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Original Paper

Free Access

Blood Leukocytes as Prognostic Parameter in Stroke Thrombectomy

Huber T.a · Kleine J.F.a · Kaesmacher J.a · Bette S.a · Poppert H.b · Zimmer C.a · Boeckh-Behrens T.a

Author affiliations

Departments of aNeuroradiology and bNeurology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany

Corresponding Author

Thomas Huber, MD

Department of Neuroradiology

Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Street 22

DE-81675 Munich (Germany)

E-Mail thomas-huber@tum.de

Related Articles for ""

Cerebrovasc Dis 2016;42:32-40

Abstract

Purpose: Despite the recent success of mechanical thrombectomy (MT) in the treatment of acute ischemic stroke, prognostic parameters and criteria for patient selection are yet uncertain. Elevated levels of white blood cells (WBCs) constitute an independent risk factor for unfavorable outcome. Here we studied the link between outcome and WBC counts obtained before and after successful MT. Methods: One hundred fifteen acute stroke patients successfully treated with MT (thrombolysis in cerebral infarction-scores 2b or 3) were included. WBC counts and C-reactive protein (CRP) levels were obtained prior to (WBC-pre, CRP-pre) and 1 day after MT (WBC-post, CRP-post). Clinical outcome measures consisted of National Institute of Health Stroke Scale (NIHSS) scores, and modified Rankin Scale (mRS) on day 90 (mRS-d90), dichotomized between scores ≤5 and >5 (NIHSS) and ≤2 and >2 (mRS). The association between WBC-/CRP-levels and outcome was assessed by correlation- and receiver-operating characteristic analyses. Results: WBC counts on day 1 after MT correlated significantly with NIHSS scores at discharge and mRS-d90. Among patients >50 years, no patient with WBC-post counts exceeding 14.2 G/l had favorable NIHSS scores (≤5), and no one with WBC-post counts ≥12.6 G/l had favorable mRS-d90 outcome-scores (≤2). Further, even WBC-pre counts ≥10.6 G/l predicted unfavorable mRS-d90-scores in this subgroup. Conclusion: Elevated WBC counts obtained in routine blood tests may constitute a simple and economic parameter to estimate outcome after successful MT. Moreover, present data suggest that in patients older than 50 years, WBC counts may help to predict outcome even when obtained prior to MT.

© 2016 S. Karger AG, Basel


Introduction

Ischemia is strongly linked to inflammation and immunity [1,2]. Acute ischemic stroke evokes a prompt and long-lasting inflammatory response after arterial occlusion that probably contributes to post-ischemic tissue damage, especially in the early stage [2,3]. Later on, inflammation may play a more regenerative role in post-ischemic tissue repair [2,3]. Initial inflammatory mediators such as TNF-α or interleukin (IL)-1β lead to upregulation of adhesion molecules like ICAM-1, P- and E-selectins, resulting in a migration of immune cells into the brain [3,4]. Neutrophils are among the first subpopulation of white blood cells (WBCs) infiltrating ischemic tissue, and their number is directly linked to infarction volume. Lymphocytes are usually recruited 1-2 days later, making the inflammatory response to ischemia a dynamic and time-dependent process [3,5].

The well-orchestrated inflammatory response is reflected in higher WBC counts, elevated levels of C-reactive protein (CRP) or IL-6 in peripheral blood samples of patients with stroke [6,7,8,9,10,11,12,13]. Moreover, growing evidence suggests that early inflammatory markers like elevated WBC counts or IL-6 not only mirror the extent of ischemic inflammation but also correlate with the clinical course and patients' outcome [7,8,9,10,11,12,13,14]. Therapeutic strategies modulating the inflammatory response in stroke patients are being pursued for many years, raising the hope of positively influencing the inflammatory response in the future [15,16,17,18,19,20,21,22].

Recanalization has a strong impact on patients' outcome in stroke due to large vessel occlusion [23] and can be achieved with high success rates by mechanical thrombectomy (MT). The recent success of MT in the treatment of acute ischemic stroke [24,25,26] emphasized this aspect and showed that fast recanalization of occluded vessels is a key factor for patients' outcome. In addition, 2 current studies showed that early arrival at the emergency department and shorter time to reperfusion were correlated with better modified Rankin Scale scores on day 90 (mRS-d90) [27,28]. Thus, time plays a crucial role for patient's outcome undergoing MT and for the inflammatory response, which is also a dynamic and time-dependent process. Since the effect of early MT on patients' outcome is powerful [24,25,26,27,28], recanalization success should be taken into account when examining the link between inflammation and patients' outcome.

Reliable prognostic parameters and criteria for patient selection prior to MT are lacking, despite some hopeful approaches like the capillary index score [29,30,31,32]. WBC count and CRP are standard parameters usually obtained with routine blood tests on admission, which might be helpful to estimate outcome in patients undergoing MT. To our knowledge, this is the first study examining whether basic WBC counts, WBC dynamics or CRP in routine blood samples allow a prediction of outcome after or even prior to successful MT in patients with acute ischemic stroke. In consideration of the strong impact of recanalization, which might act as a powerful confounder regarding patients' outcome and attenuate the predictive value of such parameters, the present analysis is restricted only to successfully recanalized patients.

Methods

Subjects

One hundred fifteen stroke patients (56 male, median age 72 years) with occlusion of the distal internal carotid artery, carotid-T, middle cerebral artery (MCA) or anterior cerebral artery were included in this retrospective single-center study. All patients underwent MT at the Department of Neuroradiology between July 2010 and September 2012, and showed a post-interventional thrombolysis in cerebral infarction (TICI) score of 2b or 3, representing successful recanalization. Seventy three patients (63%) were treated additionally with intravenous thrombolysis (alteplase) according to out institutional standard protocol.

Recanalization Rating and Clinical Scores

Recanalization was rated according to the TICI scale [33] with TICI 2b defined as reperfusion of more than 2/3 of the dependent territory distal to the occlusion. National Institute of Health Stroke Scale (NIHSS) scores were assessed on admission (NIHSS-pre) and at discharge (NIHSS-post) by qualified neurologists. Fatal outcome was scored as NIHSS of 42. The difference between initial NIHSS-pre and NIHSS-post is displayed as dNIHSS. The mRS-d90 was used to assess the functional outcome [34].

Laboratory Parameters

WBC counts (normal range 4.0-9.0 G/l) and levels of CRP, normal range <0.5 mg/dl of blood samples taken prior to MT (WBC-/CRP-pre) and after MT (WBC-/CRP-post) were retrieved from our clinical information system. Times at which the blood samples were taken had been documented by the neurologist on call in most cases. Otherwise, the times of release of the test results by the laboratory were taken as a surrogate. WBC-pre data were included only if pertinent analyses provided that they were clearly prior to MT. Differences between WBC-pre and WBC-post counts were calculated and are referred to as dWBC counts (WBC-post - WBC-pre). WBC dynamics were calculated by dividing dWBC through the elapsed time between the blood test prior to MT and after MT (usually referred to as G/l per hour).

Mechanical Thrombectomy

MT was performed according to standard techniques under general anesthesia using stent retrievers in conjunction with distal access/aspiration catheters in most cases.

Estimation of Infarct size

Noncontrast computed tomography (NCCT) scans acquired within 24 h after MT were reviewed by 2 neuroradiologists (T.H., T.B.-B.) to determine ischemic injury. The infarct size was measured by applying the Alberta Stroke Program Early CT (ASPECT) score on post-procedural NCCT scans. This score divides the MCA territory into 10 regions of interest with ASPECT = 10, indicating no infarction and a maximum ASPECT = 0 showing complete MCA infarction [35].

Statistical Analysis

Shapiro-Wilk test was applied to analyze data for normal distribution. Bivariate correlation analysis was done with two-sided Spearman correlation, since correlation parameters were non-normally distributed, except NIHSS-pre (p = 0.322 in Shapiro-Wilk test). For receiver operating characteristic (ROC) analysis, patients' outcome was dichotomized for scores ≤5 and >5 (NIHSS) and ≤2 and >2 (mRS). Statistical analysis was done with IBM SPSS statistics, release 23.0 (IBM, Armonk, N.Y., USA).

Results

Patients' Characteristics (Table 1)

During July 2010 and September 2012, 115 patients underwent successful MT in the anterior cerebral circulation with TICI scores of 2b (n = 49; 43%) and 3 (n = 66; 57%) proving effective recanalization. Median NIHSS-pre score was 14, as assessed in 107 (93%) patients. In 8 (7%) patients, no records of NIHSS could be obtained. Median NIHSS-post score was 5, derived from scores of 104 patients (90%). Fatal outcome was identified in 6 patients (5%) during hospital stay, for example, due to malignant MCA infarction, secondary intracranial hemorrhage or pneumonia. Data of mRS-d90 were available for 56 patients (49%); the remaining mRS-d90 data were not obtainable or the patient was lost to follow-up. Patients with fatal outcome on day 90 were scored as mRS of 6 (n = 13; 11%).

Table 1

Patients' characteristics, clinical and medical parameters

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Effects of WBC Counts and CRP Levels on Patients' Outcome

WBC-post counts showed a highly significant correlation for all clinical scores: NIHSS-pre (p = 0.001), NIHSS-post (p < 0.001), dNIHSS (p = 0.004), mRS-d90 (p = 0.001; online suppl. table 1; for all online suppl. material, see www.karger.com/doi/10.1159/000444369). Also, the difference in WBC counts, dWBC, showed a significant correlation for NIHSS-post (p = 0.032) and mRS-d90 (p = 0.012). A similar correlation was observed for WBC dynamics, which correlated with NIHSS-post (p = 0.026) and mRS-d90 (p = 0.010). For CRP, only one significant correlation was observed for CRP-post and NIHSS-pre (p = 0.043). Further, infarct size after MT and WBC-post counts correlated significantly (p ≤ 0.001; online suppl. fig. 1). However, no correlation was found between the infarct size and WBC-pre counts (p = 0.175) nor WBC dynamics (p = 0.322).

Considering differences in age and leukocyte distribution in our cohort we found that younger patients (<50 years, n = 10) showed higher WBC-pre (median 11.7 G/l, n = 7) and WBC-post counts (median 12.9, n = 10) compared to the whole cohort, while still having more favorable outcomes (fig. 1). Therefore, we analyzed the subgroup of patients >50 years (n = 105; 91%). Again, WBC-post counts showed a highly significant correlation for all clinical scores: NIHSS-pre (p = 0.001), NIHSS-post (p < 0.001), dNIHSS (p = 0.001) and mRS (p < 0.001; table 2). Moreover, a significant correlation between WBC-pre counts and NIHSS-pre (p = 0.029), NIHSS-post (p = 0.016) and mRS-d90 was identified (p = 0.011). dWBC revealed a significant correlation for NIHSS post (p = 0.046). Again, for CRP, only one significant correlation was observed for CRP-post and NIHSS-pre scores (p = 0.015). Additionally, correlation between age and WBC counts/dynamics did not show a significant correlation (data not shown).

Table 2

Spearman correlation between WBC counts, WBC dynamics or CRP and mRS-d90 or NIHSS scores for patients >50 years (n = 105)

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Fig. 1

Regression line between WBC-post counts and mRS-d90 for patients >50 years (black circles). Black crosses show data for younger patients (<50 years).

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We hypothesized that prognostic parameters in the context of MT should ideally provide high specificity to minimize overly pessimistic outcome prediction. For illustrative purposes, we performed ROC analyses to estimate cut-offs for WBC counts/dynamics for two thresholds in terms of specificity (>90 and >99%; fig. 2). Poor mRS-d90 scores with a specificity >90% were observed when WBC-post counts were >10.6 G/l (n = 14 patients; sensitivity 45%). Elevated WBC-post counts exceeding 12.6 G/l (n = 7) were always associated with an unfavorable mRS-d90 (specificity >99%, sensitivity 23%). NIHSS scores revealed similar results. Here, WBC-post counts >12.2 G/l (n = 16) predicted poor NIHSS-post scores with a specificity >90% (sensitivity 27%). WBC-post counts >14.2 G/l (n = 7) were always associated with poor NIHSS-post (specificity >99%, sensitivity 16%). The cut-off values for elevated WBC-post counts and WBC dynamics for patients' outcome, derived from ROC-analyses, are summarized in table 3.

Table 3

Cut-offs for WBC counts prior and after MT as wells as WBC dynamics for an unfavorable mRS-d90 or NIHSS-post score for patients >50 years (n = 105) when setting 2 thresholds for specificity (>90 and >99%)

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Fig. 2

ROC curves for patients' outcome (>50 years) for WBC-post counts and WBC dynamics. Upper row: correlation to an unfavorable outcome for WBC-post counts with higher mRS-d90 scores (left; AUC 0.789, p = 0.001) and NIHSS-post scores (right; AUC 0.725, p = 0.000). Lower row: correlation to an unfavorable outcome for WBC dynamics with higher mRS-d90 scores (left; AUC 0.725, p = 0.041) and NIHSS-post scores (right; AUC 0.686, p = 0.011) both illustrated with the corresponding ROC curve for WBC-post counts (when patient data was available for both WBC dynamics and WBC-post counts).

http://www.karger.com/WebMaterial/ShowPic/496973

WBC Counts Can Predict Outcome in Patients >50 Years Prior to MT

A significant correlation between WBC-pre counts and NIHSS-post as well as mRS-d90 scores in patients >50 years was identified. Therefore, ROC was calculated for WBC-pre counts and mRS-d90 scores (AUC 0.760, p = 0.018; fig. 3). Here, patients with WBC-pre counts >9.1 G/l (n = 15) showed an unfavorable mRS-d90 score with a specificity >90% (sensitivity 56%), whereas patients with WBC-pre counts >10.6 G/l (n = 8) always had a poor mRS-d90 score in this subgroup (specificity >99%, sensitivity 32%). A similar trend was observed for ROC analysis of WBC-pre counts and unfavorable NIHSS-post scores (AUC 0.604, p = 0.156). However, this trend did not reach statistical significance in ROC analysis.

Fig. 3

ROC curves for patients' outcome (>50 years) and WBC-pre counts: left, correlation to an unfavorable mRS-d90 score (AUC 0.760, p = 0.018); right, correlation to a poor NIHSS-post (AUC 0.604, p = 0.156).

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Discussion

MT has recently been shown to be safe and effective in the treatment of patients with acute ischemic stroke due to arterial occlusion [24,25,26]. However, some patients seem to benefit more than others from MT. This raises the demand for early prognostic parameters and criteria for patient selection even prior to MT [29,30,31,32]. In stroke, elevated levels of WBC counts are a known independent risk factor for an unfavorable outcome [7,8,9,10,11,12,13,14]. However, this topic has never been studied in the context of MT before. Since early MT has a powerful impact on patients' outcome [24,25,26,27,28,] the link between inflammatory markers and clinical outcome was examined in a cohort with successful MT to avoid the strong confounding effect of MT on outcome.

In our sample, younger patients (<50 years) showed higher median WBC counts even at the time of admission. These differences might be related to different stroke etiologies and comorbidities. Indeed, preexisting inflammatory states were frequent in the 10 patients <50 years, with 4 cases of arterial dissections [36], one case of Takayasu's arteritis [37,38], one case with ulcerative colitis [39] and one case of suspected moyamoya disease [40]. In contrast, common causes of stroke such as atrial fibrillation played the dominant role in older patients. Thus, we think that excluding these patients was reasonable to avoid confounding influences when assessing WBC counts as a predictor of outcome after stroke. However, preexisting inflammatory states may be present in older patients as well and might even increase the risk for stroke [41,42]. Certainly concomitant diseases, such as pneumonia could lead to an unfavorable clinical outcome and elevated WBC counts which has to be kept in mind. Therefore, other underlying causes for elevated WBC counts should always be considered when translating the results to other patients and cohorts.

The cut-off values for WBC counts and WBC dynamics when setting different thresholds of specificity in ROC-analysis only represent the results in our cohort. Future studies on larger cohorts are needed to determine more generalized cut-offs for WBC counts/-dynamics prior to and after MT. Thus, it is important to stress that patients with WBC counts/dynamics lower than the displayed cut-off values might still have a poor outcome in terms of mRS and NIHSS.

Previous studies showed that peak WBC counts correlate with the extent of infarct size and clinical outcome after 12 months in cohorts without endovascular therapy [7]. This correlation gets supported by our findings for WBC-post counts even though estimation of infarct size was done via ASPECT score on post-treatment NCCT scans, which is a rather rough approximation of ischemic volume. Accordingly, blood leukocytes after MT might be a surrogate parameter for infarct size. This would allow a quick estimation of infarct volume also after successful MT with a simple blood test. A previous study identified WBC counts on day 1 after stroke as an independent risk factor for poor neurological outcome, prolonged hospital stay and mortality; however, infarct size was not assessed in this study [10]. Still, in our study, we could not observe a correlation between WBC-pre counts nor WBC dynamics and infarct size after MT. Thus, blood leukocytes might additionally mirror the potentially harmful aspect of inflammation even though a clear distinction between both effects would ideally require a direct measure of parenchymal inflammatory processes. Thus, it remains uncertain to what extent WBC counts constitute a surrogate parameter.

Endovascular manipulation during MT can lead to immediate arterial wall damage as it was shown for stent retrievers and aspiration devices in animal studies [43,44]. Even in 1-year follow-ups, patients after MT showed delayed asymptomatic arterial abnormalities like stenosis or dilatation [45]. Inflammatory arterial wall damage might be a bias and could influence the cellular composition of blood samples after MT, as it was shown for pseudothrombocytopenia in patients after coronary interventions [46,47]. However, even WBC counts prior to MT correlated with patients' outcome, making this bias unlikely.

Time until recanalization is an independent risk factor for outcome after MT [27,28,48]. Further, the evolving inflammatory response to ischemia is also time dependent, as mentioned above. One might hypothesize that WBC-pre counts would represent time after stroke onset as a surrogate parameter, and that the correlation of WBC-pre counts with outcome scores could be attributable to this association. However, time to treat did not show a clear correlation with initial WBC counts (p = 0.067). Moreover, time to treat and mRS-d90 did not show a significant correlation at all (p = 0.611). Further, some additional arguments hold against this interpretation. For example, patients with low WBC counts still showed unfavorable clinical outcomes in our study even though MT was successful. Additionally, previous studies identified elevated WBC counts as an independent risk factor for the severity and the total volume of stroke [7,10].

Prediction of outcome with initial WBC counts might be of great interest in the decision-making process prior to MT, especially in controversial cases or when major contraindications against MT exist. Our study showed that WBC-pre counts may predict outcome in the subgroup of patients >50 years prior to MT. Here, WBC-pre counts correlated significantly with both, NIHSS and mRS-d90 scores in Spearman correlation, whereas ROC analysis with dichotomized patients' outcome only confirmed this finding for mRS-d90. This might be explained by the method of dichotomization of NIHSS, where only cases with NIHSS-post ≤5 were counted as favorable outcomes. Still, prediction of outcome with WBC counts prior to MT seems to be a promising approach and optimal cut-offs should be confirmed in larger studies. Since WBC counts on admission can reflect the initial inflammatory response to stroke, this parameter might also be suited as criterion for anti-inflammatory therapies, which are likely to become a promising additive therapy in the future.

Therapeutic strategies aiming at the inflammatory response in patients with stroke are being pursued for many years [15,16]. Just recently, fingolimod, a sphingosine-1-phosphate-receptor modulator that was initially introduced for oral therapy of multiple sclerosis [49], was shown to positively influence the course of stroke patients when administered for 3 days after stroke [22]. Under fingolimod therapy, lower WBC counts and a better neurologic outcome were observed [22]. Fingolimod seems to counter post-ischemic inflammation attenuating reperfusion damage, a mechanism that might be similar to protective ischemic post-conditioning, which occurs when cerebral blood flow is intermittently interrupted during the early phase of reperfusion after ischemia [22,50]. Future research on this subject will show if novel therapies like fingolimod can add substantial value in the clinical setting of acute stroke. Yet, the potential of MT might be maximized even today when inflammatory processes would be strongly considered while making therapeutic decisions.

Conclusion

Elevated WBC counts in routine blood tests after successful MT can reliably predict the clinical outcome in patients with acute ischemic stroke. In our cohort, WBC counts may further allow a prediction of unfavorable outcome even prior to MT in patients >50 years. Blood leukocytes constitute a basic and economic parameter that could be easily used for prediction of outcome even prior to MT and might therefore be beneficial in the everyday clinical setting.

Author Contribution

All authors contributed substantially to this work: T.B.-B. and T.H. conception, design, data analysis and draft; J.K., S.B. and H.P. acquisition and interpretation of data; J.F.K. and C.Z. revising the work critically for important intellectual content.

Acknowledgements

We want to express our gratitude to the patients in this study.

Disclosure Statement

None declared.

Funding

This study did not receive specific funding from public, commercial or non-profit agencies.

Ethical Standards

This study was approved by the local ethics committee at the Klinikum Rechts der Isar of the Technical University of Munich, Germany, in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments.


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  44. Park S, Hwang SM, Song JS, Suh DC, Lee DH: Evaluation of the Solitaire system in a canine arterial thromboembolic occlusion model: is it safe for the endothelium? Interv Neuroradiol 2013;19:417-424.
  45. Eugène F, Gauvrit JY, Ferré JC, Gentric JC, Besseghir A, Ronzière T, et al: One-year MR angiographic and clinical follow-up after intracranial mechanical thrombectomy using a stent retriever device. AJNR Am J Neuroradiol 2015;36:126-132.
  46. Matthai WH: Thrombocytopenia in cardiovascular patients: diagnosis and management. Chest 2005;127:46S-52S.
  47. Berkowitz SD, Sane DC, Sigmon KN, Shavender JH, Harrington RA, Tcheng JE, et al: Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization. J Am Coll Cardiol 1998;32:311-319.
  48. Ragoschke-Schumm A, Yilmaz U, Kostopoulos P, Lesmeister M, Manitz M, Walter S, et al: ‘Stroke room': diagnosis and treatment at a single location for rapid intraarterial stroke treatment. Cerebrovasc Dis 2015;40:251-257.
  49. Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, et al: A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401.
  50. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, et al: Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion. J Neurochem 2008;105:1737-1745.

Author Contacts

Thomas Huber, MD

Department of Neuroradiology

Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Street 22

DE-81675 Munich (Germany)

E-Mail thomas-huber@tum.de


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: October 22, 2015
Accepted: January 27, 2016
Published online: March 09, 2016
Issue release date: June 2016

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 3

ISSN: 1015-9770 (Print)
eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED


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  48. Ragoschke-Schumm A, Yilmaz U, Kostopoulos P, Lesmeister M, Manitz M, Walter S, et al: ‘Stroke room': diagnosis and treatment at a single location for rapid intraarterial stroke treatment. Cerebrovasc Dis 2015;40:251-257.
  49. Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R, Calabresi P, et al: A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401.
  50. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, et al: Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion. J Neurochem 2008;105:1737-1745.
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