INTRODUCTION
Trauma is the leading cause of death among Americans between the ages of 1 and 46 years[1]. 10% to 39% of the deaths in trauma patients could be attributed to blunt cardiac injury (BCI)[2–4]. Injury to the heart and aorta are the predominant cause of hemorrhage-related death in trauma patients. The reported incidence of BCI ranges from 10% in the general population of trauma patients to >70% in patients with high-impact trauma to the chest.
The diagnosis of BCI could be difficult due to lack of clear definition. Accordingly, there is substantial variation in the estimated incidence of BCI in trauma patients. The data from the Trauma Register DGU suggested 2.3% incidence of BCI in severely injured trauma patients[5]. In a study of 4,571,161 adult patients with blunt trauma, BCI was identified 0.3% (15,976) of the study population[6]. Patients with BCI can present with a wide variety of signs and symptoms depending on the angle of impact to the mediastinum[3,7]. Patients may be asymptomatic or present with arrhythmias, myocardial contusion, valve damage, acute heart failure, and secondary myocardial ischemia[8]. Extensive myocardial contusion with hemopericardium is occasionally noted in the absence of external thoracic injuries, and thus, appropriate testing should be performed depending on the impact of the injury[9].
In clinical practice, obtaining an accurate and detailed medical history could be particularly difficult in trauma patients. Low-yield diagnostics, for example, chest X-ray, electrocardiogram (ECG), and bedside ultrasonography, are routinely performed in patients with suspected BCI. High-yield modalities, for example, computed tomography, highly sensitive cardiac biomarkers, and transesophageal echocardiography, are increasingly used. Thorough examination of the heart and aorta is sometimes impossible, for example, in patients with life-threatening injury to other organ systems[10]. Triage is important in cases that involve injury to multiple people: patients at risk for cardiac complications should be immediately admitted to a highly monitored ward, whereas non-risk patients could be discharged early[11]. The key challenge in rapid triage is the lack of early symptoms of cardiac injury in some patients and the need to attend to co-existing injury to other organ systems[12].
Based on four studies[11–14], a combination of troponin I (TnI) and ECG has 100% negative predictive value. Consequently, the Eastern Association for the Surgery of Trauma recommends TnI and ECG screening from all trauma patients with suspected BCI[7]. However, the positive predictive value of the TnI/ECG combination is only 34%[11]. Against this background, we conducted a meta-analysis to identify risk factors of BCI. The results hopefully could be used to develop tools to identify BCI with high sensitivity and specificity.
METHODS
Search strategy
PubMed, Web of Science, and EMBASE databases were searched from their inception to November 20, 2021. The keywords included “blunt cardiac injury,” “blunt cardiac trauma,” and “traumatic cardiac injury.” References of the electronically retrieved articles were manually searched to identify additional articles.
Inclusion and exclusion criteria
For inclusion in the final analysis, BCI must be explicitly defined and subjects must be from trauma register centers. In addition, at least one of the following data must be reported: (1) injuries mechanism, (2) risk factors associated with BCI; and (3) mortality or length of stay for BCI patients. Editorials, reviews and case report/series were not included. Studies were excluded if they (1) the subjects were not divided into BCI group and non-BCI group, (2) did not report baseline variables, (3) were published in a non-English language, or (4) were conducted in pediatric population.
Assessment of study quality
The quality assessment was conducted using an 11-item checklist recommended by Agency for Healthcare Research and Quality (AHRQ). An item would be scored “1” if it was answered “YES.” An score of 8–11 was served as high quality.
Data extraction
Two investigators independently searched the database, and discrepancies were resolved by consensus with a third reviewer. The following information was extracted from electronically identified articles: first author’s name, nation, publication year, study type, mean age, injury severity, sample size, and definition of BCI. For analysis of the mechanism of BCI, category-specific numbers with the percentage of each mechanism of BCI were extracted. For analysis of the risk factors for BCI, relative risk (RR) with 95% confidence internal (CI) were extracted. If RR was not reported directly in the publication, the number of patients exposed to risk factors and corresponding morbidity were extracted to estimate RR and 95% CI by using the Miettinen method. The length of stay (mean ± standard deviation) and mortality number/rate were also extracted.
Statistical analysis
We assumed that RR and odds ratio reported in the original studies are valid estimates of the RR; accordingly, the results were reported as the RR for simplicity. The inverse variance model was used to calculate pooled effect estimates for mean differences (95% CI). Heterogeneity across studies was examined by using the I2 statistics. I2 that exceeds 50% was used as an indicator of substantial heterogeneity[15]. A pooled meta-analysis of injury mechanisms was conducted based on frequency with percentage. One study used the median with interquartile range to describe the injury severity score (ISS), thus the mean and standard deviation of the sample was estimated from Luo et al[16]. and Wan et al[17]. Meta-analysis of risk factors was conducted based on the total number and number of cases in BCI and non-BCI groups. For mortality risk, meta-analysis was conducted based on the total number and number of fatalities in BCI and non-BCI groups. The inverse variance method was used to derive a weighted estimate of the combined overall effect. Further analyses (BCI vs. non-BCI) were conducted to explore the effects of BCI on the length of patient’s stay, and weighted mean differences (WMD) and 95% CI were calculated for each study. To assess for potential bias in the dataset, funnel plots were generated and Egger’s test was completed using the “meta-funnel” and “meta bias” commands, respectively. All analysis was conducted using Microsoft Excel 2010 and STATA software version 11.0.
RESULTS
Characteristics of the included studies
A total of 256 records were initially identified. Screening through the title and abstract eliminated 233 records. Thirteen additional studies were excluded due to the difficulty in extracting data on risk factors, mortality or length of stay. The final analysis included a total of 10 studies and 68,039 patients (Figure 1). The characteristics of the 10 studies are presented in Table 1. Among the 10 studies, four were retrospective studies, four were cross-sectional studies, and two were prospective design. The quality of studies, as evaluated by Newcastle-Ottawa Quality Assessment Scale, are shown in Table 1.
Table 1 - General characteristics of 10 original studies included
| Authors |
Nation |
Study design |
Population |
Age (y) |
Injury severity |
Sample size |
Definitions |
Quality scores |
| Heidelberg et al. (2019)[3] |
USA |
Retrospective study |
Patients with blunt sternal fracture admitted to the trauma service at the University of Alabama at Birmingham Medical Center |
58.3 ± 19.8a in BCI; |
20.2 ± 10.17a* in BCI |
235 |
The American Association for the Surgery of Trauma for cardiac injury |
7 |
| 0.4 ± 19.1a in no BCI |
16.1 ± 8.74a* in no BCI |
| Skinner et al. (2015)[4] |
South Africa |
Retrospective observational study |
Patients with blunt thoracic trauma admitted in a single trauma intensive care unit |
34 (25–41)b |
34 (25–43)b* |
169 |
An elevated serum troponin in the presence of either clinical, ECG or transthoracic echocardiography (TTE) abnormalities in keeping with BCI |
7 |
| Hanschen et al. (2015)[5] |
Germany |
Retrospective multicentre study |
Patients recruit from the Trauma Register DGU, in which patients admitted to the hospital via emergency room with subsequent ICU/ICM care or admission to the hospital with vital signs and death before admission to ICU |
42.71 ± 21.15a |
22.51 ± 13.9a* |
47,580 |
According to the abbreviated injury score, version 2005 (AIS codes 4404xx.x, 4410xx.x, 4412xx. x, 4413xx.x, 4416xx.x, 4208xx.x) |
10 |
| Grigorian et al. (2018)[6] |
USA |
Cross-sectional study |
Adult blunt trauma patients |
48.8 ± 22.0a |
19d* |
15,976 |
The International Classification of Diseases, Ninth Revision, code 861.01 |
8 |
| Velmahos et al. (2003)[11] |
USA |
Prospective study |
Patients with major blunt thoracic trauma admitted at the Level I trauma center of the Los Angeles County and University of Southern California Medical Center |
42.0 ± 18.0a |
151 (45%) had an ISS>15* |
333 |
The presence of any or a combination of the following, if treatment was required: hypotension in the absence of bleeding or a neurogenic cause, cardiac arrhythmias, posttraumatic anatomic abnormalities revealed on echocardiography, and depressed cardiac index 2.5 L/min/m2 |
9 |
| Salim et al. (2000)[12] |
USA |
Prospective study |
Patients admitted to Level I academic trauma center who sustained blunt thoracic trauma and possible BCT |
Not reported |
Not reported |
115 |
Any of the following cardiac complications were observed: arrhythmia requiring treatment, pericardial effusion requiring treatment, unexplained hypotension (systolic blood pressure, 90 mm Hg) requiring vasopressors, or cardiogenic shock requiring inotropes |
6 |
| Ismailov et al. (2005)[18] |
USA |
Cross-sectional study |
All trauma admissions in 1997 from 19 states |
54.6 ± 22.2a |
median 3† |
2,709 |
The International Classification of Diseases, Ninth Revision, code 861.01 |
9 |
| Lancey et al. (2003)[19] |
USA |
Retrospective study |
Patients admitted to a Level I trauma center |
46.5(13–85)c |
24(9–75)c* |
47 |
Either (1) documentation of anatomic confirmation of injury by echocardiography, computed tomographic scanning, or direct visualization; or (2) fulfilling OIS electrocardiographic criteria |
8 |
| Kaptein et al. (2011)[20] |
USA |
Cross-sectional study |
Patients with traumatic cardiac injury |
Not reported |
33.8 ± 21.2a* |
616 |
The International Classification of Diseases, Ninth Revision, codes for cardiac contusions (861.01 and 861.11) |
8 |
| Pfortmueller et al. (2014)[21] |
Switzerland |
Cross-sectional study |
Patients with trauma admitted to the Department of Emergency Medicine, Inselspital |
71 (19–94)c |
4 (1–41)c* |
86 |
Not mentioned |
4 |
AIS: Abbreviated injury scale; BCI: Blunt cardiac injury; ISS: Injury severe score.
(1) Quality scores were evaluated by Newcastle-Ottawa Quality Assessment Scale. (2) Data were expressed as:
amean ± standard deviation;
bmedian (interquartile range);
cmedian (range);
dmedian. (3) Injury severity was evaluated by:
*injury severe score;
†maximum abbreviated injury severity score.
;)
Figure 1.:
Flow chart of the study selection and exclusion process.
Mechanism of injury
Mechanisms of injury were reported by seven studies[5,6,12,18–21], among which six studies reported motor vehicle collision attribution and the other six studies reported fall from height attribution. A random-effects model was used to synthesize the data due to significant heterogeneity in pooling attribution of motor vehicle collision (I2 = 99.1%, P for heterogeneity < 0.001) and fall from height (I2 = 93.0%, P for heterogeneity < 0.001). Motor vehicle collision accounted for 65.2% of the cases (pool proportion = 0.652 [0.595–0.709]). Fall from height accounted for 4.4% of the cases (pool proportion = 0.044 [0.024–0.065]) (Figure 2).
Figure 2.:
Forest plot of the mechanism of injury. A, Group of motor vehicle collision. B, Group of fall from height.95% CI: 95% confident interval.
Risk factors
Risk factors for BCI were reported from seven studies[3–6,11,12,20]. The number of studies that reported the following factors as potential risk of BCI was 4 for lung injury, 4 for rib fracture, 4 for sternal fracture, 3 for hemopneumothorax, 2 for aortic injury, 3 for shock on admission, and 4 for history of cardiac diseases. A random-effects model was used for data synthesis due to significant heterogeneity when pooling the risk of lung injury (I2 = 98.9%, P for heterogeneity < 0.001), rib fracture (I2 = 98.7%, P for heterogeneity < 0.001), sternal fracture (I2 = 97.2%, P for heterogeneity < 0.001), hemopneumothorax (I2 = 99.4%, P for heterogeneity < 0.001), aortic injury (I2 = 96.1%, P for heterogeneity < 0.001), and history of cardiac disease (I2 = 77.0%, P for heterogeneity = 0.005). The risk factor of included sternal fracture (RR = 7.21, 95% CI = 3.99–13.05), shock on arrival (RR = 2.45, 95% CI = 2.12–2.84), and a history of cardiac disease (RR = 1.87, 95% CI = 1.11–3.16) (Figure 3). The pooled analysis failed to establish significant association between BCI with lung injury (RR = 3.44, 95% CI = 0.83–14.33, P = 0.090), rib fracture (RR = 2.35, 95% CI = 0.65–8.57, P = 0.195), hemopneumothorax (RR = 2.70, 95% CI = 0.28–25.64, P = 0.387), or aortic injury (RR = 5.96, 95% CI = 0.32–109.97, P = 0.230).
Figure 3.:
Forest plot of the relative risk for blunt cardiac injury. A, Lung injury. B, Rib fracture. C, Sternal fracture. D, Hemopneumothorax. E, Aortic injury. F, Shock on arrival. G, History of cardiac disease.95% CI: 95% confident interval; ES: effect size; ID: identification.
Outcomes
Length of stay for patients with BCI were reported from four studies[3,4,11,12]. In the pooled analysis, the length of stay was 11.7 days (95% CI = 8.8–14.6 days) in the non-BCI group versus 20.5 days (95% CI = 16.8–24.1 days) in the BCI group, with the mean difference of –0.5 (95% CI = –0.6 to –0.3) (Figure 4). Mortality risk was reported in six studies[3–5,11,12,21]. Significant heterogeneity was observed (I2 = 82.2%, P for heterogeneity < 0.001). The risk of mortality was significantly higher in trauma patients with BCI as compared to those without BCI (RR = 1.70, 95% CI = 1.53–1.90) (Figure 5).
Figure 4.:
Forest plot of the difference in length of stay between patients with BCI versus without BCI. BCI: blunt cardiac injury; LCI: lower confident interval; SMD: standardized mean difference; UCI: upper confident interval.
Figure 5.:
Forest plot of relative risk of mortality associated with blunt cardiac injury. 95% CI: 95% confident interval; ID: identification; RR: relative risk.
Subgroup analysis
Considering the type of trauma, only two studies analyzed the results in patient groups with cardiac contusions[18,20]. Similar to the overall analysis, subgroup analysis in the patients with cardiac contusions failed to show significant association between BCI with either lung injury (RR = 3.19, 95% CI = 0.43–23.70) or rib fracture (RR = 3.22, 95% CI = 0.53–19.49). Four studies reported history of cardiac diseases, with average ISS from 19 to 34. In a study by Hanschen et al.[5], an ISS of 16 was used as a multiple injured patient. Subgroup analysis on multiple injured patients indicated that motor vehicle crash accounted for 62.10% (95% CI = 57.00%–67.30%) of the mechanisms for BCI and fall from height accounted for 2.5% (95% CI = 0.70%–4.30%) (Table 2).
Table 2 - Subgroup analysis of injury mechanism in patients with multiple injury (A median injury severity score of higher than 16)
| Authors |
n |
Percentage (%) |
Se |
LCI (%) |
UCI (%) |
Weight (%) |
| Motor vehicle crash |
|
|
|
|
|
|
| Hanschen et al. (2015)[5] |
47138 |
60.50 |
0.00 |
60.10 |
60.90 |
30.21 |
| Grigorian et al. (2018)[6] |
15976 |
66.30 |
0.00 |
65.60 |
67.00 |
30.09 |
| Lancey et al. (2003)[19] |
47 |
85.11 |
0.05 |
74.90 |
95.30 |
13.92 |
| Kaptein et al. (2001)[20] |
622 |
46.78 |
0.02 |
42.90 |
50.70 |
25.78 |
| Pooled ES |
|
62.10 |
|
57.00 |
67.30 |
100.00 |
| Fall from height |
|
|
|
|
|
|
| Grigorian et al. (2018)[6] |
10592 |
3.26 |
0.00 |
2.92 |
3.60 |
48.20 |
| Lancey et al. (2003)[19] |
47 |
4.26 |
0.03 |
−1.52 |
10.03 |
8.02 |
| Kaptein et al. (2001)[20] |
622 |
1.29 |
0.00 |
0.40 |
2.17 |
43.78 |
| Pooled ES |
|
2.50 |
|
0.70 |
4.30 |
100.00 |
LCI: Lower confident interval; ES: Effect size; UCI: Upper confident interval.
Quality of evidence
The article by Pfortmueller et al. had an AHRQ score of 4, and was only included in analyzing the mechanism of injury. The AHRQ score ranged from 6 to 10 for all other studies (Table 3). Thus, sensitivity analysis was not performed.
Table 3 - Quality scores on scale of agency for healthcare research and quality
| Item |
Heidelberg et al. (2019)[3] |
Skinner et al. (2015)[4] |
Hanschen et al. (2015)[5] |
Grigorian et al. (2018)[6] |
Velmahos et al. (2003)[11] |
Salim et al. (2000)[12] |
Ismailov et al. (2005)[18] |
Lancey et al. (2003)[19] |
Kaptein et al. (2011)[20] |
Pfortmueller et al. (2014)[21] |
| Define the source of information (survey, record review) |
* |
* |
* |
* |
* |
* |
* |
* |
* |
* |
| List inclusion and exclusion criteria for exposed and unexposed subjects (cases and controls) or refer to previous publications |
* |
* |
* |
* |
* |
* |
* |
* |
* |
No |
| Indicate time period used for identifying patients |
* |
* |
* |
* |
* |
* |
* |
* |
* |
* |
| Indicate whether or not subjects were consecutive if not population-based |
* |
* |
* |
* |
* |
* |
* |
* |
* |
* |
| Indicate if evaluators of subjective components of study were masked to other aspects of the status of the participants |
* |
* |
* |
Unclear |
* |
Unclear |
* |
* |
* |
Unclear |
| Describe any assessments undertaken for quality assurance purposes (eg, test/retest of primary outcome measurements) |
* |
Unclear |
* |
No |
* |
No |
* |
* |
* |
* |
| Explain any patient exclusions from analysis |
No |
* |
* |
* |
No |
No |
* |
* |
No |
No |
| Describe how confounding was assessed and/or controlled. |
* |
No |
* |
* |
* |
* |
* |
No |
* |
No |
| If applicable, explain how missing data were handled in the analysis |
No |
Unclear |
* |
* |
No |
No |
Unclear |
No |
No |
No |
| Summarize patient response rates and completeness of data collection |
No |
* |
* |
* |
* |
* |
* |
* |
* |
No |
| Clarify what follow-up, if any, was expected and the percentage of patients for which incomplete data or follow-up was obtained |
No |
No |
No |
No |
* |
No |
No |
No |
No |
No |
| Scores |
7 |
7 |
10 |
8 |
9 |
6 |
9 |
8 |
8 |
4 |
*indicates a positive response.
DISCUSSION
BCI patients often have injuries to other sites. Accordingly, clinical presentations may be nonspecific or even masked by other injuries. Physical examination is often also nonspecific. Myocardial tissue damage could serve as a definite indication of BCI but are not common and difficult to appreciate in the acute care setting.
Known mechanisms of BCI include direct impact, indirect impact, extrusion, acceleration or deceleration, impact, shock, or a combination of multiple factors[22]. Direct blow to the precordial area is the primary mechanism of BCI, and causes damage at the end of ventricular diastole when the ventricle dilates to its maximum[23]. The results of the current study demonstrated that the most common cause of BCI is motor vehicle collision, followed by a fall from height. Traffic accidents kill approximately 1.3 million people around the world each year and leave between 20 and 50 million people with non-fatal injuries[24]. When a motor vehicle crash occurs, the kinetic energy generated from deceleration compresses the sternum and spine. At the instant of impact, the sudden increase in pressure in the chest cavity can cause damage to the heart. The stress force required to produce myocardial lesions is as low as 32 km/h[25].
About 75% of BCI patients have concomitant thoracic injuries[26]. These include pulmonary contusion, rib fractures, sternal fracture, aortic injury, flail segment, and spinal injury. An autopsy-based study suggested that the severity of thoracic injury could predict cardiac involvement[27]. Traffic accidents can easily cause sternum and multiple left-side rib fractures. In the meta-analysis in the current study, among the frequently reported injuries, only sternal fracture was associated with elevated risk of BCI. About 76% of the patients with BCI have concomitant sternal fracture[28]. In BCI patients, sternal fracture is a well-recognized concomitant thoracic injury with an incidence of up to 32%[6,29]. sternal fracture could be a marker for significant force from blunt trauma that disperses to the chest, causing injury to surrounding structures, including the heart[30]. Thus, the presence of severe sternal fracture can be served as an indicator of possible cardiac trauma and therefore be followed by specific management.
Patients with a history of cardiac disease and shock on admission were also associated with higher risk of BCI. Specific type of cardiac disease, however, was not reported in the study by Salim et al.[12] and Velmahos et al[11]. In the study of 59 BCI patients with a history of cardiac disease by Laura et al., 36 patients had coronary artery disease, 12 patients had myocardial infarction, 8 patients underwent percutaneous coronary intervention, and 3 patients underwent coronary artery bypass graft[3]. Grigorian et al. analyzed the potential association between a history of myocardial infarction and BCI. Subgroup analysis by excluding the Grigorian et al. study resulted in a pooled RR for the history of cardiac disease at 2.385 (95% CI = 1.187–4.794). Marshall et al. reported that pre-existing cardiovascular disease increases the risk of cardiac concussion[31]. Overall, almost all variables related to the severity of the injury or physiologic compromise have been associated with higher risk as well as increased severity of BCI. After taking factors of ECG, TnI, ISS, history of cardiac disease, and skeletal trauma into consideration, the positive predictive value of BCI diagnosis was 71%[11]. Patients with moderate-to-severe traumatic brain injury also have a higher risk of BCI. Ali et al. reported a RR of 2.47 (95% CI = 1.099–5.532) in blunt thoracic trauma patients with Glasgow Coma Scale score (GCS) <12[11]. Another retrospective multi-center study found that unconsciousness (GCS < 8) strongly indicates BCI[5]. Because of the limited original literature, we did not perform a quantitative analysis of GCS score.
Trauma patients concomitant with BCI has a 1.70-fold risk of mortality compared to those without BCI. Higher ISS was frequently reported in BCI patients than in other trauma patients. Due to limited original articles and inconsistent scoring criteria of injury severity, we did not attempt to obtain a pooled ISS score in BCI patients. According to a retrospective multi-center study, BCI is associated with an short-term mortality of 7.2% and with an overall mortality of 13.9%[5]. The higher mortality rate may be attributed to higher injury severity and significant damage to the heart. Joseph et al. found higher number of both cardiac and non-cardiac compilations in non-surviving trauma patients with BCI than that in the survivors[2]. The elevated TnI level, a known predictor of BCI, is a surrogate marker of the severity of heart injury and the progression of arrhythmias[32]. In a study by Broder et al., patients with hypotension following blunt chest trauma required more monitoring and treatment to prevent the development of severe complications[33]. In other words, most risk factors associated with BCI are also associated with cardiac or non-cardiac complications, which further increase the mortality risk.
The hospitalization cycle of BCI patients involves two phases from accident to diagnosis and treatment after diagnosis. An initial ECG and cardiac TnI should be performed in patients with suspected BCI, but are insufficient to completely exclude BCI[34]. A prudent approach in patients with suspected BIC but normal ECG and TnI is hospital stay for 1–3 days and thorough clinical and laboratory investigations since cardiac complications may occur up to 72 hours after trauma[35]. In majority of the published studies, however, the time between admission and developing clinical symptoms of BCI is less than 24 hours[12,36,37]. The difference in actual length of hospital stay in trauma patients with vs without BCI may be greater than observed in the current study. In terms of treatment, all patients with abnormal ECG or TnI should be admitted to monitor for arrhythmia at the least. Observation for at least 48 hours for arrhythmias caused by myocardial contusion is recommended by some, although arrhythmia tends to occur within 24 hours[38]. Inotropic drugs or mechanical support should be used in patients with severe heart failure or cardiogenic shock. For those concomitant with structural injuries such as pericardial rupture or traumatic valvular injuries, timely operative repair is warranted[39].
The current study has several limitations. First, publication bias (tendency to report only statistically significant findings) is present. Also, the main injury mechanism of different types of BCI and its outcomes could be different. For example, the histological features of the most common myocardial injury are hemorrhage, edema, and local necrosis. Whereas cardiac concussion is defined as sudden cardiac death triggered by a relatively innocent blow to the precordium over the left chest wall[40]. All studies included in the meta-analysis were conducted in trauma patients with no restriction on injury severity. Due to the limited articles available, we did not conduct a subgroup analysis on risk factors. Despite the above weakness, this is the first meta-analysis to quantitatively analyze the feasible risk factors other than those specified in the guidelines associated with BCI.
CONCLUSIONS
In conclusion, BCI was associated with increased mortality and longer length of hospital stay. BCI was associated with sternal fracture, a history of cardiac disease and concomitant shock upon admission. We failed to confirm an association between BIC with lung injury, hemopneumothorax, rib fracture, or aortic injury.
FUNDING
This work was funded by the National Natural Science Foundation (#81870192).
AUTHOR CONTRIBUTIONS
JP: Conceptualization, research design, software; YJ: Methodology, performance of the research, writing and original draft preparation; GZ: Visualization, investigation; JF: Supervision. JF: Data analysis; LM: Writing- Reviewing and editing.
CONFLICTS OF INTEREST STATEMENT
The authors declare that they have no financial conflict of interest with regard to the content of this manuscript.
DATA SHARING STATEMENTThe datasets generated during and/or analyzed during the current study are available from the corresponding author.
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