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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 612-617, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200608-1141OC

Original Article

Silent Brain Infarction and Platelet Activation in Obstructive Sleep Apnea

Kenji Minoguchi1, Takuya Yokoe1, Toshiyuki Tazaki1, Hideko Minoguchi1, Naruhito Oda1, Akihiko Tanaka1, Mayumi Yamamoto1, Shin Ohta1, Christopher P. O'Donnell2 and Mitsuru Adachi1

1 First Department of Internal Medicine, Showa University, Tokyo, Japan; and 2 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Kenji Minoguchi, M.D., Ph.D., First Department of Internal Medicine, Showa University, School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan. E-mail: minochan{at}fn.catv.ne.jp


   ABSTRACT
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 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Silent brain infarction (SBI) and increased levels of soluble CD40 ligand (sCD40L) and soluble P-selectin (sP-selectin) are associated with an increased risk of cerebrovascular disease.

Objectives: The aim of this study was to evaluate whether SBI and serum levels of sCD40L and sP-selectin are increased in patients with obstructive sleep apnea (OSA).

Methods: SBI was studied by brain magnetic resonance images in 50 male patients with OSA and 15 obese male control subjects who were free of comorbidities. In addition, the effects of 3 months of treatment with nasal continuous positive airway pressure (nCPAP) on serum parameters were studied in 24 patients with moderate to severe OSA.

Measurements and Main Results: The percentage of SBI in patients with moderate to severe OSA (25.0%) was higher than that of obese control subjects (6.7%) or patients with mild OSA (7.7%). Serum levels of sCD40L and sP-selectin were significantly higher in patients with moderate to severe OSA than in obese control subjects (p < 0.05) or patients with mild OSA (p < 0.05). In addition, nCPAP significantly decreased serum levels of sCD40L (p < 0.03) and sP-selectin (p < 0.01) in patients with moderate to severe OSA.

Conclusions: These results suggest that serum levels of sCD40L and sP-selectin are elevated and SBI is more common in patients with moderate to severe OSA, leading to elevated cerebrovascular morbidity. Moreover, nCPAP may be useful for decreasing risk in patients with moderate to severe OSA.

Key Words: sleep apnea • platelet • brain infarction • atherosclerosis



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
The occurrence of stroke in patients with obstructive sleep apnea (OSA) is likely preceded by subclinical cerebrovascular disease, often termed silent brain infarction (SBI). The independent effects of OSA on the prevalence of SBI have not been clearly established.

What This Study Adds to the Field
The prevalence of SBI is increased in patients with OSA. The presence of SBI in OSA patients was associated with an elevation in markers of platelet activation (soluble CD40L and soluble P-selectin) and systemic inflammation (C-reactive protein), and these increases are reduced by nasal continuous positive airway pressure.

 
Obstructive sleep apnea (OSA) is associated with increased cerebrovascular and cardiovascular morbidity and mortality (1–5). The occurrence of stroke in patients with OSA is likely preceded by subclinical cerebrovascular disease, often termed "silent brain infarction" (SBI), which is detectable with brain magnetic resonance imaging (MRI). The independent effects of OSA on the prevalence of SBI have not been clearly established. One previous study showed relatively high, but similar, rates of SBI between patients with OSA and control subjects matched for age, body mass index (BMI), and cardiovascular disease (6). A second study showed a positive association between SBI and the nocturnal oxygen desaturation index as determined by the number of oxygen desaturations greater than 3% per hour in a high-risk community-based sample (7). However, both these previous studies were confounded by the presence of comorbidities, such as hypertension and diabetes, which potentially may obscure detection of any independent action of OSA on SBI.

Cardiovascular disease and diabetes are commonly characterized by ongoing inflammatory responses that can enhance platelet activation and increase the prevalence of SBI. A strong link also exists between OSA and inflammation, and we have previously shown that serum levels of C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)–{alpha}, matrix metalloproteinase-9, and carotid intima-media thickness are elevated in patients with OSA (8–11). In addition, levels of circulating soluble adhesion molecules and chemokines, and plasma levels of vascular endothelial growth factor, a potent angiogenic cytokine that contributes to the progression of atherosclerosis, are increased in patients with OSA (12–15). Therefore, OSA activates multiple inflammatory processes that could increase platelet activation and cause SBI, independent of established risk factors such as cardiovascular disease and diabetes.

Two important proteins associated with activation of platelets that act as a precursor to atherosclerosis are soluble CD40 ligand (sCD40L) and soluble P-selectin (sP-selectin) (16–19). CD40L is a transmembrane protein found on cells of the immune system, including platelets, and is rapidly presented to the platelet surface after stimulation (20). The surface-expressed CD40L is subsequently cleaved, generating a soluble fragment termed "sCD40L" (21), which is almost entirely of platelet origin (22). P-selectin is an adhesion molecule that is expressed on activated platelets and endothelium and is shed into plasma in a soluble form, sP-selectin (23). P-selectin is involved in leukocyte rolling and attachment, and thus can play an important role in the initiation of atherosclerosis (24). Both sCD40L and sP-selectin are important markers of platelet activation and future cardiovascular and cerebrovascular events (25, 26). In addition, levels of both sCD40L and sP-selectin are increased in patients with hypertension, hyperlipidemia, and diabetes mellitus (27–30). The relationship between serum levels of sCD40L and sP-selectin and the presence of SBI has not been previously investigated in patients with OSA without confounding comorbidities.

The purpose of the current study was to examine the relationship between OSA and SBI, in the absence of confounding cardiovascular disease and diabetes, using obese age- and BMI-matched control subjects. We hypothesized that the rate of SBI and serum levels of sCD40L and sP-selectin are elevated in patients with OSA compared with obese control subjects. Furthermore, we hypothesized that serum levels of sCD40L and sP-selectin are higher in patients with OSA and SBI compared with those without SBI, and that 3 months of nasal continuous positive airway pressure (nCPAP) therapy in patients with moderate to severe OSA reduces serum levels of sCD40L and sP-selectin. Some of the results of these studies have been previously reported in the form of an abstract (31).


   METHODS
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Fifty men with newly diagnosed OSA and 15 obese age- and weight-matched male control subjects were enrolled in the study (Table 1). All patients and control subjects were free of comorbidities (see the online supplement). All subjects were nonsmokers and not exposed to second-hand smoke, free of systemic infection for at least 2 weeks before the study, and not taking medications. The study was approved by the ethics committee of Showa University, and all patients gave written, informed consent.


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  		TABLE 1. BASELINE CHARACTERISTICS IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA AND OBESE CONTROL SUBJECTS

 
Polysomnography
Full polysomnography (PSG) monitoring was performed on all patients with OSA and control subjects using the Compumedics P-series Sleep System (Compumedics Sleep, Abbotsford, Australia). An apnea–hypopnea index (AHI) of more than 5 events/hour in conjunction with sleep-related symptoms was considered as diagnostic of OSA. An AHI of 5 or more and less than 15 indicated mild OSA, an AHI of 15 or more and less than 30 indicated moderate OSA, and an AHI of 30 or more indicated severe OSA. The Epworth Sleepiness Scale (ESS) was used to investigate changes in subjective daytime sleepiness (32).

Measurement of SBI
SBI was evaluated with MRI as described previously (33). Briefly, the whole brain was scanned, and 20 axial images were produced. Slice thickness was 5 mm and the interslice gap was 2 mm. The imaging protocol consisted of a T2-weighted spin-echo, T1-weighted spin-echo, and fluid-attenuated inversion-recovery imaging. SBI was defined as an area (>= 3 mm in diameter) of focal hyperintensity on T2-weighted images with corresponding low signal intensity on T1-weighted images. All subjects were examined by the same investigator who was blinded to clinical characteristics.

Measurement of sCD40L, sP-selectin, and CRP
All subjects went to bed at 9:00 P.M. and were awakened at 5:00 A.M. Samples of peripheral venous blood were collected at 5:00 A.M., clotted on ice, and stored at –80°C until time of assay. Serum levels of sCD40L and sP-selectin were measured with an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). High-sensitivity CRP was measured with a latex particle-enhanced immunoturbidimetric assay as described previously (34).

Treatment with nCPAP
Twenty-four patients with moderate to severe OSA were treated with nCPAP using the S6 CPAP device (ResMed, North Ryde, Australia). After 3 months of treatment, PSG was performed again while the patient received nCPAP, and blood samples collected as described above (see the online supplement for compliance data).

Statistical Analysis
Differences between two groups were investigated by unpaired t test or Mann-Whitney test according to the distribution of data with or without normality. The significance of the differences between three groups was determined by analysis of variance with Bonferroni correction. Correlations were analyzed with Spearman's rank correlation. To assess the relative strength of association of serum levels of sCD40L and sP-selectin with possible contributing factors, we used a stepwise multiple regression analysis of the patients with OSA and obese control subjects as a single group. Data are expressed as mean ± SEM, and p < 0.05 was considered to indicate significance.


   RESULTS
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 ABSTRACT
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 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subject Characteristics
Characteristics of the patients with OSA and obese control subjects, including age, sex, BMI, waist/hip ratio, metabolic variables, PSG variables, ESS, and serum levels of CRP, sCD40L, and sP-selectin, and the prevalence of SBI are shown in Table 1. AHI, percentage of time with SaO2 less than 90%, arousal index, and ESS were significantly higher in patients with moderate to severe OSA than in those with mild OSA or in obese control subjects. The lowest SaO2 and total sleep time were significantly lower in patients with moderate to severe OSA than in those with mild OSA or in obese control subjects.

SBI in Patients with OSA and Obese Control Subjects
The prevalence of SBI was higher in patients with OSA (16.0%) compared with obese control subjects (6.7%, p < 0.05). In addition, the prevalence of SBI was higher in patients with moderate to severe OSA (25.0%) compared with patients with mild OSA (7.7%, p < 0.05) or obese control subjects (6.7%, p < 0.05; Table 1). SBI was found in the subcortical white matter in control subjects and patients with mild OSA. SBI was located in subcortical white matter (54%), in the basal ganglia and thalamus (43%), and in the brain stem (3%) in patients with moderate to severe OSA. Lesions identified as SBI were wedge-shaped or round and all were greater than 3 mm in the largest dimension and varied in number between 2 and 9 in individual patients and control subjects.

Serum Levels of sCD40L and sP-selectin
Serum levels of sCD40L and sP-selectin were significantly elevated (p < 0.05) in patients with moderate to severe OSA compared with patients with mild OSA or obese control subjects (Table 1). Moreover, in patients with OSA and SBI, there were increased serum levels of sCD40L (7.70 ± 1.27 vs. 5.01 ± 0.38 ng/ml, p < 0.01), sP-selectin (93.9 ± 12.0 vs. 77.5 ± 3.6 ng/ml, p < 0.05), and CRP (0.28 ± 0.04 vs. 0.18 ± 0.02 mg/dl, p < 0.05) compared with patients with OSA and no SBI (Figure 1).


Figure 1
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  		Figure 1. Serum levels of soluble CD40 ligand (sCD40L) (A), soluble P-selectin (sP-selectin) (B), and C-reactive protein (CRP) (C) in patients with obstructive sleep apnea who had silent brain infarction (SBI; n = 8) or who did not have SBI (n = 42).

 
Correlation between Markers of Inflammation and Platelet Activation and PSG in Patients with OSA and Obese Control Subjects
There was a significant correlation between AHI or percentage of time with SaO2 less than 90% and serum levels of CRP, sCD40L, and sP-selectin (Table 2). Serum levels of CRP were significantly correlated with serum levels of sCD40L (r = 0.49, p = 0.0001) and sP-selectin (r = 0.38, p = 0.002). In addition, serum levels of sCD40L were also significantly correlated with serum levels of sP-selectin (r = 0.45, p = 0.002). None of the other assessed variables, including age, cholesterol, triglycerides, ESS, BMI, or waist/hip ratio, had significant correlations with CRP, sCD40L, or sP-selectin (Table 2). Thus, in men with OSA, elevated serum levels of sCD40L or sP-selectin were positively associated with increased levels of the inflammatory marker CRP, as well as with AHI and the magnitude of nocturnal hypoxic stress.


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  		TABLE 2. CORRELATION COEFFICIENTS BETWEEN SERUM LEVELS OF sCD40L OR sP-SELECTIN AND AGE, POLYSOMNOGRAPHIC VARIABLES, METABOLIC VARIABLES, AND LEVELS OF C-REACTIVE PROTEIN IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA AND OBESE CONTROL SUBJECTS

 
Stepwise Multiple Regression Analysis in Patients with OSA and Obese Control Subjects
In this study, we used the serum levels of sCD40L or sP-selectin as a dependent variable and evaluated the order of inclusion in the model of the following independent variables: age, total cholesterol, triglycerides, BMI, ESS, AHI, percentage of time with SaO2 less than 90%, and serum levels of CRP. Among the eight independent variables, percentage of time with SaO2 less than 90% was the strongest predictor of serum levels of sCD40L (p = 0.047) or sP-selectin (p = 0.005) in patients with OSA and obese control subjects.

Effect of nCPAP on Serum Levels of sCD40L and sP-selectin in Patients with Moderate to Severe OSA
In 24 patients with moderate to severe OSA who successfully completed 3 months of treatment, BMI did not change significantly and no new cardiovascular diseases were detected during the 3 months of treatment with nCPAP. Treatment with nCPAP significantly decreased the AHI (44.9 ± 3.9 to 2.7 ± 0.8 events/h, p < 0.001), increased the lowest nocturnal SaO2 (74.5 ± 2.3 to 92.2 ± 4.0%, p < 0.001) and total sleep time (329.8 ± 26.9 to 406.2 ± 38.7 min, p < 0.01), and decreased the percentage of time with an SaO2 of less than 90% (25.9 ± 3.3 to 0.13 ± 0.4%, p < 0.001) and the arousal index (46.1 ± 5.0 to 17.0 ± 3.4/h, p < 0.01). Treatment with nCPAP also significantly decreased overnight serum levels of sCD40L (6.95 ± 0.79 to 4.62 ± 0.67 ng/ml, p < 0.03; Figure 2A), sP-selectin (86.9 ± 6.4 to 67.2 ± 4.8 pg/ml, p < 0.01; Figure 2B), and CRP (0.28 ± 0.04 to 0.16 ± 0.03 mg/dl, p < 0.01).


Figure 2
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  		Figure 2. Effect of nasal continuous positive airway pressure (nPAP) on serum levels of sCD40L (A) or sP-selectin (B) in patients with moderate to severe obstructive sleep apnea (n = 24).

 

   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we found that the presence of SBI and serum levels of sCD40L and sP-selectin were significantly higher in patients with moderate to severe OSA than in patients with mild OSA or obese control subjects. In addition, patients with OSA and SBI had higher serum levels of sCD40L and sP-selectin than did patients with OSA who did not have SBI. There was a significant correlation between the AHI or duration of nocturnal hypoxia and serum levels of sCD40L or sP-selectin in patients with OSA. Last, 3 months of treatment with nCPAP caused significant reductions in both serum levels of sCD40L and sP-selectin in patients with moderate to severe OSA. These results suggest that platelet activation is increased in patients with moderate to severe OSA, and, in combination with an increased prevalence of SBI, may lead to an elevated risk of cerebrovascular morbidity.

Only one previous study, by Davies and colleagues (6), has attempted to examine the relationship between OSA and SBI. The prevalence of SBI in patients with OSA was reported at 33%, a level similar to the 25% prevalence we show in our current study in patients with moderate to severe OSA. However, in Davies and colleagues' study, the control subjects, matched for age, BMI, alcohol and cigarette consumption, treated hypertension, and ischemic heart disease, had a prevalence of SBI (35%) that was the same as in the OSA patient group. In contrast, our data in matched obese control subjects and in patients with mild OSA showed considerably lower rates of SBI (6.7 and 7.7%, respectively) compared with patients with moderate to severe OSA. The low prevalence of SBI in our control subjects and patients with mild OSA is likely related to our exclusion of any control subjects or patients with OSA and diabetes, hypertension, or ischemic heart disease. Because these comorbidities are known to increase platelet activation and potentially impact on the development of SBI, it is important to exclude these factors when examining the independent effects of OSA on SBI.

It is often difficult in MRI studies to distinguish between lesions due to SBI and enlarged Virchow-Robin spaces. However, two studies suggest that it is possible to differentiate most lacunar infarctions from enlarged Virchow-Robin spaces on the basis of their location, shape, and size (35, 36). In our study, lesions identified as SBI were wedge-shaped or round and all were 3 mm or greater in the largest dimension and varied in number between 2 and 9 in individual patients and control subjects. In obese control subjects and patients with mild OSA, the location of lesions identified as SBI was restricted to the subcortical white matter. In patients with moderate to severe OSA, SBI was identified by lesions in subcortical white matter (54%), the basal ganglia and thalamus (43%), and the brain stem (3%). Thus, on the basis of location, shape, and size, our MRI findings are consistent with a specific identification of lesions representing SBI.

The changes in markers of inflammation and platelet activation that we report also support a potential causal pathway between OSA and the development of SBI. We show that patients with moderate to severe OSA have significantly elevated levels of CRP, sCD40L, and sP-selectin compared with obese control subjects and patients with mild OSA. Moreover, the levels of these markers of inflammation and platelet activation were higher in patients with OSA who exhibited SBI compared with those without SBI. Recent studies suggest that CRP is both a marker of inflammation and a factor in the pathogenesis of atherosclerosis, in part by activating endothelial cells and coronary artery smooth muscle cells. CRP is a prooxidant that induces production of monocyte chemoattractant protein-1 and expression of adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (37, 38). We, and others, have previously shown that CRP is elevated in patients with OSA (8, 39). Similarly, other studies also report that the serum levels of sCD40L are elevated in adult patients with OSA (40) and serum levels of sP-selectin are increased in pediatric patients with OSA (41). However, the relationship between CRP levels and platelet activation markers, such as sCD40L and sP-selectin, has not been studied previously in patients with OSA who are free of metabolic and cardiovascular comorbidities. In the present study, we demonstrated that serum levels of CRP were significantly correlated with serum levels of sCD40L and sP-selectin in patients with OSA. Therefore, our results suggest that, if OSA is the proximal mediator of increased systemic inflammation and platelet activation, these factors may play a potential role in the progression of atherosclerosis in patients with OSA.

The hypoxic stress of OSA is potentially a proximal mediator of the systemic inflammation and platelet activation that lead to SBI in patients with OSA. A recent study from a high-risk Japanese community-based population reported that the presence of SBI was significantly elevated in the highest quartile of subjects exhibiting nocturnal hypoxia (7), consistent with an association between nocturnal hypoxic stress and SBI. Our current data also demonstrate a significant positive correlation between arterial oxygen desaturation and serum levels of CRP, sCD40L, and sP-selectin. In contrast, no correlation was evident for age, BMI, or waist-to-hip ratio for CRP, sCD40L, and sP-selectin. Taken together, these data suggest that hypoxia may mediate increases in systemic inflammation and platelet activation and increase the risk of developing SBI.

If the hypoxic stress of OSA is a causal factor in promoting an inflammatory, platelet-activated state, then treatment with nCPAP should act to decrease levels of CRP, sCD40L, and sP-selectin. Indeed, we have previously demonstrated that 3 months' treatment with nCPAP decreases serum levels of CRP (42), and, in the current study, we show that serum levels of sCD40L and sP-selectin are significantly reduced in response to a comparable period of treatment in patients with OSA. Similarly, Kobayashi and colleagues demonstrated that serum levels of sCD40L in patients with OSA were significantly decreased by nCPAP (40). However, a study by Robinson and colleagues (43) reported elevated levels of sP-selectin in patients with OSA, but sP-selectin levels were unaffected by a 1-month period of treatment with nCPAP. The difference between our data and that of Robinson and colleagues' (43) is potentially related to the longer treatment period of 3 months in our study and the presence of comorbid conditions that may independently increase sP-selectin and obscure the beneficial effects of reduced hypoxic stress. Thus, we provide evidence, under conditions in which comorbidities that impact on inflammation and platelet activation are minimized, that treatment of the nocturnal hypoxic stress in patients with OSA can reduce serum levels of sCD40L and sP-selectin and potentially lower the risk for development of SBI.

Despite our efforts to exclude comorbid conditions that are known to increase cerebrovascular risk and to recruit age- and weight-matched obese control subjects, there are limitations in our study that need to be acknowledged. First, the current study reports findings from male subjects only, and potentially a different relationship between OSA, CRP, sCD40L, sP-selectin, and the prevalence of SBI may exist in female subjects. Second, the study was conducted on a relatively small number of subjects, although we would anticipate that the statistical significance of the changes that we report between patients with OSA and obese control subjects and in patients with OSA before and after 3 months of nCPAP would be even greater in larger study cohort. Third, we did not make repeat measurements of serum levels of sCD40L and sP-selectin in control subjects or in patients with mild OSA at 3 months for comparison with the subjects with moderate to severe OSA who underwent 3 months of nCPAP treatment. Thus, we cannot rule out the possibility that day-to-day variability of these markers potentially contributed to the significant reductions in sCD40L and sP-selectin that we report after 3 months of nCPAP treatment. Fourth, we measured levels of sCD40L from serum that was clotted on ice to minimize the release of sCD40L ex vivo. Consequently, our data do not directly assess the in vivo levels of sCD40L. Finally, the clinical relevance of the decreases in CRP, sCD40L, and sP-selectin that we see with nCPAP treatment on reducing the incidence of subsequent SBI or stroke would need to be determined using a long-term prospective study design.

In conclusion, we have shown that the prevalence of SBI is increased in patients with moderate to severe OSA compared with obese control subjects or patients with mild OSA. Moreover, the presence of SBI in patients with OSA was associated with an elevation in markers of inflammation and platelet activation. The increased levels of sCD40L and sP-selectin in patients with OSA correlated with the degree of nocturnal hypoxic stress and arousals, and was reduced when breathing abnormalities during sleep were treated with nCPAP. Thus, hypoxic stress in patients with moderate to severe OSA may be associated with activation of platelets and increased prevalence of SBI. Therefore, nCPAP may be an important treatment intervention for decreasing the cerebrovascular risk in this susceptible patient population.


   FOOTNOTES
 
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form August 13, 2006; accepted in final form December 13, 2006


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 METHODS
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 DISCUSSION
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