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Volume 14 No. 12
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Accepted Papers





Scientific Investigations

The Evolution of Sleep Apnea Six Months After Acute Ischemic Stroke and Thrombolysis

Jaana K. Huhtakangas, MD1; Tarja Saaresranta, MD, PhD2; Risto Bloigu, MSc3; Juha Huhtakangas, MD, PhD4
1Respiratory Medicine Unit, Institute of Clinical Medicine, Oulu University Hospital, MRC Oulu, Finland; 2Turku University Hospital, Division of Medicine, Department of Pulmonary Diseases and Sleep Research Centre, Department of Pulmonary Diseases and Clinical Allergology, University of Turku, Turku, Finland; 3Medical Informatics and Statistics Research Group, University of Oulu, Oulu, Finland; 4Department of Neurology, Oulu University Hospital and University of Oulu, Oulu, Finland

ABSTRACT

Study Objectives:

Our goal was to investigate the evolution of prevalence, severity, and type of sleep apnea among patients who had an ischemic stroke, with or without treatment with thrombolysis after 6 months.

Methods:

We prospectively studied 204 patients who had an ischemic stroke (110 in the thrombolysis and 94 in the non-thrombolysis group). After follow-up, 177 patients were eligible for a final analysis (98 in the thrombolysis group and 79 in the non-thrombolysis group). An unattended sleep study with a three-channel portable device was performed both on admission and after the 6-month follow-up.

Results:

The patients receiving thrombolysis were younger than those in the non-thrombolysis group (mean 65.5 versus 69.6 years P = .039). Sleep apnea, defined as a respiratory event index (REI) ≥ 5 events/h, was diagnosed in 92.7% patients, 93.9% versus 91.1% (P = .488) in the thrombolysis and non-thrombolysis groups, respectively. The prevalence remained unchanged during follow-up. Mild sleep apnea progressed to moderate or severe sleep apnea in 69.2% of the patients. Globally, mean central apneas per hour increased by 2.2% (P = .002), whereas obstructive apneas declined by 1.7% (P = .014). The mean change of oxygen desaturation index was −6.1% (P < .001) in the thrombolysis group, −1.8% (P = .327) in the non-thrombolysis group, and 4.2% (P = .001) in the whole group. In the non-thrombolysis group, the risk for new sleep apnea incidence increased by 6.1-fold (P = .024) at follow-up when compared to the thrombolysis group.

Conclusions:

Sleep apnea prevalence remained high in patients who had an ischemic stroke at 6 months post-stroke. The risk for developing sleep apnea after stroke was significantly lower among patients undergoing thrombolysis.

Clinical Trial Registration:

Registry: ClinicalTrials.gov; Title: Ischaemic Stroke and Sleep Apnea in Northern Part of Finland; Identifier: NCT01861275; URL: https://clinicaltrials.gov/ct2/show/NCT01861275

Citation:

Huhtakangas JK, Saaresranta T, Bloigu R, Huhtakangas J. The evolution of sleep apnea six months after acute ischemic stroke and thrombolysis. J Clin Sleep Med. 2018;14(12):2005–2011.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Sleep apnea prevalence is high among patients who had a stroke. We studied the evolution of prevalence, type, and severity of sleep apnea among patients who had an ischemic stroke with or without thrombolysis treatment after 6 months in northern Finland.

Study Impact: Our study showed that sleep apnea prevalence remained high, obstructive apneas declined, and central apneas increased at 6-month follow-up. A novel contribution of this study is the finding that thrombolysis appears to independently associate with the lower frequency of new cases of sleep apnea after stroke.

INTRODUCTION

Sleep apnea is characterized by nocturnal hypoxemia, sympathetic activation, and cardiovascular stress.1 Untreated sleep apnea causes poor quality of sleep and daytime sleepiness, resulting in a decrease in life quality.2,3 Recent prevalence estimates for sleep apnea in the middle-aged general population are as high as 14% for men and 5% for women.4 The prevalence of sleep apnea is high among patients who had a stroke with estimates ranging from 62.5% to 86%.57 According to the previous studies with patients who had a stroke, the prevalence of sleep apnea decreased by 9.8% to 22% within 6 to 12 weeks after stroke,8,9 and apneahypopnea index (AHI) 23% to 40% within 4 to 24 weeks follow-up.811

Numerous hemodynamic, neural, metabolic, endothelial, coagulatory, and inflammatory changes, caused by respiratory events and recurrent hypoxemia, connect sleep apnea with stroke.10,12,13 Sleep apnea is an independent risk factor for stroke.1416 Patients who had a stroke with sleep apnea have a high risk for mortality, cardiovascular events, and prolonged hospital stay as well as impaired functional recovery.15,17 However, it is important to note that stroke may aggravate or cause sleep apnea.18

In a previous study,7 we observed the prevalence of sleep apnea to be higher (96.4% versus 85.1%) in patients treated with thrombolysis as compared to those not treated with thrombolysis in the acute phase of ischemic stroke. Importantly, the effect of thrombolysis on the evolution of sleep apnea is currently unknown. Thus, the purpose of this study was to examine the differences in the normal evolution of sleep apnea during the first 6 months postdiagnosis between patients who had a stroke treated with or without thrombolysis. We analyzed the change in prevalence, the type, and severity of sleep apnea in patients who had an ischemic stroke at 6 months after stroke. We hypothesized that obstructive apneas per hour will show similar levels of decline in both groups; however, central apneas were hypothesized to show a greater decline in patients receiving thrombolysis.

METHODS

We recruited 204 consecutive patients who had an ischemic stroke, age 18 years or older, who were admitted to the Stroke Unit at the Department of Neurology of the Oulu University Hospital during April 2013 and January 2015. The exclusion criteria were confusion or inability to understand study protocol. The patients were followed prospectively for a period of 6 months. The inclusion criterion was an ischemic stroke confirmed by an independent on-call neurologist on admission to our hospital on the basis of clinical examination, and either computed tomography or magnetic resonance imaging of the head. The thrombolysis treatment was administered within 4.5 hours from the onset of symptoms for patients who were independent, had National Institutes of Health Stroke Scale (NIHSS) scores higher than 2, and did not have any contraindications for thrombolysis treatment. The exclusion criteria for thrombolysis therapy for stroke were defined according to the Finnish Current Care Guideline for Ischemic stroke.19 We obtained sleep recordings for 204 patients, of whom 110 received thrombolysis, and 94 did not. Cooperative patients participated voluntarily, and gave their written informed consent. After the 6-month follow-up we obtained relevant sleep recordings for 177 patients, of whom 98 had received thrombolysis, and 79 had not. The study protocol was approved by the ethics committee of the Northern Ostrobothnia Hospital District. Baseline data of study patients have been reported previously.7

At 6 months after stroke, we measured weight, neck, and waist circumference, and performed sleep recording by a portable device (ApneaLink Plus, Resmed, Sydney, Australia). We recorded current medication, changes in medication, occurrence of new vascular events (stroke or myocardial infarction), new illnesses, and mortality. Daytime sleepiness was assessed by the Epworth Sleepiness Scale (ESS, 0 to 24).20 Stroke outcome was estimated by the modified Rankin Scale (mRS, scale 0–5).21

An unattended sleep study with a portable three-channel type 4 device (ApneaLink Plus; SCOPER OCST classification by Dr. Nancy Collop is S0C4O1xP0E2R2),22 was performed on patients both at baseline and after the 6-month follow-up. Nasal continuous positive airway pressure (CPAP) users were asked to discontinue the treatment for 1 night prior to the cardiorespiratory sleep study in order to enable comparisons between the baseline and follow-up sleep studies. The sleep recordings were scored manually (American Academy of Sleep Medicine [AASM] criterion)23 by the same scorer without blinding. In order to attempt to ensure objectivity and an even quality of scoring, 10% of sleep recordings were randomly reanalyzed, and the results remained the same. The criterion of obstructive, central, and mixed apnea, as well as hypopnea, have been described in detail previously.7 We used the threshold for arterial oxyhemoglobin decreases of ≥ 4% per hour (ODI4). Unattended cardiorespiratory polygraphy recorded data on nasal airflow with nasal prongs connected to pressure transducer, oxygen saturation via finger probe pulse oximeter, and respiratory movements via thoracic belt. Sleep recordings with the minimum durations of 4 hours were accepted for analyses. The number of respiratory events per hour of successful recording time was expressed by respiratory event index (REI). Sleep apnea was defined as an REI ≥ 5 events/h.

At 6-month follow-up, there were 27 dropouts including 11 deceased patients (Figure 1). Thus, 177 patients (86.8%) participated in the follow-up. Among the deceased, 3 versus 5 had severe sleep apnea, 1 versus zero had moderate sleep apnea, and zero versus 2 had mild sleep apnea, in the thrombolysis and non-thrombolysis groups, respectively. The mean time interval from baseline to death was 68.3 (standard deviation [SD] 51.0) days in the thrombolysis group and 23.3 (SD 19.8) days in the non-thrombolysis group.

Flowchart.

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Figure 1

Flowchart.

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Statistical Analyses

Demographic and sleep data are reported as means and SD. The chi-square test or the Fisher exact test was applied to categorical variables, whereas normally distributed variables were assessed by the t test. We used the two-sample test of proportion to evaluate the equality of proportions for both the mRS scores and sleep apnea severity. Analysis of variance was used to both estimate correlations between CPAP and REI or ODI4 changes during the study, as well as for multiple comparisons. The mRS score change from the baseline to the 6-month follow-up was assessed by the McNemar-Bowker test. Group comparisons were performed using the Mann-Whitney U test in instances where the data were non-normally distributed. Logistic regression analyses were performed to evaluate the predictors of sleep apnea. Values of P < .05 were considered statistically significant. Statistical analyses were computed using IBM SPSS (version 22.0, IBM Corp., Armonk, New York, United States).

RESULTS

In the entire cohort, 63.3% of patients were male, and the sex distribution did not differ between the groups as summarized in Table 1. The patients treated with thrombolysis were younger (mean age difference 4.1 years; P = .039), had less daytime sleepiness (mean ESS scores 3.0 versus 3.8, P = .045), and had a lower prevalence of atrial fibrillation (7.1% versus 27.8%, P < .001) as compared to the patients in the non-thrombolysis group. All patients with the exception of one had higher mRS scores at the end of follow-up as compared to on admission to the hospital at the onset of stroke. There were no between-group differences in weight, waist circumference, prevalence of hypertension, peripheral arterial disease, diabetes, hypercholesterolemia, coronary artery disease, or hypercholesterolemia. During follow-up, in the thrombolysis group, coronary artery disease was diagnosed in two patients, one patient experienced myocardial infarction, and three patients received a diagnosis of atrial fibrillation. New, nonfatal ischemic stroke was verified in 8 patients with thrombolysis (8.2%), and in 4 patients without thrombolysis (5.1%) (P = .415). In addition, 2 patients (2%) had a new transient ischemic attack in the thrombolysis group.

Characteristics of patients at baseline and 6-month follow-up.

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Table 1

Characteristics of patients at baseline and 6-month follow-up.

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The main results of this study are shown in Table 2. After the 6-month period, the global prevalence of sleep apnea was 92.7% in this study, which did not differ between the thrombolysis (93.9%) and the non-thrombolysis groups (91.1%, P = .488). During the 6-month follow-up, the prevalence of sleep apnea did not change (−2.0% in the thrombolysis group versus +8.8% in the non-thrombolysis group, P = .488). At follow-up, the thrombolysis group had more hypopneas (mean 22.0 events/h versus 16.0 events/h, P = .005) as compared to the non-thrombolysis group. At 6 months, the prevalence of neither severe (46.9% versus 36.7%, P = .172) nor mild sleep apnea (20.4% versus 27.8%, P = .249) differed between the thrombolysis and the non-thrombolysis groups, respectively. Sleep apnea severity worsened in the mild sleep apnea group (baseline REI 5–15 events/h), with 69.2% of the group progressing to moderate to severe sleep apnea (REI ≥ 15 events/h). By contrast, 20.2% of the patients with moderate to severe sleep apnea improved by only having mild sleep apnea after follow-up.

Clinical outcomes of patients at baseline and 6-month follow-up.

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Table 2

Clinical outcomes of patients at baseline and 6-month follow-up.

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The changes in the clinical parameters are shown in Table 3. During follow-up, ESS and the mean lowest oxygen saturation decreased in both groups. In addition, ODI4 showed a reduction in the thrombolysis group. Central apnea index increased in both groups. The mean change in ESS scores was −1.7% (P < .001) in the thrombolysis group versus −1.0% (P = .001) in the non-thrombolysis group, and −1.4% (P < .001) in the entire cohort. The mean lowest oxygen saturation declined in the whole group by 2.3% (P = 0.005), in the thrombolysis group by 2.4% (P = .046) and in the nonthrombolysis group by 2.2% (P = .043). The mean change of ODI4 was −6.1% (P < .001) in the thrombolysis group, −1.8% (P = .327) in the non-thrombolysis group, and 4.2% (P = .001) in the whole group. REI showed no significant change (Figure 2). In the whole group, mean central apnea index increased by 2.2% (P = .002), with increases seen in both the thrombolysis (2.02%, P = .024) and non-thrombolysis (2.5%, P = .029) groups. Mean obstructive apnea index declined by 1.7% (P = .014) in the whole study population. Mean mixed apnea index declined in the whole study group by 0.07% (P = .010).

Average change in parameters of sleepiness and cardiorespiratory polygraphy after 6 months.

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Table 3

Average change in parameters of sleepiness and cardiorespiratory polygraphy after 6 months.

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REI change after 6 months in the thrombolysis and non-thrombolysis groups.

REI = respiratory event index.

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Figure 2

REI change after 6 months in the thrombolysis and non-thrombolysis groups.

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Nasal CPAP treatment was initiated for 21 patients, with 1 patient having CPAP on hospital admission. In the whole study group, thrombolysis and nasal CPAP treatment together predicted the decline of mean REI (P = .005); this was not seen for mean ODI4 (P = .828).

Adjusted odd ratios of the predictors for new diagnosis of sleep apnea are shown in Table 4. Patients in the non-thrombolysis group had a 6.1-fold risk for new sleep apnea (P = .024) when compared to the thrombolysis group at follow-up. Neither age, ESS scores, nor atrial fibrillation were significant risk factors for new diagnosis of sleep apnea.

Logistic regression analysis for predictors of sleep apnea after stroke.

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Table 4

Logistic regression analysis for predictors of sleep apnea after stroke.

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DISCUSSION

Total sleep apnea prevalence increased from 89.8% to 92.7% within 6 months after stroke. This was produced by an increase of sleep apnea from 82.3% to 91.1% in the non-thrombolysis group. By contrast, in the thrombolysis group, sleep apnea prevalence declined from 95.9% to 93.9%. Patients without thrombolysis treatment had a sixfold risk for the development of sleep apnea within 6 months after stroke as compared to those treated with thrombolysis, independent of age, daytime sleepiness, and atrial fibrillation.

A novel and important finding indicated that thrombolysis in our study had a strong independent protective association for the development of new sleep apnea within 6 months after stroke. ODI4 decreased in the thrombolysis group. Intermittent hypoxemia is an important pathological mechanism in sleep apnea essentially linking sleep apnea to stroke. Hypoxemia causes oxidative stress, that is, systemic inflammation, which may cause progression of atherosclerosis, whereas severe hypoxemia can result in cerebral ischemia and increase risk of stroke.6 Nocturnal hypoxemia (oxygen saturation below 90%) is a risk factor for the incidence of stroke for patients having sleep apnea, especially when desaturation comprises more than 10% of sleep time.24 A systematic review reported that after stroke, OSA is a risk factor for both recurrent vascular event and all-cause mortality.25 In patients who had a stroke, oxygen desaturation and sleep apnea correlate independently with functional impairment and prolonged hospitalization.26,27 Nevertheless, the outcomes of CPAP treatment after stroke are controversial,2830 with further investigations needed to clarify this issue. In our study only 8 patients (5 in the thrombolysis group and 3 in the non-thrombolysis group) had sleep apnea diagnosis confirmed prior to the presenting stroke. The number of patients who had OSA prior to the presenting stroke was too small for statistical analysis.

Our finding of increased overall post-stroke sleep apnea prevalence in Northern Finland stands in contrast with previous studies reporting a decrease in sleep apnea prevalence.8,10 Furthermore, in the current study, the mean central apnea index increased in both study groups, contrary to previous evidence.5,8,10,31,32 The increase in sleep apnea prevalence in our entire cohort was instigated by data from patients treated without thrombolysis at baseline. Further, in most patients with mild sleep apnea, the severity increased to moderate or severe sleep apnea. The central apnea index increased in a similar manner in both groups. The mean ESS scores declined in both study groups, which is in line with previous studies.8,10 However, the fairly small ESS differences were unlikely to be clinically significant.33

The definition used for sleep apnea may affect the increase in prevalence rate of sleep apnea after stroke. We used the cutoff point of REI ≥ 5 events/h, when even a mild increase in REI may result in detecting new cases of sleep apnea. However, this possibility was not supported by our findings because the prevalence of mild sleep apnea in terms of REI showed a similar pattern to that of moderate or severe sleep apnea. Unlike the current study, most previous sleep studies of patients who had a stroke have used polysomnography. However, this fails to account for either the increase in sleep apnea prevalence in patients treated without thrombolysis, or the decrease in those with thrombolytic treatment.

While our patients were older as compared to the majority of previous studies, BMI was comparable5,31 with the exception of the study by Turkington et al.34 The mRS scores worsened at month 6 as compared to admission in all patients except for one case. Our patients had severe ischemic strokes with remarkable comorbidities, which may represent one potential explanation for the worsening of the mRS scores. Older age together with an increase in mRS scores may result in lower physical activity thereby contributing to an increase in REI, since physical activity is known to decrease REI.35,36 However, this is an unlikely explanation, as sleep apnea prevalence increased only in the non-thrombolysis group with the mRS scores worsening for both groups. Good et al.26 reported poorer stroke recovery after one year in those patients with ODI > 5 events/h, whereas other studies have failed to report any significant association between REI and functional outcome.10,17,31 In line with previous findings,10 7.9% of participants in our study had new, nonfatal vascular events within 6 months post-stroke. Previous studies have neglected to report whether they have solely included patients who had a stroke with thrombolysis. If this is the case, then this may explain the differences between the findings from our study and previous evidence. A further explanation may be that our finding for some reason is specific to the Finnish population.

In contrast with the previous studies with follow-up periods of 3 to 6 months, our study patients had a greater central apnea index than obstructive apnea index at the 6-month follow-up.8,10,31

The current results provide support to the hypothesis that obstructive apnea index will decline similarly in both groups. In the study of Parra et al.,8 obstructive apnea index remained unchanged during follow-up (4.7 to 4.6), with the obstructive apnea index being consistent with that in the current study. However, contrary to our initial hypothesis, our study demonstrated that central apnea index increased significantly in both groups, albeit a smaller increase was observed in the thrombolysis group (2.0% versus 2.5%). One potential explanation for the significant increase in central apneas in our study relative to previous evidence may be that the patients in the thrombolysis group had severe strokes, resulting in higher mRS scores post follow-up.5,10,37 Mixed apneas were rare in our study. The most common respiratory events comprised hypopneas in both groups. Bravata et al.38 and Hui et al.11 noted a higher incidence of events of obstructive apneas and lower of hypopneic apneas than those in the current study. Relative to the current study, Bravata et al.38 reported a similar central apnea index, whereas Hui et al.11 observed central apneas with a lower frequency.

In our study, relative to those not treated with thrombolysis, patients receiving thrombolysis had an increased likelihood and severity of sleep apnea, as well as more severe stroke (as estimated by the mRS scores). The severity of stroke could therefore explain the higher prevalence of sleep apnea among the thrombolysis patients. However, the overall stroke severity, as estimated by the Scandinavian Stroke Scale, is found not to correlate with the development of upper airway obstruction.34 Reperfusion injury, intracerebral hematoma, or massive edema can accompany thrombolysis with intravenous tissue plasminogen activator (tPA) therapy and cause deterioration.39,40 There is some experimental evidence that tPA promotes excitotoxic or ischemic neuronal death.41

This is the first known follow-up study evaluating sleep apnea prevalence among patients who had a stroke and who were undergoing thrombolysis. Auto-CPAP may represent a new therapeutic approach for selected patients with acute cerebral infarction, appearing to improve neurological recovery from stroke.30 Thus, future investigations should be directed toward assessing whether patients after thrombolysis may show greater benefit from auto-CPAP as compared to other patients who had an ischemic stroke. We found that thrombolysis and nasal-CPAP treatment together predicted the declining of REI. However, patients discontinued their CPAP treatment for 1 night prior to the follow-up sleep study, which may not be an adequate time period to abolish the CPAP effect on REI or ODI. The withdrawal of nasal CPAP is found to increase ODI4 after 2 or more consecutive nights; however, this effect is not seen after one night of withdrawal.42 We considered it ethically dubious to request patients to abstain from their treatment for longer than just 1 night. However, although patients who had a stroke might benefit of CPAP therapy, low motivation may challenge this treatment. Few of our patients who had a stroke were motivated to start CPAP therapy contrary to most patients with OSA in our population. Our patients who had a stroke had quite a high burden of comorbidities. They perceived that symptoms of sleep apnea did not disturb them and CPAP treatment might deteriorate their quality of life.

The strengths of our study include the consecutive recruitment procedure together with the prospective design. Compared to previous studies, the current sample was more sizeable, the proportion of female patients was higher, and the patients' age range was very wide ranging from 22 to 95 years.5,6,31,34 The main limitation of the current study concerns the between-group difference on the basis of the criteria for thrombolysis, which can explain that the patients treated with thrombolysis have a lower rate of sleep apnea than others. Patients who were eligible for thrombolysis may represent a healthier population with fewer risk factors (less atrial fibrillation, younger age) for sleep apnea at baseline. Moreover, stroke is an established risk factor for OSA.10 Our results suggest that if stroke is not treated with tPA, it increases the risk of developing OSA after stroke.

That might partly explain the difference. The NIHSS score was evaluated only at hospital admission, and the mRS was the sole measure to evaluate the recovery of stroke. As single night sleep studies were performed on both time-points, it is difficult to control for night-to-night variability. However, this is unlikely to have a differential effect for the thrombolysis versus the control group.

Our study provides support to previous evidence indicating that sleep apnea prevalence remains high after 6 months poststroke. A novel and important finding indicated that thrombolysis had a strong and independent association with lower frequency of new cases of sleep apnea within 6 months poststroke.

DISCLOSURE STATEMENT

Work for this study was performed at Oulu University Hospital, Department of Neurology. All authors have seen and approved the manuscript. This study was supported by The Finnish Anti-Tuberculosis Association Foundation, Jalmari and Rauha Ahokas Foundation, Vëinö and Laina Kivi Foundation, Tampere Tuberculosis Foundation and The Research Foundation for Respiratory Diseases. The ApneaLink Plus (Resmed, Sydney, Australia) devices were provided by Resmed Finland. Tarja Saaresranta has received speaking fees from Resmed Finland. The other authors report no conflicts of interest.

ABBREVIATIONS

AASM

American Academy of Sleep Medicine

BMI

body mass index

CI

confidence interval

CPAP

continuous positive airway pressure

ESS

Epworth Sleepiness Scale

mRS

modified Rankin Scale

NIHSS

National Institutes of Health Stroke Scale

ODI

oxygen desaturation index

ODI4

oxyhemoglobin decrease of ≥ 4%

OR

odds ratio

REI

respiratory event index

SD

standard deviation

tPA

tissue plasminogen activator

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