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ORIGINAL RESEARCH |
From 1the Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada; 2Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; 3Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; 4Sepracor Inc., Marlborough, Massachusetts; 5Department of Psychiatry and Behavioral Neurosciences, Henry Ford Hospital Sleep Center, Detroit, Michigan.
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ABSTRACT |
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METHODS: This was a double-blind, placebo-controlled study with 410 women (aged 40–60; perimenopausal or early postmenopausal) who reported insomnia defined as sleep latency of at least 45 minutes and total sleep time less than or equal to 6 hours per night for at least 3 nights per week over the previous month. Patients were randomly assigned to eszopiclone 3 mg or placebo nightly for 4 weeks. Sleep data were collected once a day. Physician global assessments of menopause, menopause-specific questionnaire, Greene Climacteric Scale, the Montgomery Asberg Depression Rating Scale, and the Sheehan Disability Scale were collected at baseline and end of treatment.
RESULTS: Patients receiving eszopiclone reported improvements in sleep induction, sleep maintenance, sleep duration, sleep quality, and next-day functioning relative to placebo (P<.05). Patients receiving eszopiclone reported fewer total awakenings and awakenings due to hot flushes (P<.05). Eszopiclone use led to greater improvement in Montgomery Asberg Depression Rating Scale scores (P<.05) and physician global assessments of menopause scores (P<.001); total Greene Climacteric Scale score and the vasomotor and psychological sub-scores (P<.05); vasomotor and physical domains of the menopause-specific questionnaire (P<.05); and family life/home domain of the Sheehan Disability Scale (P<.05).
CONCLUSION: In this study, eszopiclone provided significant improvements in sleep and positively impacted mood, quality of life, and menopause-related symptoms in perimenopausal and early postmenopausal women with insomnia.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00366093
LEVEL OF EVIDENCE: I
Declining estrogen levels during perimenopausal and postmenopausal years might also be associated with the occurrence of sleep disturbances.11 Estrogen is known to exert effects on sleep-related factors including body temperature regulation, circadian rhythms, and stress reactivity.12 However, studies on estrogen therapy for the treatment of insomnia among menopausal women have shown mixed results.13,14 With recent studies questioning the long-term safety of estrogen therapy for menopausal women,15 some physicians and their patients are seeking nonhormonal treatment options to manage menopause-related physical symptoms and sleep problems and to improve quality of life.16
Eszopiclone is a non-benzodiazepine cyclopyrrolone, approved by the U.S. Food and Drug Administration for the treatment of insomnia, with safety and efficacy demonstrated in adult and geriatric patients, including short-term and long-term use.17,18 In this study, we examined the efficacy of eszopiclone compared with placebo for the treatment of insomnia in perimenopausal and early postmenopausal women. The study also evaluated the extent to which treatment for insomnia with eszopiclone may impact menopause-related symptoms (eg, awakenings due to hot flushes), mood changes, and quality of life.
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MATERIALS AND METHODS |
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Women aged 40 to 60 years (inclusive) who met DSM-IV criteria for insomnia in the context of the menopausal transition (ie, onset of insomnia was temporally associated with the menopausal transition) were recruited for this study. Eligible study participants were perimenopausal or early postmenopausal, according to the following Stages of Reproductive Aging Workshop criteria24: early menopausal transition (Stage -2) with variable cycle length (more than 7 days different from normal); late menopausal transition (Stage -1) with two or more skipped cycles and an interval of amenorrhea of 60 or more days; or early post menopausal (Stage +1a) with amenorrhea for a period of up to 12 months.
Participants were required to meet additional criteria for insomnia, defined as reported sleep latency 45 or more minutes and sleep duration 6 or fewer hours for greater than three times per week for 1 month. The onset of the menopausal transition must have preceded the symptoms of insomnia with no other causes for developing secondary insomnia. Exclusion criteria included any other known causes of insomnia (including obstructive sleep apnea), history of substance abuse or dependence, consumption of more than two alcoholic beverages per day or 14 per week, use of prescription medications known to affect sleep, and use of over-the-counter medications affecting sleep or mood. Patients with major depressive disorder or other major Axis I psychiatric disorders (assessed with the Mini International Neuropsychiatric Interview, DSM-IV) were not enrolled.
Patients meeting criteria for insomnia despite receiving stable doses of hormone therapy (HT) were allowed into the study, and a subgroup analysis was prospectively analyzed between baseline HT users and non-users.
The primary outcome measure was sleep latency, defined as the mean of the daily sleep latency values obtained during the first week of double-blind treatment via the interactive voice-response system. These data were also used to assess changes in wake time after sleep onset (key secondary endpoint), total sleep time, quality and depth of sleep, and daytime function.
Menopause-related outcome measures that were collected via the interactive voice-response system (hot flushes) were analyzed using the mean values during weeks 1, 2, 3, and 4 and over the double-blind average. Additionally, the insomnia severity index, Greene Climacteric Scale, menopause quality of life, Sheehan Disability Scale, Montgomery Asberg Depression Rating Scale, and Physician Global Assessment were analyzed with the data collected at study visits.
Safety was assessed using clinical laboratory tests (full hematology, serum chemistry, and urinalysis), 12-lead electrocardiograms, vital signs, physical examinations, and documentation of adverse events occurrences.
A sample size of 440 patients was planned, utilizing a 1:1 (eszopiclone:placebo) randomization ratio. This sample size was based on the expected attrition rate of 80% over the course of the study and on the desire to detect a treatment difference in the key secondary endpoint, wake time after sleep onset, of 0.185 between the two treatment groups on the log scale (17% reduction), using a two-sided 5% significance level. With this sample size, the study had 90% power to detect a treatment difference in sleep latency, the primary endpoint, of 0.14 on the log scale (13% reduction), assuming a standard deviation on the log scale of 0.40. Patients were randomly assigned to treatment groups using permuted blocks of size 4 within each clinical site. The statistical analyses utilized all randomly assigned patients (intent-to-treat analysis), and all statistical tests were two sided. Change from baseline analyses were conducted using analysis of covariance (ANCOVA), with treatment and clinical site as the explanatory variable and baseline as the covariate. Sleep latency and wake time after sleep onset measures were log transformed before analysis. Sleep latency and wake time after sleep onset values greater than 540 minutes and all total sleep time values greater than 840 minutes were prospectively excluded from the analyses (less than 0.5% of all values), as these values were felt to be erroneous. Treatment comparisons for categorical variables used 
2 tests.
Data and statistical analyses for this study were fully available to all authors. Statistical analyses were performed by the sponsor and its representatives. The sponsor placed no limitations on the data analyses, the interpretation of the results, or the writing of this manuscript. All authors were involved with the preparation of the manuscript and vouch for the completeness and accuracy of the data and analyses presented.
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RESULTS |
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The most common reasons for study withdrawal were adverse events (5.5% in the eszopiclone group and 1.4% in the placebo group; P<.05) and protocol violations (1.5% in the eszopiclone group and 2.9% in the placebo group; P=.34). No between-group differences were observed at study entry with respect to demographic characteristics (Table 1) or severity of menopause-related symptoms. The majority of women were white and the mean age was approximately 49 years. Only 19 women (4.6%) reported being on HT at baseline (10 in the eszopiclone group and 9 in the placebo group), for an average of 351 days.
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At study entry, the majority of patients reported taking between 45 and 59 minutes to fall asleep, sleeping between 5 and 6 hours per night, having between three and five nocturnal awakenings per night, and experiencing a wake time during the night between 30 minutes and 1 hour. The majority reported that their sleep quality was fair and that their depth of sleep was light. Also, 73.7% of patients reported that they had decreased ability to function during the day associated with their sleep pattern.
Eszopiclone significantly decreased both sleep latency (P<.001) and wake time after sleep onset (P<.01) relative to placebo at all weekly timepoints (Fig. 2A and 2B). The average reduction in sleep latency over the 4-week study period was 25.8 minutes with eszopiclone versus 10.1 minutes with placebo (P<.001). Similar improvements were observed for wake time after sleep onset (reduction of 30.9 minutes versus 16.0 minutes, respectively; P<.001). Additionally, eszopiclone significantly increased nightly total sleep time relative to placebo across the treatment period (P<.01, Fig. 2C) with an average increase over the 4-week study period of 56.6 minutes in the eszopiclone group compared with 33.6 minutes in the placebo group (P<.001). Results in the subgroup of HT users were consistent with those of the intent-to-treat population, although the differences between groups were not significantly different due to the small sample size in each group (10 patients in the eszopiclone group and 9 patients in the placebo group).
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Significant improvements were observed with eszopiclone relative to placebo in other sleep and daytime function measures over the double-blind period including sleep quality, depth of sleep, daytime alertness, ability to function, ability to concentrate, and physical well-being (P<.05; Fig. 3). Eszopiclone significantly improved sleep quality and depth of sleep at all weekly timepoints.
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At week 4, there were significantly more eszopiclone-treated patients with no clinically meaningful insomnia ("insomnia not clinically significant," defined as an insomnia severity index total score 7 or less) compared with placebo-treated patients (58% versus 35%, respectively, P<.001), and mean insomnia severity index scores were significantly lower at weeks 2 and 4 with eszopiclone treatment (Fig. 4). Additionally, insomnia severity index–assessed sleep quality, feeling refreshed/rested, daytime fatigue, attention/concentration, and relationship enjoyment parameters were significantly improved with eszopiclone compared with placebo (data not shown; P<.05).
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No signs of eszopiclone rebound effects on sleep parameters were evidenced as total sleep time, sleep latency, and wake time after sleep onset remained improved from or similar to baseline for up to 7 days after treatment discontinuation (ie, after run-out period; data not shown).
After receiving 4 weeks of eszopiclone for the treatment of insomnia, study participants reported greater improvement compared with placebo in several menopause-related measures including fewer awakenings (mean of 1.12±1.05 for eszopiclone versus 1.42±1.29 for placebo; P<.01), fewer awakenings due to hot flushes (mean of 0.29±0.55 versus 0.37±0.76, respectively; P=.05), lower Greene Climacteric Scale total score as well as psychological and vasomotor sub-scores, and lower vasomotor and physical sub-scores of the menopause-specific quality-of-life questionnaire (P<.05, Fig. 5A and 5B). Patients treated with eszopiclone also showed significant improvement in mood compared with those who received placebo, assessed by Montgomery Asberg Depression Rating Scale total score at week 4 (mean score 8.36±7.15 for eszopiclone versus 9.97±6.86 for placebo; P<.05). Significantly greater changes from baseline at week 4 were noted with eszopiclone in the Sheehan Disability Scale in the family/home domains (mean change of –0.84±2.29 for eszopiclone versus –0.70±2.08 for placebo; P<.05), while the social (–0.81±2.20 versus –0.69±2.18; P=.09) and work/school (–0.89±2.39 versus –0.84±2.07; P=.48) domains were not significantly different. There were no significant treatment differences in change from baseline menopause and mood parameters at the end of the run-out period.
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In addition to patient-reported improvements in menopause-related symptoms, the Physician Global Assessment of menopausal symptoms at week 4 indicated that there were significantly more eszopiclone-treated patients who were "very much improved" or "much improved" and significantly fewer eszopiclone patients who had "no change" in menopause symptoms relative to placebo patients (P<.001, Fig. 6). No significant difference was observed between eszopiclone and placebo for number or severity of daytime hot flushes at each week or over the 4-week treatment period.
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No serious adverse events were reported during the double-blind treatment period. Seven patients (5.5%) reported adverse events that led to discontinuation of double-blind eszopiclone (one event each of back pain with chest pain, nausea, arthralgia, anxiety, and insomnia and two events of unpleasant taste). The discontinuation due to back and chest pain occurred 2 days after the administration of eszopiclone in a patient with relevant medical history of lower back pain and heartburn. These events were assessed by the investigator as moderate in severity, and the patient’s final physical examination and electrocardiographs were normal. Two patients (1.4%) reported events that led to discontinuation of double-blind placebo (one event of headache and one event of anxiety). The most frequently reported adverse events were unpleasant taste, headache, and back pain (Table 2). Rates of individual adverse events were similar between treatment groups with the exception of unpleasant taste, which was higher in the eszopiclone group (17.6% versus 0.5% in the placebo group). Potentially related adverse events (all events but those considered "not related" by the investigator) were higher in the eszopiclone group (42.7%) than in the placebo group (27.9%), but most of this difference was driven by higher rates of unpleasant taste in the eszopiclone group. Most adverse events were assessed as mild to moderate in severity with low rates of severe events in both treatment groups (3.4% in the eszopiclone group and 1.5% in the placebo group). There were six reported accidental injuries (two in the eszopiclone group and four in the placebo group). The two in the eszopiclone group (left knee strain and rollerblade fall) were both considered by the investigator not related to study drug. Changes from baseline to week 4 for all laboratory parameters, vital signs, and electrocardiogram results in eszopiclone-treated patients were not clinically significant and were similar to those observed with placebo.
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Adverse event rates during the single-blind placebo run-out period, which were assessed separately to evaluate withdrawal symptoms, were similar between treatment groups (Table 2). Central nervous system adverse events were few: 1 event of paresthesia after double-blind placebo and 2 events occurring in one patient (agitation, dizziness) after double-blind eszopiclone. None led to study discontinuation.
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DISCUSSION |
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This study examined a well-characterized population of perimenopausal and early postmenopausal women, based on Stages of Reproductive Aging Workshop criteria. In addition, the study criteria allowed us to select a population sample in which the onset of menopausal symptoms had preceded the development of insomnia (ie, the development of insomnia was temporally associated with the menopausal transition), and no other reasons for the occurrence of co-morbid insomnia were detected (eg, depression, anxiety, etc.). The study design also allowed us to examine the potential impact of treating insomnia with eszopiclone on other domains that are commonly affected during the menopausal transition, including patients’ subjective reports of vasomotor symptoms, awakenings due to hot flushes, mood, and quality of life.
Despite the exclusion a priori of patients with any Axis I psychiatric disorder (other than insomnia), patients enrolled in the study presented with mild psychological symptoms and impaired psychosocial functioning. These problems may have been triggered by the emergence of sleep problems or may have been associated with the hormonal and/or psychosocial changes inherent to the menopausal transition per se. Nonetheless, treatment of insomnia with eszopiclone resulted in positive changes in mood and quality of life.
Treatment of insomnia with eszopiclone resulted in reduction of awakenings due to nocturnal hot flushes, with a positive impact on sleep quality and on subsequent daytime function. The reduction of awakenings attributed to nocturnal hot flushes was observed regardless of the severity of vasomotor symptoms at study entry (data not shown). However, an objective assessment of nocturnal hot flushes was not included in this study, which limits our interpretation of the reduction in awakenings due to hot flushes. It is unlikely that treatment with eszopiclone would exert a direct impact on the occurrence/severity of hot flushes objectively evaluated, since a significant reduction in diurnal hot flushes was not subjectively reported by patients throughout the study. One could hypothesize that the improvement in sleep maintenance (as measured by wake time after sleep onset and total sleep time) with eszopiclone resulted in decreased awareness of the occurrence/severity of nocturnal hot flushes or increased threshold for awakenings caused by vasomotor symptoms. In addition, a more restful night could have had a positive effect on daytime function and well-being and possibly influenced patients’ ability to perceive/tolerate diurnal vasomotor symptoms, as noted by improvement in vasomotor sub-scores of the Greene Climacteric Scale and the menopause-specific quality-of-life questionnaire.
Other additional treatment differences noted in the eszopiclone group included a reduction in depressive scores (Montgomery Asberg Depression Rating Scale) and an improvement of psychological complaints assessed by the Green Climacteric Scale sub-scores. Improvement in quality of life was also noted based on improvements in the physical and vasomotor domains of the menopause-specific quality-of-life questionnaire and in the family/home domain of the Sheehan Disability Scale. Again, rather than a direct effect of eszopiclone on mood and quality of life, these positive changes may have derived from the improvement in sleep, with subsequent enhancement of daytime ability to function, concentration, and well-being. Our findings are in contrast to a recently published placebo-controlled study evaluating the efficacy of zolpidem in the treatment of insomnia during menopause in a population enriched both for hot flushes and for sleep maintenance insomnia.25 Zolpidem was associated with significant improvements in sleep, but no improvements relative to placebo were observed in scales used to assess quality of life and daytime function.
Other studies have confirmed the additional benefits of treating insomnia with eszopiclone when this condition coexists with other medical/psychological problems. Fava and colleagues26 compared 2 months of treatment with eszopiclone and fluoxetine co-therapy with fluoxetine-placebo monotherapy in male and female patients with major depressive disorder and co-existing insomnia. Patients treated with co-therapy had significantly greater improvements in both sleep and depression compared with those receiving antidepressant alone.
In summary, women treated with eszopiclone fell asleep quickly, stayed asleep longer (with reduction in awakenings and awakenings due to nocturnal hot flushes), reported improved sleep quality, and had additional benefits in mood, daytime well-being and ability to function, and quality of life compared with placebo. Future studies should include objective measures for the assessment of vasomotor symptoms and investigate the benefits of long-term eszopiclone use for the treatment of insomnia in menopausal women in the presence of comorbid anxiety and depression.
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Footnotes |
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Corresponding author: Claudio N Soares, MD, PhD, Associate Professor, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Director, Women’s Health Concerns Clinic, 301 James Street South, FB#638, Hamilton, ON L8P 3B6, Canada; e-mail: csoares{at}mcmaster.ca.
Financial Disclosure Support for this study provided by Sepracor Inc. Drs. Rubens and Caron are employees of and own stock or stock options in Sepracor Inc. Drs. Soares, Cohen, Joffe, and Roth have acted as research consultant for Sepracor Inc. in the past 3 years.
doi:10.1097/01.AOG.0000245449.97365.97
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REFERENCES |
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2. Li RH, Wing YK, Ho SC, Fong SY. Gender differences in insomnia: a study in the Hong Kong Chinese population. J Psychosom Res 2002;53:601–9.[Medline]
3. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders: an opportunity for prevention? JAMA 1989;262:1479–84.[Abstract]
4. Mauri M, Reid RL, MacLean AW. Sleep in the premenstrual phase: a self-report study of PMS patients and normal controls. Acta Psychiatr Scand 1988;78:82–6.[Medline]
5. Lee KA, Zaffke ME. Longitudinal changes in fatigue and energy during pregnancy and the postpartum period. J Obstet Gynecol Neonatal Nurs 1999;28:183–91.[Medline]
6. Shinkoda H, Matsumoto K, Park YM. Changes in sleep-wake cycle during the period from late pregnancy to puerperium identified through the wrist actigraph and sleep logs. Psychiatry Clin Neurosci 1999;53:133–5.[Medline]
7. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351–8.
8. Shin C, Lee S, Lee T, Shin K, Yi H, Kimm K, et al. Prevalence of insomnia and its relationship to menopausal status in middle-aged Korean women. Psychiatry Clin Neurosci 2005;59:395–402.[Medline]
9. Ohayon MM. Severe hot flashes are associated with chronic insomnia. Arch Intern Med 2006;166:1262–8.
10. Guilleminault C, Palombini L, Poyares D, Chowdhuri S. Chronic insomnia, postmenopausal women, and sleep disordered breathing: part 1. Frequency of sleep disordered breathing in a cohort. J Psychosom Res 2002;53:611–5.[Medline]
11. Moe KE. Reproductive hormones, aging, and sleep. Semin Reprod Endocrinol 1999;17:339–48.[Medline]
12. Kruijver FP, Swaab DF. Sex hormone receptors are present in the human suprachiasmatic nucleus. Neuroendocrinology 2002;75:296–305.[Medline]
13. Polo-Kantola P, Erkkola R, Helenius H, Irjala K, Polo O. When does estrogen replacement therapy improve sleep quality? Am J Obstet Gynecol 1998;178:1002–9.[Medline]
14. Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839–54.
15. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33.
16. Hackley B, Rousseau ME. CEU: Managing menopausal symptoms after the women’s health initiative. J Midwifery Womens Health 2004;49:87–95.[Medline]
17. Krystal AD, Walsh JK, Laska E, Caron J, Amato DA, Wessel TC, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003;26:793–9.[Medline]
18. Scharf M, Erman M, Rosenberg R, Seiden D, McCall WV, Amato D, et al. A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia. Sleep 2005;28:720–7.[Medline]
19. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001;2:297–307.[Medline]
20. Hilditch J, Lewis J, Peter A, van Maris B, Ross A, Franssen E, et al. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas 1996;24:161–75.[Medline]
21. Greene JG. Constructing a standard climacteric scale. Maturitas 1998;29:25–31.[Medline]
22. Asberg M, Montgomery S. A comprehensive psychopathological rating scale. Acta Psychiatr Scand 1978;S27:24–8.
23. Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol Jun 1996;11:89–95.
24. Soules M, Sherman S, Parrott E, Rebar R, Santoro N, Utian W, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001;76:874–8.[Medline]
25. Dorsey CM, Lee KA, Scharf MB. Effect of zolpidem on sleep in women with perimenopausal and postmenopausal insomnia: a 4-week, randomized, multicenter, double-blind, placebo-controlled study. Clin Ther 2004;26:1578–86.[Medline]
26. Fava M, McCall WV, Krystal A. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry 2006;59:1052–60.[Medline]
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