Mirtazapine does not improve sleep disorders in Alzheimer s disease: results from a double-blind, placebo-controlled pilot study

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1 the treatment of these disorders, particularly in community-dwelling patients with AD. The number of antidepressant prescriptions issued for the treatment of insomnia has increased over the past decade. Of the top-five drugs most commonly prescribed for this purpose, four (trazodone, mirtazapine, amitriptyline, and mianserin) are antidepressants. 4,5 Recently, trazodone at a dose of 50 mg has proved effective in increasing night-time sleep in community-dwelling AD patients. 6 Mirtazapine is an antidepressant with antiserotonin and antihistamine activities, particularly on receptors of the 5-hydroxytryptamine(2) family (5-HT 2), and drowsiness appears as an adverse effect of low-dose use. Current evidence tends to indicate that inhibition of the 5-HT 2A subclass of receptors can induce slowbs_bs_banner doi: /psyg PSYCHOGERIATRICS 2016; : ORIGINAL ARTICLE Mirtazapine does not improve sleep disorders in Alzheimer s disease: results from a double-blind, placebo-controlled pilot study Francisca M. SCORALICK, 1,2 Luciana L. LOUZADA, 1 Juliana L. QUINTAS, 1 Janeth O.S. NAVES, 2 Einstein F. CAMARGOS 1,3 and Otávio T. NÓBREGA 2,3 1 Department of Clinical Medicine, Geriatric Medical Center, Brasilia University Hospital, 3 Graduate Program in Medical Sciences, University of Brasilia, Brasília, and 2 Graduate Program in Health Sciences, University of Brasília, Brasília, Brazil Correspondence: Dr Otávio T. Nóbrega PhD, Geriatric Medical Center, HUB, Brasilia University Hospital, SGAN 605 Av. L2 norte, Asa Norte, Brasilia, DF, CEP , Brazil. otavionobrega@unb.br Received 3 August 2015; revision received 27 November 2015; accepted 30 December Trial registration: Mirtazapine for Sleep Disorders in Alzheimer s Disease; #NCT ; Key words: Alzheimer s, antidepressant, insomnia, mirtazapine, sleep disorders. Abstract Aim: The aim of this study was to test the efficacy and safety of mirtazapine in the treatment of sleep disorders in patients with Alzheimer s disease by means of a randomized, double-blind, placebo-controlled trial. Measurements were obtained for 7 days before intervention (baseline) and for 2 weeks after the onset of treatment. Methods: Alzheimer s disease patients with sleep disorders (n = 24) received 15-mg mirtazapine (n = 8) or placebo (n = 16) once daily at 2100 hours for 2 weeks. Patients were evaluated with actigraphy and structured scales before and after intervention. Historical control was employed. Results: Treatment with mirtazapine or placebo had no effect on cognitive and functional status as assessed by the Mini-Mental State Examination and the Katz scale, respectively. There were no differences between groups in the frequency or severity of the adverse events reported. Compared with the placebo group, mirtazapine users showed increased daytime sleepiness but no improvement in the duration or efficiency of nocturnal sleep after treatment. Conclusions: This study showed no significant therapeutic effects of 15-mg mirtazapine in community-dwelling Alzheimer s disease patients with sleep disorders. Instead, this study found evidence of worsening of daytime sleep patterns. INTRODUCTION Sleep disorders (SD) are common in patients with Alzheimer s disease (AD) and may occur due to degenerative neuropathological changes. The most common symptoms are confusion, wandering, nocturnal awakenings, excessive sleepiness during the day, and changes in the sleep wake rhythm. 1 In addition to increasing the risk of falls and reducing the quality of life of AD patients and their caregivers, SD may aggravate cognitive and functional decline and contribute to the institutionalization of patients. 2 There is evidence of the benefits of nonpharmacological intervention in the management of SD in AD patients, especially sleep hygiene, physical activity, and light exposure. 3 However, there is a paucity of evidence on the use of drugs for 2016 The Authors 1

2 F. M. Scoralick et al. wave sleep in poor sleepers. 7 Therefore, despite the lack of evidence, mirtazapine is commonly prescribed off-label for the treatment of SD in patients with AD. 8 To date, studies have reported the effects of mirtazapine on sleep in healthy individuals, 9 depressed adults, 10 and depressed elderly patients. 11 In AD patients with SD, only three studies have addressed the treatment of these disorders with mirtazapine. 8,12 15 A case report of three patients suggested improvement of SD symptoms based on a caregiver s evaluation of mirtazapine use at doses of mg. 12 A retrospective study of 20 patients with dementia and SD who were treated with up to 30-mg mirtazapine found that 17 patients (85%) achieved a good clinical response according to their caregivers. 8 A prospective uncontrolled study suggested mirtazapine s efficacy in treating 13 agitated patients with AD; in particular, it decreased nocturnal agitation. 13 Although these studies suggest the efficacy of mirtazapine in treating SD in AD patients, their observational and uncontrolled nature (without comparison with placebo or other drugs) renders the results unsuitable to support the use of mirtazapine in current clinical practice. Therefore, the present trial was set up to compare the effects of 15-mg mirtazapine and placebo on sleep parameters assessed by actigraphy in community-dwelling AD patients diagnosed with SD. METHODS This randomized, double-blind, placebo-controlled pilot study was conducted from November 2012 to March 2014 at the Geriatric Medical Center of University General Hospital in Brasilia, Brazil, as the main institution, in collaboration with Geriatric Services of the Hospital Regional da Asa Norte (Brasilia) and the Municipal Health Department of Joinville (Joinville, Brazil). The research project was approved by the Institutional Review Board (no. 052/2012) of the University of Brasilia. The trial is registered at ClinicalTrials.gov (no. NCT ). Participants Eligible participants were all community-dwelling patients aged 60 years or over who had a diagnosis of probable AD. Diagnoses were based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, 14 and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer s Disease and Related Disorders Association). 16 All participants had (formal or informal) caregivers to monitor them during the 21-day protocol. A diagnosis of SD was established based on the caregiver s emotional distress as assessed by the Sleep and Night-time Behaviour item of the Neuropsychiatric Inventory (score 2) and according to criteria suggested by Yesavage et al. 17,18 Patients were excluded if they had a mean nocturnal total sleep time (NTST) >8 hours as assessed by actigraphy, developed an acute sleep disturbance in the 4 weeks preceding enrolment in the study, or reported previous use of mirtazapine. Because wrist actigraphy was used to monitor sleep wake patterns, patients with movement disorders or upper limb paresis were excluded. Patients with a diagnosis of other types of dementia or meeting the clinical criteria for schizophrenia, schizoaffective disorders, delusional disorders, delirium, or mood disorders with psychotic features were also excluded. Eligible patients should have kept their dosing regimen stable for at least 4 weeks prior to enrollment in the study and were not allowed to change medications during the trial. Written informed consent was obtained from all individual participants or their caregivers prior to enrolment. Data on the 14 patients assigned to the control group were obtained from the clinical trial NCT , which was also conducted at University General Hospital using the same methodology, so part of the placebo group (87%) consisted of historical controls. The decision to include historical placebo controls was mainly based on ethical grounds, to avoid rendering a larger number of demented patients without intervention for several weeks. Intervention Patients were randomly assigned to receive 15-mg mirtazapine or placebo once daily at 2100 hours for 14 consecutive days. Before intervention, all patients underwent medical examination, including the administration of cognitive rating scales, such as the Mini- Mental State Examination (MMSE) and the Clinical Dementia Rating, 19,20 depression screening using the Cornell Scale for Depression in Dementia, 21 assessment of functional status using the Katz Activities of Daily Living scale, 22 and assessment of the degree of sleep impairment by the Neuropsychiatric Inventory (Sleep and Night-time Behaviour item). 17 If necessary, The Authors

3 Mirtazapine for insomnia in AD patients the patient s medical record was reviewed to confirm the diagnosis of probable AD. Patients who met the clinical inclusion criteria were subjected to in-home actigraphic measurement of sleep for 7 consecutive days (baseline period). The actigraphic data for each patient were then analyzed, and patients who had a mean NTST 8 hours and no acute sleep disturbance (inclusion criteria) were enrolled in the study. The caregiver of each enrolled participant was provided with the medication required for 14 days. Each enrolled participant received medication use recommendations and was instructed to wear the actigraph for the 14-day intervention period. In addition, caregivers received guidance on sleep hygiene practices and were asked to maintain the patient on a regimen of caffeine abstinence after 1500 hours and limit his/her alcohol intake to a maximum of two drinks per day. Actigraphy Wrist actigraphy was used to measure sleep parameters in all patients. Activity was recorded with an Actiwatch of the Respironics brand (Mini-Mitter Co., Bend, OR, USA) and analyzed with the Actiware software (version , 2010). Caregivers were instructed to place the actigraph on the patient s nondominant wrist and to ensure the patient wore the device during bathing or other activities in water. Outcome measures The following actigraphic sleep data were recorded and calculated by a computer algorithm for a 12-h nocturnal period ( hours) and a 12-h daytime period ( hours) as appropriate: (i) NTST; (ii) nocturnal awakenings; (iii) night-time sleep percentage; (iv) night-time waking after sleep onset; (v) gain of at least 30 min in NTST; (vi) daytime total sleep time; and (vii) number of daytime naps (naps). The primary end-point with respect to the efficacy of mirtazapine in SD was the difference between the two treatment arms (placebo and mirtazapine) in terms of changes from baseline in mean actigraphic sleep data. Differences in baseline characteristics across groups were also assessed. Secondary efficacy end-points included changes from baseline in cognition and functional status as determined by changes from baseline in mean MMSE and Katz scale scores, respectively. Adverse events were determined by spontaneous patient or caregiver reports and classified as mild, moderate, or severe according to the Clinical Dementia Rating scale. Adherence to treatment was measured by manually counting the number of pills that were returned by each patient at the end of the study. Good adherence was defined as at least 85% consumption of supply dispensed. Randomization Randomization sequence was created by the principal investigator using the True Random Number Service ( The random number generator mode was used to produce random alphanumeric, three-digit codes. The codes were handed to an independent pharmacist for medication preparation. The mirtazapine and placebo were in standard capsule form and identical in appearance. They were prepacked in bottles, which were individually labelled for each patient with the identifying code and administration time. All individuals involved in the study were blinded to the treatment assignment, and the final randomization list was not accessed until the analysis of all actigraphic sleep data was completed. The randomization ratio was 2:1 (two control participants per each treatment participant). Statistical analysis Baseline data were compared between the two groups using the χ 2 test or, in case of sample size with fewer than five patients per group, Fisher s exact test for categorical variables. Student s t-test was used for continuous variables with normal distribution and the Mann Whitney U-test for variables with a non- Gaussian distribution. All variables that showed a statistically significant difference between groups at baseline were used as covariates for adjustment in post-treatment analyses. The mean post-treatment values were compared between the two groups by MANCOVA, assuming the interdependence of the dependent variables. For this purpose, actigraphic sleep data obtained after treatment were used as dependent variables in the model, treatment arms (mirtazapine and placebo) as independent variables, and the baseline values of each parameter as covariates as appropriate. The null hypothesis was rejected in each statistical test when P < Statistical analysis was performed using the Statistical Analysis System version 9.3 (SAS Institute, Inc., Cary, NC, USA) The Authors 3

4 F. M. Scoralick et al. RESULTS Thirty-three patients were initially enrolled for assessment of eligibility for intervention according to the inclusion and exclusion criteria. Nineteen were excluded at initial interview or after baseline assessments because of caregiver sleep misperception (n = 9), patient non-compliance with use of the actigraph (n = 7), refusal to participate (n = 1), death (n = 1), and lack of caregiver (n = 1). Therefore, 14 patients with a diagnosis of AD and SD fulfilled the clinical evaluation and actigraphic measurement of sleep (7-day baseline period). Of these, 3 ended up randomized to the placebo group and 11 to mirtazapine group. In the mirtazapine group, one patient discontinued medication due to excessive sedation after the first dose. The data of two patients in the mirtazapine group and one in the placebo group could not be recovered from the actigraph because of device decalibration. The data of 14 historical controls were used to compose the final sample, which consisted of 24 patients (mirtazapine group, n = 8; placebo group, n = 16). The main baseline demographic and clinical characteristics of current control subjects were comparable to data from historical controls, according to Fisher s exact test or the Mann Whitney U-test. The most common SD were night waking (n = 23, 95.8%), frequently getting up during the night (n = 19, 79.2%), wandering at night (n = 18, 75.0%), difficulty falling asleep (n = 17, 70.8%), getting up, getting dressed, and attempting to go out (n = 12, 50.0%), waking up too early in the morning (n = 18, 75.0%), and severe daytime sleepiness (n = 10, 41.7%). Baseline measurements The baseline demographic and descriptive characteristics of the study sample are shown in Table 1. Most participants were women (n = 18, 75.0%). The mean age 1 standard deviation of the total sample was years, and the mean MMSE score 1 standard deviation was Although 17 (70.8%) patients had moderate to severe dementia, functional independence was partially preserved for activities of daily living. Because demographic and descriptive variables showed no statistically significant differences between the groups at baseline, these variables were not re-examined in the final analysis. Two sleep parameters (NTST and naps) were significantly different between groups at baseline (Table 2). Compared with the placebo group, patients Table 1 Baseline demographic and descriptive characteristics of study participants Variable Mirtazapine (n = 8) Placebo (n = 16) P-value Age Sex Female 6 (75.0%) 12 (75.0%) Male 2 (25.0%) 4 (25.0%) Marital status Married 3 (37.5%) 7 (43.7%) Widowed 4 (50.0%) 6 (37.5%) Other 1 (12.5%) 3 (18.8%) Education level Illiterate 1 (12.5%) 4 (25.0%) <4 years 5 (62.5%) 3 (18.7%) 4 years 2 (25.0%) 9 (56.3%) CDR Mild 4 (50.0%) 5 (31.2%) Moderate 1 (12.5%) 7 (43.8%) Severe 3 (37.5%) 4 (25.0%) CSDD Katz AD treatment Anticholinesterase 3 (37.5%) 11 (68.7%) Memantine 1 (12.5%) 4 (25.0%) Antipsychotics (yes) 1 (12.5%) 2 (12.5%) Other hypnotics (yes) 0 (0.0%) 1 (6.2%) Data are expressed as mean 1 SD or frequency (%). P-value calculated by Student s t-test for continuous variables and by χ 2 test or Fisher s exact test for categorical variables. AD, Alzheimer s disease; CDR, Clinical Dementia Rating; CSDD, Cornell Scale for Depression in Dementia; Katz, Katz Activities of Daily Living Scale. Table 2 Baseline actigraphic measurement of sleep for each study group Variable Mirtazapine (n = 8) Placebo (n = 16) P-value NTST (min) WASO (min) Awakenings %Sleep DTST (min) Naps (n) Student s t-test or Mann Whitney U-test. Data are expressed as mean 1 SD. %sleep, night-time sleep percentage; awakenings, nocturnal awakenings; DTST, daytime total sleep time; NTST, nocturnal total sleep time; WASO, night-time waking after sleep onset. receiving mirtazapine had a longer total sleep time (about 90 min more than placebo) and took more naps (about 60% more than placebo). These differences at baseline were included in the final adjusted model. Post-treatment measurements The use of mirtazapine had no positive effect on any of the nocturnal sleep parameters analyzed in this The Authors

5 Mirtazapine for insomnia in AD patients study. Compared with the placebo group, patients receiving mirtazapine had a gain of 55.3 min in NTST, although this difference was not statistically significant (95%CI: 4.6, 115.1; P = 0.2) (Table 3). Exactly half of mirtazapine users had a gain of at least 30 min in nocturnal sleep, whereas about one-third of placebo users (31.2%) had the same gain (P = 0.41). Despite a decrease of 18 min in night-time waking after sleep onset in the mirtazapine group, there was no statistically significant difference between groups in this parameter (95%CI: 54.0, 17.9; P = 1.00). Variables that had a potential interdependence (NTST, night-time waking after sleep onset, nocturnal awakenings, and night-time sleep percentage) were included in the MANCOVA model, but the betweengroup differences remained statistically nonsignificant (Hotelling s trace [4.15] = 0.237, F = 0.89, P = 0.49). The use of mirtazapine had a significant effect on daytime sleep duration, resulting in a gain of 68.4 min of sleep during the day (95%CI: 35.0, 101.9; P = 0.00), but it did not affect the number of naps during the day (95%CI: 6.3, 6.9; P = 1.00). Adherence and adverse events Overall adherence to treatment was high ( 85%). Regarding spontaneously reported adverse events, one mirtazapine user had mild epistaxis, while in the placebo group one patient complained of pruritus, one of worsening of memory, one of dyspepsia, and two of anxiety. All complaints were classified as mild events, with no significant difference between the groups (Fisher s exact test, P = 0.62). Treatment with mirtazapine or placebo had no effect on the cognitive or functional status of patients (Table 3). Sample size Taking our own results into account, we would require a sample size of 37 patients per group if we were to detect a difference of 60 min in NTST between patients receiving mirtazapine and placebo, given a two-sided significance level of 5% and a power of 80%. DISCUSSION The results of the present pilot study showed that mirtazapine had no positive effect on nocturnal sleep parameters in community-dwelling AD patients with SD, but it led to a significant increase in daytime Table 3 Results of actigraphic measurement of sleep before and after intervention for each study group (primary and secondary end-points) Mean (95%CI) Difference mirtazapine vs placebo (95%CI) P-value Mirtazapine (n = 8) Placebo (n = 16) Baseline Post-treatment Baseline Post-treatment Endpoint Primary end-point NTST (min) (320.1, 446.8) (341.0, 486.9)* (225.3, 338.6) (241.4, 338.3) 55.3 ( 4.6, 115.1) WASO (min) (103.1, 228.6) (107.9, 211.4)** (145.9, 235.9) (158.8, 228.3) 18.2 ( 54.4, 17.9) Awakenings (n) 29.0 (17.8, 40.3) 29.7 (20.3, 39.2)* 22.8 (19.6, 26.0) 23.7 (19.8, 27.7) 1.2 ( 4.1, 6.5) %Sleep 63.9 (56.1, 71.6) 66.7 (62.3, 71.1)* 54.7 (46.3, 63.1) 52.9 (46.0, 60.2) 7.8 (0.9, 14.7) DTST (min) (92.3, 234.2) (152.1, 325.3) (79.0, 173.0) (87.7, 179.9) 68.4 (35.0, 101.9) Naps (n) 42.4 (30.1, 54.8) 43.0 (26.4, 59.5) 28.5 (20.2, 36.7) 28.6 (20.6, 36.6) 0.3 ( 6.3, 6.9) Secondary end-point KATZ score 4.1 (0.6, 7.7) 4.1 (0.6, 7.7) 7.2 (4.7, 9.7) 6.6 (4.4, 8.7) 0.1 ( 1.8, 1.8) MMSE points 10.6 (4.4, 16.8) 10.7 (4.7, 16.8) 11.9 (8.3, 15.5) 11.3 (7.6, 15.0) 0.7 ( 0.5, 1.8) Intragroup comparison: *P < 0.01; **P < 0.05; P-value calculated by post-hoc test following ANCOVA with means adjusted for baseline values, with Bonferroni correction. %Sleep, night-time sleep percentage; awakenings, nocturnal awakenings; CI, confidence interval; DTST, daytime total sleep time; Katz, Katz Activities of Daily Living Scale; MMSE, Mini-Mental State Examination; NTST, nocturnal total sleep time; WASO, night-time waking after sleep onset The Authors 5

6 F. M. Scoralick et al. sleepiness. Although the use of mirtazapine was able to add 55 min to NTST, increasing mean nocturnal sleep values by 8%, there was no significant difference between the mirtazapine and placebo groups. We believe that a type II error may be the main factor contributing to this result because of the small sample size and the preliminary nature of the study. Counterintuitively, our results do not allow us to state that the mean gain of 68 min observed in daytime total sleep time negatively affected (i.e. a worsened pattern) night-time sleep parameters. This is because correlations could not be determined statistically or by visual inspection of the data, and NTST and nighttime sleep percentage showed an increase in absolute (yet non-significant) terms with mirtazapine use. Increased sleepiness during the day caused by mirtazapine use has been described in many settings, where a decrease in daytime sleepiness throughout the course of treatment has also been reported Studies have shown a decrease in sleepiness after 2 weeks of mirtazapine administration, 26 and this phenomenon may be attributed to tolerance developed to the antihistamine effects of mirtazapine. 27 However, this longer-term outcome could not be confirmed by our trial. It is known that the higher the dose of mirtazapine, the lower its antihistamine effect. Therefore, the marked daytime somnolence induced by mirtazapine at a daily dose of 15 mg, as used in our study, may be attenuated by increasing the dose to 30 mg or more, prompting the need for additional investigation. Another possible explanation for our results may be the regression toward the mean effect. 28 Because mirtazapine users showed a longer total sleep time at baseline (about 90 min more) than placebo users, it is possible that the hypnotic action of the drug did not produce an effect with a sufficient magnitude to surpass the placebo effect in this condition. Future studies should take these baseline differences into account in order to obtain more homogeneous groups. Despite our efforts at statistical control (covariance analysis) and experimental control (randomization of participants), we may have been unable to avoid the bias produced by this phenomenon in our analyses. In intervention studies using psychoactive drugs, one of investigators main concerns is the effects that somnolence caused by these medications may have on cognition. In the current study, mirtazapine had no effect on cognitive function (P = 0.96) or functional status (P = 0.23) compared with placebo. In studies using mirtazapine in healthy individuals and depressed patients, 10,29 the effect of daytime sleepiness on cognition was assessed by sustained attention and driving tests, but no changes were observed after drug use, even in those reporting daytime somnolence. Conversely, nocturnal sleep gains may improve a patient s cognitive performance, but a more sensitive battery of cognitive tests, the inclusion of patients in the early stages of dementia, and a longer follow-up are required for this analysis. There have been reports of patients taking mirtazapine who develop a voracious appetite with intense cravings for carbohydrates. 30 However, follow-up of the AD patients analyzed herein revealed no cases of weight gain or important changes in eating habits reported by caregivers. The use of mirtazapine for a short period may explain the absence of a weight effect. Consistent with this observation, Nelson et al. found that in elderly patients, particularly in octogenarians, weight gain appears to occur more slowly than in younger patients. 31 Also, mirtazapine can stabilize the weight loss associated with AD. 32 Although the present results did not support the clinical indication of mirtazapine for the treatment of SD in AD patients, the low frequency of adverse events observed among mirtazapine users may point to a good drug safety profile in the age group studied here when prescribed for the usual indication. A similar result was described by Papakostas et al. in a meta-analysis of 10 randomized trials comparing mirtazapine with selective serotonin reuptake inhibitors. 24 They found no difference in discontinuation rates due to adverse events or lack of efficacy between the two antidepressant agents. This pilot study had several strengths, including a sample exclusively of community-dwelling elderly patients with AD and objective measurements of sleep parameters. However, our study has some limitations. First, historical controls accounted for 87.5% of the placebo group. We believe that this methodological aspect did not have a significant impact on data analysis because the subjects were comparable in important features. Researchers have pointed out positive aspects of using historical control data, especially in increasing statistical power and reducing type I errors. 33 In addition to allocating patients in a The Authors

7 Mirtazapine for insomnia in AD patients randomization ratio of 2:1, all patients (historical and current) were followed by the same medical team, and the statistical analysis was performed by external, blinded examiners. Second, polysomnography was not performed, precluding the possible exclusion of other sleep disturbances. However, actigraphy has been established in the literature as a reliable method for this type of analysis, showing good correlation with polysomnography. 34 Third, cognitive function was assessed using only the MMSE, thereby preventing a more careful analysis of this variable. It is possible that expecting a marked effect on sleep (>90 min) as a side-effect of an antidepressant drug may not be a feasible goal. Another factor that may have contributed to the results was the impossibility of including patients with other behavioural disorders associated with SD because of difficulties using an actigraph. All things considered, this is the first study to objectively assess daytime sleep patterns in a group of elderly patients receiving mirtazapine. Conclusion The results of the present pilot study demonstrated that mirtazapine did not affect the parameters of nocturnal sleep in community-dwelling AD patients with SD, but it led to an increase in daytime sleep duration. More studies are required to further evaluate the efficacy and safety of mirtazapine (as well as of other drugs) in the treatment of AD patients with SD. ACKNOWLEDGMENTS The authors thank Audrey Cecília Tonet Furioso, PhD, for technically advising on actigraphy, and Eduardo F. Silva, PhD, for conducting the statistical analysis. This work was supported by a grant (#550315/2008-0) and a fellowship for productivity in research (#310157/ ) provided by CNPq to O.T. Nóbrega. This was a non-industry-supported study. The authors have no financial conflicts of interest to declare apart from Dr Einstein F. 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