. RESULTS: Eight major research questions were identified as priorities for future research. These were: What is the prevalence of hyperacusis in adults and children? What are the risk factors associated with hyperacusis? What is the natural history of hyperacusis? How is 'pain hyperacusis' perceived? What mechanisms are involved in hyperacusis? What is the relationship between hyperacusis and tinnitus? Can a questionnaire be developed that accurately measures the impact of hyperacusis and can be used as a treatment outcome measure? What treatments, alone or in combination, are effective for hyperacusis? CONCLUSION: This clinical/researcher-led project identified major research questions in hyperacusis. A further development to identify patient-prioritized research will follow.

Effect of sound generator on tinnitus and hyperacusis.

OBJECTIVE: Sound generator (SG) plays a role as effective sound therapy of tinnitus retaining therapy (TRT) in patients with severe tinnitus (Category 1) or hyperacusis (Category 3). This study was performed to evaluate the therapeutic effect of SGs. METHODS: A total of 120 tinnitus patients who visited our tinnitus clinic and were treated with SG along with TRT from January 2008 to December 2016 were included. The patients were divided into two groups by tinnitus category; 78 patients of category 1 and 42 patients of category 3. Their medical records including questionnaires regarding tinnitus severity were retrospectively reviewed to evaluate the therapeutic effect of SGs on tinnitus and hyperacusis. RESULTS: Category 3 patients included more female patients, were younger than category 1 patients (p = .001), and were prescribed SG earlier due to their severe symptom of hyperacusis. (p = .004) All patients showed significant improvements on all categories of tinnitus visual analogue scale (VAS) scores and tinnitus handicap inventory (THI) scores after six months use of SG (p < .05). Loudness discomfort levels measured by pure tone audiometry were significantly improved in category 3 group after six months use of SGs. CONCLUSION: SG with TRT seems to be an effective treatment modality for all tinnitus patients, especially those with comorbid hyperacusis.

Characteristics of somatic tinnitus patients with and without hyperacusis.

OBJECTIVE: Determine if somatic tinnitus patients with hyperacusis have different characteristics from those without hyperacusis. PATIENTS AND METHODS: 172 somatic tinnitus patients with (n = 82) and without (n = 90) hyperacusis referred to the Tinnitus Unit of Sapienza University of Rome between June 2012 and June 2016 were compared for demographic characteristics, tinnitus features, self-administered questionnaire scores, nature of somatic modulation and history. RESULTS: Compared to those without hyperacusis, patients with somatic tinnitus and hyperacusis: (a) were older (43.38 vs 39.12 years, p = 0.05), (b) were more likely to have bilateral tinnitus (67.08% vs 55.56%, p = 0.04), (c) had a higher prevalence of somatic modulation of tinnitus (53.65% vs 36.66%, p = 0.02) and (d) scored significantly worse on tinnitus annoyance (39.34 vs 22.81, p<0.001) and subjective hearing level (8.04 vs 1.83, p<0.001). CONCLUSION: Our study shows significantly higher tinnitus modulation and worse self-rating of tinnitus and hearing ability in somatic tinnitus patients with hyperacusis versus somatic tinnitus patients without hyperacusis. These differences could prove useful in developing a better understanding of the pathophysiology and establishing a course of treatment for these two groups of patients.