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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 803-811

Predictive prognostic value of neutrophil–lymphocytes ratio in acute coronary syndrome


1 Department of Cardiology, Faculty of Medicine, Menoufiya University, Shebeen El-Kom, Egypt
2 Department of Cardiology, Health Insurance Hospital, Qena, Egypt

Date of Submission30-Jan-2018
Date of Acceptance21-Apr-2018
Date of Web Publication17-Oct-2019

Correspondence Address:
Markos Z Salama
El Mostasharen Street, Kalf El-Mohafza, Qena Governate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_35_18

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  Abstract 


Objective
To evaluate the relations between preprocedural neutrophil/lymphocyte (N/L) ratio and in-hospital outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI).
Data sources
We utilize the medical journals, medical text books, and Medline databases (PubMed, Medscape, and Science Direct) which have updated research with keywords 'neutrophil/lymphocyte ratio and acute coronary syndrome' in the title of the paper and all materials available on the Internet from 2013 to 2017.
Study selection
The initial search presented 1270 articles of which 21 met the inclusion criteria. The articles studied the correlation between N/L ratio and the occurrence of no-reflow, along with assessment of the prognostic value of N/L ratio in patients with STEMI.
Data extraction
If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, and adequate information and defined assessment measures were made.
Data synthesis
Comparisons were made by meta-analysis with the results tabulated.
Findings
The levels of inflammatory markers such as the N/L ratio should be routinely checked in all patients presenting with acute STEMI as they may help in the prediction of prognosis; they may guide the emergency physician to provide the best type of therapy in such cases, and they may be useful in the follow-up of patients after reperfusion.
Conclusion
Preprocedural N/L ratio was an independent prognostic factor for both in-hospital mortality and adverse outcomes among the STEMI patients who underwent primary PCI during the hospital stay. N/L ratio was an independent predictor of no-reflow/reflow and angiographic grade after PCI.

Keywords: neutrophil/lymphocyte ratio, primary percutaneous coronary intervention, ST-segment elevation myocardial infarction


How to cite this article:
Reda AA, Ibrahim WA, Salama MZ. Predictive prognostic value of neutrophil–lymphocytes ratio in acute coronary syndrome. Menoufia Med J 2019;32:803-11

How to cite this URL:
Reda AA, Ibrahim WA, Salama MZ. Predictive prognostic value of neutrophil–lymphocytes ratio in acute coronary syndrome. Menoufia Med J [serial online] 2019 [cited 2019 Nov 21];32:803-11. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/803/268823




  Introduction Top


Increasing evidences indicate that inflammation may contribute to both initiation and progression of atherosclerosis, and to acute rupture of atherosclerotic plaques with superimposed thrombus formation [1].

Several markers of inflammation have been identified as predictors of future ischemic vascular disease in asymptomatic patients. Many prospective studies and meta-analyses have shown that leukocyte count and C-reactive protein (CRP) are independent risk factors for myocardial infarction (MI) [2].

Moreover, a number of studies have suggested that high levels of total white blood cell (WBC) count and CRP may be considered as independent prognostic factors in patients with acute coronary syndromes (ACS) and/or after cardiac revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) surgery [1],[3],[4],[5].

On the other hand, evidence on the role of polymorponuclear leukocytes in cardiovascular disease is less compelling. It has been suggested that neutrophil count may be associated with an increased risk of coronary artery disease and with the presence of multiple complex coronary stenosis [6],[7]. Furthermore, recent studies have hypothesized a role of neutrophil count as an independent predictor of poor outcome or recurrence of cardiovascular events in patients with acute cardiovascular disease, and laboratory studies advocated many different mechanisms by which neutrophils may contribute to the development of ischemic vascular events [8],[9],[10].

This is of particular interest since the measurement of a simple inflammatory marker could improve the risk stratification of these patients. However, results of the studies are conflicting and neutrophil count may be influenced by other concomitant risk factors. Thus, whether neutrophils should be considered a prognostic factor in patients with acute cardiovascular disease and whether this measure could add information beyond total WBC count and CRP dosage remains to be established. Therefore, we conducted a systematic review of the literature with the aim of identifying all the available evidence to clarify the role of neutrophils as a prognostic risk factor in patients with MI/ACS and/or cardiac revascularization.

The aim of this study was to evaluate the relations between preprocedural neutrophil/lymphocyte (N/L) ratio and in-hospital outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI).


  Patients and Methods Top


Methods

A protocol was prospectively developed, detailing the specific objectives, criteria for study selection, approach to assess study quality, outcomes, and statistical methods.

Study identification

We tried to identify all published studies that evaluated the role of neutrophils as a risk factor for clinical outcomes using the Medline (1999–2009, week 33) and Embase (1999–2009, week 33) electronic databases. We decided to not include studies published before 1999 since the patients included in older studies may not be representative of patients with ACS or undergoing cardiac revascularization currently treated in our clinics due to the difference in cardiovascular therapies and surgical techniques. The search strategy was developed without any language restriction, and used the subject headings and keywords presented in Supplementary [Table 1] (http://www.thrombosis-online.com). We supplemented our search by searching the American Heart Association Scientific Meeting abstracts from January 1999 to December 2008 using 'polymorph nuclear leukocyte' and 'neutrophil' as search terms and by manually reviewing the reference lists of all retrieved articles for additional published or unpublished trials.
Table 1: Parameters describing neutrophils and clinical outcomes in acute coronary syndromes

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Study selection

All studies were independently assessed for the inclusion criteria. They were included if they fulfilled the following criteria:

  1. Published in English language
  2. Published in peer-reviewed journals
  3. Focused on NLR effect on patients with acute coronary syndrome undergoing PCI
  4. Discussed the role of NLR as a prognostic factor in patients with STEMI undergoing primary PCI and its effect on angiographic flow after PCI
  5. If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.


Studies were included if they met the following criteria: (a) patients had a diagnosis of acute MI or unstable angina (UA) or ACS and/or were treated with PCI or CABG surgery. (b) Diagnosis of cardiovascular disease was objectively confirmed, MI, UA, and ACS were adjudicated if ischemic symptoms, ECG changes consistent with ischemia, and elevated cardiac enzyme levels were documented (c). Information on neutrophils was provided (including absolute or relative neutrophilia and/or N/L ratio). (d) At least one of the following clinical outcomes was evaluated during the acute phase or after a follow-up: death, development of a new episode or a recurrence of MI, UA, ACS, or development or worsening of heart failure (HF) or rehospitalization or stroke. (e) Patients were 18 years or older. Only studies written in English language were included. We excluded all the studies in which cardiovascular disease was diagnosed only on the basis of clinical symptoms and not confirmed by objective data. To assess the agreement between reviewers for study selection, we used the k statistic, which measures agreement beyond chance [11].

Study validity assessment

Two unmasked investigators independently completed the assessment of study validity.

Although in observational studies the use of quality scoring systems or quality scales is controversial [12], study quality was assessed by the following items for cohort studies: type of study (prospective or retrospective), patient selection (consecutive patients without potential bias of selection), and the total number of patients lost to follow-up (less or more than 5% of patients). A total of three points defined high-quality studies; two or fewer points defined low-quality studies. For each fulfilled item, one point was given. For case–control studies, the following items assessed the study quality: patient selection (consecutive patients without potential bias of selection); control group (consecutive enrolment or matched for age and sex). A total of two points defined high-quality studies; one or zero points defined low-quality studies.

Data extraction

Study quality assessment included whether ethical approval was gained, prospective design, eligibility criteria specified, appropriate controls used, adequate follow-up achieved, and defined outcome measures were made.

The analyzed publications were evaluated according to the evidence-based medicine criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for evidence-based medicine in addition to the Evidence Pyramid.

US preventive services task force

  1. Level I: Evidence obtained from at least one properly designed randomized, controlled trial
  2. Level II-1: Evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


We independently extracted the data on the study (year of publication, design, study center) and patient characteristics (number of patients studied, mean age, variation in age, gender, and race) and on the clinical outcomes (death, development of a new episode, or a recurrence of MI, UA or development or worsening of HF, rehospitalization, and stroke).

Quality assessment

The quality of all studies was assessed. Important factors included the study design, attainment of ethical approval, and evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that the confounding factors would be reported and controlled and appropriate data analyses made in addition to an explanation for missing data.

Data synthesis

A structured systematic review was performed with the results tabulated.

Statistical analysis

A formal combined meta-analysis of studies included was not appropriate due to the heterogeneity of the population considered, in the neutrophils measure (absolute neutrophil count, relative count, and N/L ratio), event type (ACS or revascularization procedure) and in the outcomes assessed among the trials (mortality, recurrence of cardiovascular event, HF development, composite, and others). Thus, a narrative synthesis of collected data was undertaken for the included studies. Data are presented as mean, percentage, and range of variation.

Only odds ratios and 95% confidence intervals of the association between neutrophils count and HF development during hospitalization or within the first 30 days were calculated. The data were pooled using a random-effects model (the Der Simionan and Laird method). Statistical heterogeneity was evaluated using the I2 statistic, which assesses the appropriateness of pooling the individual study results [13]. The software Review Manager (RevMan, version 5.0.16 for Windows; Oxford, UK; The Cochrane Collaboration, 2008) supported the analysis.


  Results Top


We identified 1270 potentially relevant studies from Embase and Medline databases. Further 96 abstracts were found. We excluded 1319 studies after title and abstract screening using predefined inclusion and exclusion criteria; the remaining 47 studies were retrieved in full for a detailed evaluation. One additional study was identified through a manual review of references. The agreement between reviewers for study selection was optimal (K = 0.92). Of the 48 retrieved studies, 27 were excluded for the following reasons: 12 did not match the inclusion criteria, 10 were editorial or narrative review, and five reported duplicated data. Twenty-one studies were therefore included in this systematic review: 20 published as full text and one as abstract [8],[9],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26]. The study identification and selection progression is detailed in [Figure 1].
Figure 1: Flowchart of the study selection.

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Study characteristics

Baseline characteristics of patients included in the studies and results of these studies are summarized in Supplementary [Table 1] (http://www.thrombosis-online.com). Studies size ranged from 71 to 9015 patients [19],[25], for a total of more than 34 000 patients.

Four reanalyses of randomized, clinical trials, nine prospective cohorts, seven retrospective cohorts, and one case–control studies were included in our systematic review.

The association between clinical outcomes and neutrophils was reported either as absolute neutrophil count (20 studies), relative count (six studies) or N/L ratio (six studies) [Table 1] and [Table 2]. Comparison of neutrophils and other more established markers of inflammation (WBC count and/or CRP) were performed in six studies.
Table 2: Parameters describing neutrophils and clinical outcomes in patients submitted to cardiac revascularization procedures

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Study quality

Quality assessment items are summarized in [Table 3]. Eight studies were of high quality.
Table 3: Quality assessment of included studies

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Seventeen out of the 21 studies reported significant associations between neutrophil parameters and mortality and/or the adverse clinical events considered for the purposes of this review [Figure 2] and [Figure 3].
Figure 2: Patients in studies relating neutrophils with mortality.

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Figure 3: Number of patients in studies relating neutrophils with adverse clinical events.

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Thirteen studies analyzed neutrophils in relation to clinical outcomes following an ACS. Ten of the 13 studies found a significant relationship between neutrophils and adverse clinical events [8],[12],[13],[14],[15],[16],[17],[18], whereas three did not [Table 1] [19],[20].

Five studies reported long-term mortality data after acute MI/ACS for a follow-up period ranging from 6 months to more than 8 years [8],[12],[15],[18]. All these studies showed that neutrophils measured within 24 h after symptoms onset were predictors of mortality after ACS, using neutrophil count [12],[15] and/or N/L ratio [12],[18]. Furthermore, Grau et al. [8], in the population of CAPRIE study including 5974 post-MI patients, showed a strong predictive value of neutrophilia for vascular deaths and recurrent ischemic vascular events. In addition to these long-term follow-up data, Tamhane et al. [18] showed that patients in the higher tertile of N/L ratio had higher in-hospital mortality.

Three additional studies focusing on patients submitted to fibrin lytic therapy, reported a short-term follow-up of 30–35 days. The CLARITY-TIMI28 study on 2865 patients found an association between the absolute neutrophil count and cardiovascular death [16], whereas no significant relationship was observed in the other two studies enrolling 312 and 394 patients, respectively [20]. Data on postdischarge mortality, meshed with other clinical outcomes, were reported in two additional studies [13],[19].

Huang et al. [13] reported that N/L ratio was borderline-significantly higher in patients with major adverse cardiac events after a median follow-up of 21 months post-ACS. Conversely, Zouridakis et al. [19] did not find any correlation between neutrophils and clinical outcomes (18/22 events were readmission for recurrent angina) in a population of 71 patients with UA although the authors described an inverse relationship between clinical outcomes and lymphocyte count.

Three studies on patients with MI focused on the relationship between neutrophils and new-onset HF as a primary outcome [13],[14], whereas the other two studies considered it as a secondary outcome [16],[23].

Three studies defined HF as the occurrence of signs/symptoms suggestive of a reduction of ejection fraction of less than 40% within the first 4 days after MI, while, in the other two, the presence of HF has been evaluated at 28–30 days [16],[23]. Absolute [14],[16],[23] and/or relative neutrophilia [14],[17] were significantly associated with the occurrence of HF and low ejection fraction.

We were able to summarize the results of four studies [16],[17] for a total of 2140 patients. The presence of neutrophila was associated with a significantly higher risk of HF development (odds ratio: 4.22; 95% confidence interval: 2.32–7.67) although heterogeneity among the studies was substantial (I2 = 73%) [Figure 4].
Figure 4: Pooled odds ratios (OR) and 95% confidence intervals (CIs) of neutrophils count and heart failure development during hospitalization or within the first 30 days.

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Besides the data on mortality previously analyzed, a few authors described a relationship between neutrophils and HF [16], hospital readmissions for HF [15], reinfarction at 6 months, and both in-hospital and 6-month stroke [18], whereas Dragu et al. [15] found a similar rate of rehospitalization for recurrent MI among patients with different neutrophil counts.

Eight studies reported neutrophils in relation with clinical outcomes following a cardiac revascularization procedure, and seven studies found a relationship between neutrophils and clinical events [Table 2].

PCI was performed in six of eight studies [9],[21],[22],[23],[24],[25], three of which [9],[23],[24] included primary PCI only. CABG surgery was performed in two studies, including acute and nonacute cardiac revascularizations [26] or excluding patients with emergency revascularizations [27].

Takahashi et al. [23] reported an increased risk of in-hospital cardiac deaths and HF after primary PCI in 260 patients with neutrophilia assessed at admission. Kruk et al. [24] found similar results in a comparable population of 1078 patients although these findings were not statistically significant at the multivariate analysis. Long-term mortality, at 36 and 52 months, was also associated with absolute neutrophil count in the 2099 patients from the EPIC study and in the study by Takahashi and colleagues [21],[23].

One additional study Duffy et al. [22] reported that long-term survival at a mean follow-up of 32 months was lower in patients with higher N/L ratio, and that this ratio was an independent predictor of mortality after multivariate adjustments in a mixed population of patients undergoing a scheduled endovascular procedure (n = 191) or treated in the setting of ACS (n = 855).

Moreover, elevated neutrophil count obtained 24 h after primary PCI was a predictor of composite clinical outcomes including death, reinfarction, HF, all cardiac rehospitalizations, life-threatening ventricular arrhythmias, and new cardiogenic shock [9]. At last, in a retrospective analysis of the Mayo PCI registry (including both emergency and nonemergency procedures) on 9015 patients who underwent successful coronary stenting and survived to hospital discharge [25], preprocedural lymphocyte count was negatively associated with long-term mortality in a 5.1 years follow-up, whereas neutrophils showed a positive, though not significant, trend of association with long-term mortality.

Finally, Newall et al. [26] and Gibson et al. [27] studied 1938 and 3024 CABG surgery patients, respectively, finding that N/L ratio and neutrophil count were associated with long-term mortality in a mean follow-up of 1 and 3.6 years, respectively.

Although a relationship among neutrophils, total WBC count and/or CRP, and adverse clinical outcomes was described in 17 studies, an analysis including both neutrophils and WBC count and/or CRP was reported only in five [8],[12],[15],[24],[27], and two studies, respectively [15],[24].

Four out of five studies reported a superiority of neutrophils on total WBC count in predicting adverse clinical events [8],[12],[15],[27]. Interestingly, the N/L ratio remained a predictor of all-cause mortality in the subgroup of patients with normal total WBC count [27].

Dragu et al. [15] showed that the addition of neutrophil count to a model including total WBC and CRP improved its ability in the prediction of postdischarge mortality and that the risk associated with elevated neutrophil count were greater for each quartile of CRP. Conversely, although in the study by Kruk et al. [24] neutrophils were significantly correlated with mortality post primary PCI in univariate analysis, only total WBC count and CRP remained significant predictors in multivariate analysis.


  Discussion Top


In the first systematic review on the association between neutrophila and clinical outcomes in acute MI/ACS and/or cardiac revascularization by PCI or CABG surgery, we identified 21 publications including more than 34 000 patients. A significant relationship between clinical outcomes and neutrophils measured either/or as absolute count, relative count, and neutrophil/lymphocyte ratio was reported in 17 studies thus highlighting the role of this circulating inflammatory cell type in myocardial damage. Most of the studies in ACS patients found that neutrophils measured on admission are related to the mortality rate and to major clinical adverse outcomes. Studies with negative findings either were carried out in a small patient population of UA patients, most of whom had readmission for recurrent angina as the clinical outcome over the follow-up [19] or had a short-term follow-up (≤35 days) in addition to a relatively small sample size [20]. Furthermore, in two of these studies there was an association between neutrophils count or an inverse relation with non-neutrophils count and angiographic endpoints such as the TIMI flow [20]. Also, the subsequent development of HF was consistently found to be related with neutrophilia in selected studies with both short- and long-term follow-up periods. These findings have been further confirmed by a very recent study published by Gurm HS et al. [21] MI patients in which the neutrophil count was independently associated with death and HF after a mean follow-up period of 4.9 years. A predictive value of neutrophils and/or N/L ratio after PCI was reported in all the studies but one, irrespective of the indications for cardiac revascularization. The only study with negative findings showed a significant inverse relationship between lymphocytes and mortality together with a nonsignificant positive trend between neutrophil count and death in a mixed population of acute and nonacute patients. Unfortunately, since this study was published as an abstract only, separate data could not be retrieved [25]. Considering primary PCI patients, the studies by Chia et al. [9] Takahashi et al. [23] and Kruk et al. [24] found a consistent relationship between neutrophils measured on admission or 24 h after PCI and short- and/or long-term clinical outcomes. Lastly, preoperative neutrophils or N/L ratio were powerful predictors of mortality in patients undergoing CABG surgery [26],[27]. The high number of patients included in our study strengthens the value of this subset of circulating leukocytes as a reliable marker of adverse outcomes. Although only a few studies reported concomitantly neutrophils and total WBC or serial markers of inflammation such as CRP, most of the studies showed that neutrophils were independent predictors of cardiovascular outcomes.

The potential detrimental role of neutrophils in participating in myocardial injury after ischemia and reperfusion has been suggested years ago, and a growing body of evidence indicates that these cells may act directly to determine myocardial tissue damage besides being part of the acute inflammatory response to tissue injury [10],[28]. In ACS, these cells are functionally activated [29],[30], and local neutrophil infiltration has been documented in culprit plaque lesions suggesting that neutrophils play a role in mediating destabilization of atherosclerotic plaques [31]. A cross-talk between neutrophils and platelets has been recognized and neutrophils are recruited to the injury sites either through the classical recruitment cascade or by adhering to platelets which are attached to the endothelial cells [32]. Moreover, microparticles derived from stimulated polymorph nuclear leukocytes may enhance coagulation and perpetuate thrombus formation because they can activate platelets and enhance platelet P-selectin expression [33].

After PCI, neutrophil functional changes consistent with a release of oxygen-free radicals during the procedure and an upregulation of β2 integrin Mac-1 on the cell surface were observed [29],[34]. Restenosis in balloon-injured arteries is associated with neutrophil infiltration [35], and different types of stenting may modulate neutrophil responses differently. Activation of Mac-1 on the surface of neutrophils was accelerated 24–48 h after bare metal stenting and was more striking in patients with restenosis [36]. In contrast, the activation of Mac-1 was suppressed after sirolimus-eluting stenting [36]. At last, although early events of reperfusion can be compared with an inflammatory-like response involving activation of neutrophils and subsequent interaction with the vascular endothelium, the involvement of this cell type with a causal role in ischemia-reperfusion injury is not yet completely understood [37].

Our study has some limitations. Due to the changing diagnosis and treatments of MI/ACS occurring over the past 20 years, the patient populations of the various studies could differ regarding the clinical characteristics and outcomes. Moreover, the heterogeneity of the characteristics of included studies did not allow us to use a more formal meta-analytical approach. Our results should be interpreted with caution since many included studies are of low quality. Furthermore, about half of the studies reported rigorous exclusion criteria for potential confounding factors such as ongoing infections, known malignancies, and steroid therapy. Lastly, studies reported neutrophils as absolute count, relative count, and N/L ratio, and which of these ways of assessing neutrophils is more closely associated with clinical outcomes remains to be established. Future studies should clarify if the addition of neutrophil count or markers indicating functional activation of these cells to CRP and total WBC count may be used to further improve the risk stratification for adverse clinical events.

Despite the potential confounding factors and the different pathophysiological mechanisms underlying the relationship between neutrophilia and cardiovascular outcomes in patients with ACS and/or in patients undergoing reperfusion procedures, the uniform nature of our results strengthens our conclusions. Irrespective of the timing chosen to evaluate neutrophils (on-admission/24 h after symptoms or after PCI), this measure appears as a clear indicator of adverse outcomes. On one hand, the consistent finding that neutrophil count may predict clinical outcomes in patients with MI/ACS and/or cardiac revascularization by PCI or CABG surgery highlights the potential application of this inexpensive and readily available inflammatory marker for risk stratification in these patients. On the other hand, nonunivocal findings of some studies included in our systematic review suggest caution in the interpretation of results and other studies are necessary to confirm our findings.


  Conclusion Top


Preprocedural N/L ratio was an independent prognostic factor for both in-hospital mortality and adverse outcomes among STEMI patients who underwent primary PCI during the hospital stay. N/L ratio was an independent predictor of no-reflow/reflow and angiographic grade after PCI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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