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RESEARCH ARTICLE
Asia Pac J Clin Trials Nerv Syst Dis 2018,  3:97

Efficacy of vestibular stimulation treatment in the depressive phase of bipolar disorder: study protocol for a randomized, double-blind, controlled trial


1 Vest Brain, Centro de Estudios Neuro-Vestibulares, Santiago, Chile
2 Clínica Psiquiátrica Universitaria, Hospital Clínico, Universidad de Chile, Santiago, Chile; Psychiatry Department, Tufts University School of Medicine, Boston, MA, USA
3 Clínica Psiquiátrica Universitaria, Hospital Clínico, Universidad de Chile, Santiago, Chile; Psychiatry Department, Tufts University School of Medicine, Boston, MA, USA; Millennium Institute for Depression and Personality Research, Ministry of Economy, Macul, Santiago, Chile

Date of Web Publication27-Aug-2018

Correspondence Address:
Ana Maria Soza
Vest Brain, Centro de Estudios Neuro-Vestibulares, Santiago
Chile
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Source of Support: This study was supported by Vest Brain, Centro de Estudios Neurovestibulares and the Fund for Innovation and Competitiveness of the Chilean Ministry of Economy, Development and Tourism, through the Millennium Scientific Initiative (grant IS130005; to PAV)., Conflict of Interest: None


DOI: 10.4103/2542-3932.238435

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  Abstract 

Background and objectives: Bipolar disorder (BD) is a neuropsychiatric disorder characterized by the oscillation of mood states between hypoactive/pessimistic (depressive phase) and hyperactive/optimistic states (manic/hypomanic phase). Previous studies evidenced that a particular technique of neuro-vestibular stimulation is an effective treatment for major depression. This study will investigate the efficacy of the said vestibular stimulation technique in the depressive phase of BD, and will compare it with sham vestibular stimulation.
Design: A double-blind, randomized controlled study.
Methods: One hundred and twenty patients with bipolar type I or II, currently undergoing a depressive phase, will be randomized into the experimental group (n = 60) or control group (n = 60), receiving three sessions of real/sham vestibular stimulation.
Outcome measures: The primary outcome is the change in Montgomery Asberg Depression Rating Scale scores from baseline to post 4 and 12 weeks. The secondary outcome is the vestibular activity assessed at baseline, post 4 and 2 weeks.
Discussion: Currently, no treatment has proved efficacy for bipolar depression. Studies have demonstrated that lateralized neuro-vestibular stimulation is an effective treatment for mayor depression but has not been studied in the depressive phase of bipolar disorder. This investigation will give the first evidence supporting or denying the use of vestibular stimulation treatment in BD depression.
Ethics and dissemination: This study protocol was approved by the Ethics Committee of SSMO (Servicio de Salud Metropolitano Oriente) in Santiago, Chile (approval No. 08032016) on March 8, 2016. The results of the study will be published in scientific journals and other media.
Trial registration: ClinicalTrials.gov Identifier: NCT02778256.

Keywords: bipolar disorder; depressive phase; vestibular stimulation treatment for depression; rotary chair


How to cite this article:
Soza AM, Barroilhet SA, Vöhringer PA. Efficacy of vestibular stimulation treatment in the depressive phase of bipolar disorder: study protocol for a randomized, double-blind, controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:97-101

How to cite this URL:
Soza AM, Barroilhet SA, Vöhringer PA. Efficacy of vestibular stimulation treatment in the depressive phase of bipolar disorder: study protocol for a randomized, double-blind, controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 Dec 19];3:97-101. Available from: http://www.actnjournal.com/text.asp?2018/3/3/97/238435


  Introduction Top


Background

Bipolar disorder (BD) affects 140 million people worldwide. According to the World Health Organization, the prevalence of BD type I and II is 0.6% and 0.4%, respectively. This psychiatric disorder is an important cause of disability occupying the sixth place in disability-adjusted life years (DALYs) for individuals aged 15–44 years (Bartoli et al., 2018).

BD is characterized by noticeable changes of mood that interfere with healthy development in most life aspects. It produces emotional instability, cognitive impairment, and physiologic body symptoms that are difficult to treat with currently available treatments.

In clinical practice, although mood stabilizers drugs may diminish the frequency of mood oscillations, cyclic changes of mood (between manic/hypomanic and depressive phases) is difficult to prevent.

The depressive phases of BD are profound, severe and usually resistant to available therapies, resulting in high rates of suicidality. BD accounts for 25% of all consumed suicides (American Psychiatric Association, 2013). Between 25% and 50% of people with BD will have a suicide attempt in life, and between 7% and 15% of patients diagnosed with BD will die from suicide. The diagnosis of BD accounts for a probability of dying by suicide that is 15 times greater than the general population. The reason for attempts vs. consumed suicides in the general population is 35:1, whereas in patients with BD this ratio rises to 3:1 (Simon et al., 2007). In Chile, where this study is being carried out, ~1500 people commit suicide each year, with a national rate of 15 per 100,000 inhabitants, according to the latest data from 2008 (Otzen et al., 2014). BD increases costs through an increased risk of premature death, as 1 in 5 patients would commit suicide (Novick et al., 2010). In 2003, the costs in the USA were estimated at $30.4 to $43.7 trillion. The lifetime cost of the disease would be $13 billion (1998 estimate), while the individual cost per patient would be at least $3400 per year. In Europe, the situation is similar, suicide rates range between 21–54%, 70% of the bipolar are unemployed, and 72% have invalidity pensions. This mental condition generates 2 trillion dollars of unemployment expenses with annual losses that reach 200 million by suicide (Fajutrao et al., 2009).

The high rates of adverse outcomes related to BD, inquiry the efficacy of currently available drugs for the depressive phase of BD. Some scholars argue that a high proportion of these patients do not respond to antidepressants (Sachs, 2003; Goodwin et al., 2007; Ghaemi et al., 2010). Therefore, to find effective treatments for the depressive phase of BD is currently a global priority, and may avoid the suffering of these patients and their families. It also would be helpful in diminishing social and national losses due to unemployment and lack of productivity and may contribute to decreasing the leading cause of suicides at national and world level.

Studies have shown the effect of vestibular stimulation therapies (stimulation of the balance system receptors of the inner ear) in psychiatric disorders. Dodson (2004) described the remission of a state of mania resistant to all treatment, after applying vestibular caloric water irrigation in one ear. McKay et al. (2013) reported changes of mood after caloric (water) stimulation in one ear in healthy participants.

Interestingly, animal studies have shown the existence of vestibular-hypothalamic regulation control of chronobiological hormonal secretion rhythms, and of autonomic activity (Fuller and Fuller, 2006), suggesting the role of the vestibular system in the regulation of circadian physiologic cycles involved in the generation of phase changes in BD. Studies also showed abnormal patterns of vestibular function in patients with major depression (Soza Ried and Aviles, 2007), and a double-blind, randomized clinical trial demonstrated that a particular protocol of lateralized neuro-vestibular stimulation was an effective treatment for depression (Soza, 2014).

The present work aims to study the efficacy of neuro-vestibular stimulation for the depressive phase of BD. Currently, The most widely used drugs for the treatment of bipolar diseases include mood stabilizing drugs, antipsychotics, and antidepressants. The use of antidepressants is not always effective for the depressive phase. Here we attempt to evaluate a different treatment consisting of neuro-vestibular stimulation for the depressive phase of BD.

Objective

This double-blind placebo-controlled randomized clinical trial was designed to assess the efficacy of vestibular stimulation therapy in treating the depressive phase of BD.


  Methods/Design Top


Study design

One hundred and twenty bipolar type I or II patients will be randomized to the experimental and placebo groups. Randomization will be in blocks according to type (TAB I or II), sex (male-female), rapid or non-rapid cycler classification. Patients in the experimental group (n = 60) will receive three sessions of lateralized vestibular stimulation, while subjects in the control group (n = 60) will receive a sham vestibular stimulation. Patients will not be able to distinguish whether they will receive real or sham stimulation, and psychiatrists (doing follow-ups of mood) will be blinded to group assigned.

Patients in both arms will receive psychopharmacologic treatment as indicated. The random separation of two groups that come from the same universe would enables visualization of the effect of the vestibular stimulation. Thus, we expect that the main difference between the two groups will be due to the treatment under study.



This study protocol was approved by the Ethics Committee of Servicio de Salud Metropolitano Oriente (SSMO) in Santiago, Chile (approval No. 08032016) on March 8, 2016, and will be performed in accordance with the Declaration of Helsinki. The protocol adheres to the recommendations provided by the the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting (Chan et al., 2013) (Additional file 1 [Additional file 1]).

Study setting

The selection of patients will be performed at the Mood Disorders Program of the Department of Psychiatry North of the University of Chile, at the psychiatrist’s consultations offices. After baseline assessment, the patients will be sent to “Vest Brain, Centro de Estudios Neurovestibulares” to be randomized to the experimental or control group, and accordingly, receive three sessions of real or sham vestibular stimulation as at the very neurovestibular center. Follow-up assessment after vestibular stimulation will be performed by psychiatrists at their consultation offices in a blinded manner [Figure 1].
Figure 1: Flow chart of the study.
Note: ITT: Intention-to-treat.


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Study participants

The study participants correspond to 120 patients from a universe of 400 patients with depression who attend the program of mood disorders of the Department of Psychiatry North of the University of Chile. This center treats approximately 100–150 patients with BD per year, 2–4 bipolar patients in depressive phase per week, 4–6 per month, 48–72 per year. We estimate that the trial would take two to three years to recruit the entire sample. Of this universe will be excluded those who do not meet the inclusion criteria and those who do not wish to sign informed consent (Additional file 2 [Additional file 2]). Patients younger than 18 or older than 65 will be excluded from the study. Those with previously diagnosed neurological diseases and pregnant women will be excluded as well. Age limits were imposed for several reasons: the difficulty in the continuity and follow-up of these patients, difficulties in informed consent and the great diversity of responses to treatment due to the immaturity of the nervous system in children and deterioration in the elderly. We exclude pregnant women because their physiological condition is very different from the other subjects. Carriers of neurological diseases have been excluded because their neuro-vestibular response may differ from normal.

The patients will be informed of the nature of the research and its procedures. Those who voluntarily participate in and sign the informed consent form will be enrolled in the study. Each patient recruited will be sent to Vest Brain, Center for Neurovestibular Studies where on arrival they will be allocated randomly to the experimental group (real vestibular stimulation), or to the control group (sham stimulation). The maximum period between the recruitment and treatment at the Neurovestibular Studies Center will be 3 days, ideally the same day or the next day. If patients take more than 7 days to receive treatment, a new assessment will be performed.

Inclusion criteria

BD patients entering either real or sham stimulation group of the study will meet the following criteria:

  • Man or woman
  • Age 18–65 years
  • Patients must have a diagnosis of BD type I or II based on clinical evaluations confirmed by the results of the Structured Clinical Interview for the DSM-IV Manual of Mental Illnesses TR, Patient Version (SCID-P) for mood disorders administered by the two experienced psychiatrists
  • A minimum score of 20 on the Montgomery-Asberg De pression Scale (MADRS)
  • The absence of a diagnosis of any neurological disease
  • Lack of personality disorder diagnosis according to clinical diagnosis of an experienced psychiatrist
  • No alcohol or drug abuse in the last 3 months
  • Non-pregnancy
  • No change of medications in 2 days before the enrollment.
  • Provision of informed consent


Exclusion criteria

  • History of dependence on alcohol or substances in the last three months
  • An increased risk of suicide (MADRS item 10 equal or higher than 5 points)
  • Decompensated or untreated medical illness
  • Pregnancy
  • History of epilepsy, neurological disease, and presence of personality disorders that will be detected by the two clinical investigators


Withdrawal criteria

The patients will be withdrawn from the study at any time of the research if they willingly decline in continuing their participation.

Sample size

Based on a previous study, “Randomized clinical trial to evaluate the effectiveness of the vestibular stimulation as a coadyuvant treatment in major depression” project number 210I044 of the Chilean National Founds for Health Investigation (FONIS 210I044) (Soza, 2014), it was estimated a difference of 19.6 points on the Hamilton scale, between the treated and untreated. Assuming a standard deviation of 14 points, we need 50 patients per group to obtain results with 80% of power and a significance of 0.05 with two sides. If we also estimate a 10% dropout, we should recruit approximately 60 patients. The cut-off point for calculating the required sample size was based on the decreasing of 20 or more points on the Hamilton scale because that was the difference found in the previous study with vestibular stimulation in unipolar depressive patients.

Recruitment

Eligible patients signing the informed consent form at the psychiatric consultation will go to the Centro de Estudios Neurovestibulares (VEST-BRAIN) for vestibular assessment.

Interventions

Each patient recruited by the psychiatrist should schedule with the Neurovestibular Center an appointment for the first session of vestibular stimulation (treatment/placebo). This first session should be performed up to 5 days after being evaluated by the psychiatrist.

In VEST-BRAIN, patients’ data will be recorded, and an initial vestibular exam (rotatory vestibular test) will be performed in all patients in the 1st, 2nd, 3rd sessions and at 90-day follow-up assessment. The patients will be told what the test consists of; for the recording of the signal, three electrodes will be placed; one in each temple and the front, a conductive gel will be used. After that, the eye movements will be calibrated, allowing the patient to look at the points on the screen opposite. The patients should then close his eyes and tilt his head down 30° while the chair begins to turn to the right with an acceleration of 25°/s for 4 seconds, and then turn in the opposite direction for the same amount of time.

Experimental group: Patients will receive three sessions of vestibular stimulation consisting of rotatory, caloric air, and optokinetic stimulation (Vest-Brain Rotary Chair, model VB-002, made in Chile; Kaloristar Arctic, made in Germany).

Control group: Patients will receive sham vestibular stimulation consisting of the three kinds of vestibular stimulations (rotatory-caloric-optokinetic) under thresholds intensities that will be corroborated by the absence of vestibular response assessed by electronystagmography.

Randomization

Block randomization of five patients will be used, which will be stratified based on three variables: bipolar I vs. bipolar II, and presence or absence of a fast cycler, ensuring the equal distribution of characteristics in both groups. In this way two groups will be randomized to the experimental and control group with ~60 patients in each.

Blinding

Psychiatrists who perform mood evaluation will be blinded to the group (experimental/control) which the patient has been allocated to. Participants will also be blind to group assigned.

Outcome measures

Primary outcome

The primary outcomes are depression score changes assessed by MADRS (Montgomery and Asberg, 1979) from baseline to days 30 and 90 after the first session of neuro-vestibular stimulation. MADRS used in this study corresponds to the Spanish version validated in Chile. It has been widely used in scientific work in the Chilean population. For all analysis, an intention-to-treat (ITT) technique will be used. For the primary analysis, we will use a mixed multivariate model of repeated measures that evaluate change in MADRS score over time between the two groups: weeks 0, 4, 12 between the experimental and control groups. We will study the percentages of remission of depression (MADRS scale score lower than 7) and the response to the treatment between both groups. The response criterion corresponds to a reduction of the score of the MADRS scale to 50% of the baseline.

Secondary outcome

The secondary outcome is the neuro-vestibular function assessed by electronystagmography while horizontal rotation is provided to the subject sitting in a computer controlled rotary chair. The activity of the vestibular system will be measured through the velocities of the slow phase of the vestibular nystagmus, specifically, the analysis of the vestibular nystagmus generated by the rotation of the chair. The speed of the slow phase of the nystagmus caused by the right turn will be analyzed and compared with that produced by the left turn.

Other secondary outcomes to be analyzed will be the slow phase velocity of the nystagmus, the rhythmicity of nystagmus, and the type of slow ocular tracking.

The time frame and measures are depicted in [Table 1].
Table 1: Measures and time frame

Click here to view


Data collection

The electronystagmography records that contain the vestibular activity of the patients will be stored in the computer for reanalysis.

An expert medical technologist will analyze each registry. From each vestibular response (left and right rotation), the slow phase velocity of the six most representative nystagmus will be averaged.

Data of each group will be collected in a database (http://data.mendeley.com)

Data analysis

We will use average and standard deviation for continuous variables and percentages for categorical variables. The Pearson’s chi-squared test or Fisher’s exact test will be applied to associate two categorical variables. For a continuous categorical variable, we will use the Student’s t-test for independent samples or Mann-Whitney U analysis. Also we will use Pearson’s or Spearman’s correlation to associate two continuous variables and t-tests for related samples, and Wilcoxon tests in order to analyze changes in variables between the beginning and end of the study in each group. The significance level will be α = 0.05. A statistician will analyze the database with Statistical software R, version 3.5.1 (2018-07-02) of Free Software Foundation’s GNU General Public License.

Auditing

The Ethics Committee of the West Metropolitan Health Service of Santiago, Chile, will audit the progression of the research.

Confidentiality

All patient data will be kept confidential.

Ethics and dissemination

This study protocol was approved by the Ethics Committee of SSMO in Santiago, Chile (approval No. 08032016) on March 8, 2016. The study results will be published in scientific journals or other media.


  Discussion Top


BD is a highly prevalent psychiatric condition in varied countries. The depressive phase of this disease is difficult to treat using current available strategies. It leads to increased rates of suicidality and inability to work, raising the costs for the society and the suffering for the patients and the family. There is an urgent need to seek efficient solutions to this problem. The physiologic relationship between the vestibular activity and chronobiologic system that controls circadian rhythms and emotional cycles in BD, and the previous evidence of the efficacy of the vestibular stimulation in monopolar depression sustain the importance to test the efficiency of this treatment in BD. Positive results of this investigation will allow the improvements in the quality of life of BD patients, their family and of the society.


  Trial Status Top


This study is currently recruiting patients.

Additional files

Additional file 1: SPIRIT checklist.

Additional file 2: Informed Consent Form.

Author contributions

Study design, conduct of real/sham vestibular stimulation, and writing of the manuscript: AMS. Calculation of the sample size, patient screening, assessment of the clinical progression in patients, and reviewing this paper: SAB and PAV. All authors approved the final version of the paper.

Conflicts of interest

The authors declare that they have no conflicts of interests.

Financial support

This study was supported by Vest Brain, Centro de Estudios Neurovestibulares and the Fund for Innovation and Competitiveness of the Chilean Ministry of Economy, Development and Tourism, through the Millennium Scientific Initiative (grant IS130005; to PAV). The funders did not participate in data collection and analysis, article writing or submission.

Institutional review board statement

This study protocol was approved (approval No. 08032016) by the Ethics Committee of SSMO (Servicio de Salud Metropolitano Oriente) in Santiago, Chile.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the form the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of Millennium Institute for Depression and Personality Research, Ministry of Economy, Chile, Macul, Santiago.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices), will be published in https://data.mendeley.com/. It will be available for Researchers who provide a methodologically sound proposal to achieve aims in the approved proposal. Proposals should be directed to amsozaried@vestbrain.cl. To gain access, data requestors will need to sign a data access agreement. Data will be available for 5 years at a third party website (www.vestbrain.cl). The following documents also will be available beginning 3 months and ending 5 years following article publications: study protocol, statistical analysis plan, informed consent form.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Funding: This study was supported by Vest Brain, Centro de Estudios Neurovestibulares and the Fund for Innovation and Competitiveness of the Chilean Ministry of Economy, Development and Tourism, through the Millennium Scientific Initiative (grant IS130005; to PAV). [16]

 
  References Top

1.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th ed. American Psychiatric Association, Washington DC.  Back to cited text no. 1
    
2.
Bartoli F, Clerici M, Di Brita C, Riboldi I, Crocamo C, Carrà G (2018) Effect of clinical response to active drugs and placebo on antipsychotics and mood stabilizers relative efficacy for bipolar depression and mania: A meta-regression analysis. J Psychopharmacol 32:416-422.  Back to cited text no. 2
    
3.
Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, Hróbjartsson A, Mann H, Dickersin K, Berlin JA, Doré CJ, Parulekar WR, Summerskill WS, Groves T, Schulz KF, Sox HC, Rockhold FW, Rennie D, Moher D (2013) SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 158:200-207.  Back to cited text no. 3
    
4.
Dodson MJ (2004) Vestibular stimulation in mania: a case report. J Neurol Neurosurg Psychiatry 75:168-169.  Back to cited text no. 4
    
5.
Fajutrao L, Locklear J, Priaulx J, Heyes A (2009) A systematic review of the evidence of the burden of bipolar disorder in Europe. Clin Pract Epidemiol Ment Health 5:3.  Back to cited text no. 5
    
6.
Fuller PM, Fuller CA (2006) Genetic evidence for a neurovestibular influence on the mammalian circadian pacemaker. J Biol Rhythms 21:177-184.  Back to cited text no. 6
    
7.
Ghaemi SN, Ostacher MM, El-Mallakh RS, Borrelli D, Baldassano CF, Kelley ME, Filkowski MM, Hennen J, Sachs GS, Goodwin FK, Baldessarini RJ (2010) Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry 71:372-380.  Back to cited text no. 7
    
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Goodwin FK, Jamison KR, Ghaemi SN (2007) Manic-depressive illness: bipolar disorders and recurrent depression. Oxford University Press, New York, USA.  Back to cited text no. 8
    
9.
McKay R, Tamagni C, Palla A, Krummenacher P, Hegemann SC, Straumann D, Brugger P (2013) Vestibular stimulation attenuates unrealistic optimism. Cortex 49:2272-2275.  Back to cited text no. 9
    
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Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382-389.  Back to cited text no. 10
    
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Novick DM, Swartz HA, Frank E (2010) Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. Bipolar Disord 12:1-9.  Back to cited text no. 11
    
12.
Otzen T, Sanhueza A, Manterola C, Escamilla-Cejudo JA (2014) Trends in suicide mortality in Chile from 1998 to 2011. Rev Med Chil 142:305-313.  Back to cited text no. 12
    
13.
Sachs GS (2003) Decision tree for the treatment of bipolar disorder. J Clin Psychiatry 64 Suppl 8:35-40.  Back to cited text no. 13
    
14.
Simon GE, Hunkeler E, Fireman B, Lee JY, Savarino J (2007) Risk of suicide attempt and suicide death in patients treated for bipolar disorder. Bipolar Disord 9:526-530.  Back to cited text no. 14
    
15.
Soza AM (2014) Vestibular stimulation as adjuvant therapy in major depression. In: Fonis 10 Years Supporting Applied Research in Chile (Communications Department of CONICYT, ed). Santiago.  Back to cited text no. 15
    
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Soza Ried AM, Aviles M (2007) Asymmetries of vestibular dysfunction in major depression. Neuroscience 144:128-134.  Back to cited text no. 16
    


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