Microbial etiology of pneumonia in patients with decreased renal function
Microbial etiology of pneumonia in patients with decreased renal function
Chun-you Chen 0 2 3
Shih-chang Hsu 1 2 3
Hui-ling Hsieh 2 3
Chi-won Suk 2 3
Yuan-pin Hsu 1 2 3
Yuh-mou Sue 2 3
Tso-Hsiao Chen 2 3
Feng-yen Lin 2 3
Chun-ming Shih 2 3
Jaw- w 2 3
Shing-jong Lin 2 3
Po-hsun Hu 2 3
Chung- te LiuID 2 3
0 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan
1 Emergency Department, Department of Emergency and Critical Medicine, Wan Fang Hospital, Taipei Medical University , Taipei, Taiwan , 3 Department of Emergency Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan , 4 Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University , Taipei, Taiwan , 5 Graduate Institute of Medical Science, National Defense Medical Center , Taipei, Taiwan , 6 Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University , Taipei, Taiwan , 7 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan , 8 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan , 9 Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital , Taipei, Taiwan , 10 Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital , Taipei, Taiwan , 11 Cardiovascular Research Center, National Yang-Ming University , Taipei, Taiwan , 12 Department of Medical Research, Taipei Veterans General Hospital , Taipei, Taiwan , 13 Institute of Pharmacology, National Yang-Ming University , Taipei, Taiwan , 14 Institute of Clinical Medicine, National Yang-Ming University , Taipei, Taiwan, 15 Board of Directors , Taipei Medical University , Taipei , Taiwan
2 Editor: Wisit Cheungpasitporn, University of Mississippi Medical Center , UNITED STATES
3 Data Availability Statement: The dataset used in this study was approved by the ethics committee and Institutional Review Board of Taipei Medical University. Accordingly, data availability for any additional application will be possible only with the permission of ethics committee and Institutional Review Board of Taipei Medical University. Please make request at:
Overall, 1554 patients hospitalized with pneumonia (mean age, 76.1 ? 16.7) were included,
and 162 patients had died at the end of hospitalization. The cutoff eGFR value predicting
mortality was <55 mL/min/1.73 m2, which defined decreased renal function in this study.
Patients with decreased renal function demonstrated a significantly higher risk of fungi and
Staphylococcus aureus (S. aureus) infection. On the other hand, this group of patients
047], the Novel Bioengineering and Technological
Approaches to Solve Two Major Health Problems
in Taiwan sponsored by the Taiwan Ministry of
Science and Technology Academic Excellence
Program [MOST 106-2633-B-009-001], the
Ministry of Health and Welfare
[MOHW106-TDU-B211-113001], and Taipei Veterans General Hospital
[V105C-0207,V106C-045]. The funders had no role
in study design, data collection and analysis,
decision to publish, or preparation of the
Competing interests: The authors have declared
that no competing interests exist.
showed significantly higher neutrophil-to-lymphocyte ratio (NLR), which associated with
higher mortality. Additionally, patients with S. aureus had a significantly lower eGFR,
lymphocyte count and a higher NLR.
These findings suggested the altered immunity and vulnerability to S. aureus infection in
patients with decreased renal function, which may be the underlying cause of worse
outcomes of pneumonia in this group of patients.
Pneumonia is a major cause of death worldwide [
]. Based on the report of the Global
Burden of Disease Study, lower respiratory tract infection was the second leading cause of death in
2013, accounting for 3.85% of total deaths . With a global incidence of 1.5?14 per 1000
], pneumonia-related costs are also a serious burden to healthcare [
such, the treatment of pneumonia remains a major issue. In patients with chronic kidney
disease (CKD), pneumonia is a significant cause of infection-related hospitalization [
Several studies have demonstrated an increased risk of pneumonia-related hospitalization and
mortality in patients with CKD [
]. Moreover, in patients hospitalized with pneumonia,
acute kidney injury (AKI) is associated with adverse outcomes [
]. These findings indicate
the association between decreased renal function and adverse outcomes for pneumonia.
The microbiological aspects of disease are an essential part of the treatment of pneumonia
]. Generally, Streptococcus pneumoniae is the most common pathogen that causes this
disease, contributing to 12?68% and 10?15% of cases in Europe  and the United States
], respectively. Other common pathogens include Haemophilus influenzae,
Staphylococcus aureus, Moraxella catarrhalis, and Pseudomonas aeruginosa [
]. However, for patients
with decreased renal function, the microbiologic characteristics of pneumonia remain
unknown. Disclosing such microbiologic characteristics might yield improved outcomes for
pneumonia patients with renal impairment.
Previous studies indicated worse pneumonia-related outcomes in patients with decreased
renal function, which might be explained by suboptimal immunity in this population. Indeed,
altered immunity was demonstrated in patients with end-stage renal disease (ESRD) [
However, the association between altered immunity and outcomes of infection in patients
with decreased renal function had not been defined. Hence, the investigation of immune cell
profiles might represent a strategy to reveal the association between suboptimal immunity and
outcome for patients with pneumonia and decreased renal function.
As such, disclosing the microbiological features and immune cell profiles might be helpful
to improve our understanding and the outcome of pneumonia patients with decreased renal
function. To that end, we conducted a retrospective study of patients who were hospitalized
Materials and methods
Study design and subjects
In the present study, adult patients hospitalized with pneumonia at Wan Fang Hospital, Taipei
Medical University between January 2013 and December 2015 were included. All patients
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were admitted to the emergency department with pneumonia and were hospitalized. The
primary discharge diagnosis was community-acquired or healthcare-associated pneumonia.
Patients < 20 years of age were excluded. This study was approved by the ethics committee
and Institutional Review Board of Taipei Medical University (N201805061) and the informed
consent was waived. The present study was also conducted in accordance with the tenets of the
1975 Declaration of Helsinki, as revised in 2000.
Definition of covariates and outcomes
The presence of CKD was defined as an estimated glomerular filtration rate (eGFR) less than
60 mL/min/1.73m2 for more than 3 months before the indexed hospitalization. AKI was
defined by increase in serum creatinine by 0.3 mg/dL within 48 hours or increase in serum
creatinine to 1.5 times baseline within the prior 7 days, based on KDIGO Clinical Practice
Guideline for Acute Kidney Injury suggested in 2012 [
]. For a patient lacking past serum
creatinine values, CKD and AKI were defined according to the discharge diagnosis. Patients
with ESRD were included in the present study and were defined as initiation of maintenance
dialysis before the indexed hospitalization by reviewing medical records. Diabetes mellitus
(DM), congestive heart failure (CHF), and chronic obstructive pulmonary disease (COPD)
were defined according to the discharge diagnoses. The baseline laboratory data obtained at
the emergency department were used for statistical analyses. In the present study, eGFR was
calculated by the equation suggested by the Chronic Kidney Disease Epidemiology
Collaboration in 2009 [
]. Of note, for patients with ESRD, the eGFR was uniformly regarded as 5 mL/
min/m2 for statistical analyses for two reasons. First, eGFR calculated from serum creatinine
levels might be disturbed by hemodialysis sessions before the visit to the emergency
department, confounding the statistical analyses. Second, eGFR < 5 mL/min/m2 is the criteria for
the initiation of maintenance dialysis, as defined by the National Institute Insurance of
For analysis of immune cell profiles, absolute cell counts expressed in cell/mm3 [
with the neutrophil-to-lymphocyte ratio (NLR) and the monocyte-to-lymphocyte ratio (MLR)
were used. For microbiological analyses, the pathogen was defined as the bacteria cultured
from the first sputum specimen upon the indexed hospitalization. Patients without available
microbiology reports were excluded from these analyses. The outcome of the present study
was in-hospital mortality defined as death at the end of the indexed hospitalization.
Continuous variables with normal distribution were presented as a mean ? standard deviation,
and continuous variables deviated from a normal distribution were presented as the median
(25th and 75th percentiles). Categorical variables were presented as frequency and percentage.
Statistical analyses of continuous variables were conducted using a two-tailed t-test for
unpaired samples or a non-parametric method, as appropriate, depending on the distribution
of the data. For statistical analyses of categorical variables, the chi-square test was used. In
cases of multiple comparisons, Bonferroni correction was used. A receiver operating
characteristics (ROC) curve with Youden criteria was used to determine the optimal eGFR cutoff
value to predict mortality. The associations between predictors and outcomes were tested by
multivariate logistic regression models. The significance of the association was expressed as
the odds ratio with the 95% confidence interval. Statistical analysis was performed using SAS
9.4 (SAS Institute Inc, Cary, NC, USA)
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Demographic and laboratory characteristics of patients with pneumonia
The present study included 1554 patients hospitalized with pneumonia, of whom 63.5% were
males, and the mean age was 76.1?16.7 years. Overall, 79 (5.1%) patients had ESRD and 162
(10.4%) were deceased at the end of hospitalization. The mortality group had a significantly
older age, as well as more patients with CKD, AKI, acute-on-chronic kidney injury and ESRD.
Notably, the patients with DM, CHF, and COPD were not significantly different between the
survival group and the mortality group. Biochemistry panels revealed significantly higher
serum blood urea nitrite, creatinine, aspartate aminotransferase (AST), and alanine
aminotransferase (ALT) and significantly lower serum albumin in the mortality group. In addition,
the mortality group exhibited significantly higher white blood cell (WBC) counts, lower
lymphocyte counts, and higher NLR and MLR values. The neutrophil, monocyte, and platelet
counts were similar between the two groups. The mortality group was also associated with an
increased number of bacteremia, ventilator use, ICU admission events, longer hospital
durations, as well as higher SMART-COP and CURB65 scores (Table 1).
Based on the above findings, the potential risk factors for mortality were tested by logistic
regression. The predictors with p-values < 0.2 based on univariate logistic regression,
including age, DM, hemoglobin, neutrophil count, NLR, MLR, serum AST, ALT, and albumin levels,
were included in multivariate analyses. Based on the multivariate logistic regression model,
only eGFR and serum albumin levels remained significantly associated with mortality,
indicating the important effect of eGFR on pneumonia patient outcome (Fig 1).
Microbiological analysis of sputum samples from pneumonia patients and
relationship with renal function
As eGFR was shown to be significantly associated with mortality for patients hospitalized with
pneumonia, an ROC curve with Youden criteria was used to determine the optimal eGFR
cutoff value to predict this event. The ROC curve had an area under the curve of 0.66, and the
Youden criteria showed that eGFR of 55 mL/min/1.73 m2 was the optimal cut-off value to
To investigate the relationship between renal function and pneumonia-related mortality,
microbiological analyses of sputum from patients with eGFR 55 and <55 mL/min/1.73m2
was performed. Notably, only 1371 patients with available microbiology reports were included.
Overall, the microbial profiles from the sputum samples of the two groups were significantly
different (P < 0.001 based on a chi-square test). The events of gram-negative bacillus (GNB)
and gram-positive coccus (GPC) were not significantly different between the two groups
(significance defined by Bonferroni correction as p < 0.006 and < 0.017 for each specific pathogen
of GNB and GPC, respectively). The group with eGFR < 55 mL/min/1.73 m2 had a
significantly increased incidence of fungi and a decreased incidence of mixed anaerobics in their
sputum. Pathogen-specific analysis showed that the group with eGFR < 55 mL/min/1.73 m2
had a significantly lower incidence of Pseudomonas aeruginosa (Ps. aeruginosa), but a
significantly increased incidence Escherichia coli, Klebsiella pneumoniae and S. aureus (Table 2).
Logistic regression was used to confirm the association between eGFR and microbiologic
characteristics. Multivariate (adjusted by age and gender) logistic regression analyses showed
that patients with eGFR < 55 mL/min/1.73 m2 were at a significantly higher risk of fungi and a
lower risk of mixed anaerobics. Pathogen-specific analysis showed that patients with
eGFR < 55 mL/min/1.73m2 were at a significantly lower risk of P. aeruginosa and a
significantly higher risk of S. aureus (Fig 2).
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n = 162
83.1 ? 11.2
37 (22, 61)
1.3 (0.8, 2.3)
53.0 (26.7, 81.9)
33 (22, 51)
23 (14, 43)
13.9 ? 8.1
9909 (6585, 14425)
836 (458, 1443)
629 (377, 1067)
10.6 (5.2, 24.9)
0.7 (0.4, 1.3)
226 (134, 276)
15 (6, 30)
4 (3, 6)
2 (2, 3)
?by Exact Wilcoxon two-sample test.
CKD, chronic kidney disease; AKI, acute kidney injury; ACKI, acute-on-chronic kidney injury; DM, diabetes mellitus; CHF, congestive heart failure; COPD, chronic
obstructive pulmonary disease; ICU, intensive care unit; BUN, blood urea nitrite; eGFR, estimated glomerular filtration rate; WBC, white blood cell count; NLR,
neutrophil-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Continuous variables with
normal distribution were expressed as mean ? standard deviation, while those deviated from normal distribution were expressed as medium (1st, 3rd quartile).
The above findings indicated that patients with decreased renal function were at increased
risk of S. aureus and fungi in the sputum, which might underlie the association between
decreased renal function and pneumonia-related mortality.
Immune cell profiles and outcome of pneumonia patients with and without
The group with eGFR < 55 mL/min/1.73 m2 had significantly lower platelet, basophil,
eosinophil, and lymphocyte counts, as well as significantly higher NLR and MLR. Otherwise, WBC,
neutrophil, and monocyte counts were similar between the two groups (Table 3).
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Fig 1. Risk factors for in-hospital mortality in patients with pneumonia. Odds ratio for mortality was calculated by multivariate logistic regression. DM, diabetes
mellitus; eGFR, estimated glomerular filtration rate; NLR, neutrophil-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio; AST, aspartate aminotransferase; ALT,
alanine aminotransferase, CI, confidence interval.
As features of immune cell profiles differ between renal function groups, logistic regression
was used to confirm the association between immune cell profiles and mortality in patients of
each renal function group. In patients with eGFR 55 mL/min/1.73 m2, only higher platelet
counts were significantly associated with mortality (Fig 3A). In contrast, in patients with
eGFR < 55 mL/min/1.73 m2, both higher WBC counts, neutrophil counts and NLR were
significantly associated with higher pneumonia-related mortality (Fig 3B). The above findings
identified different immune cell profiles and their association with pneumonia outcome in
patients with and without decreased renal function.
Characteristics and outcomes of patients with S. aureus infection
Patients with S. aureus infection were significantly older with a higher percentage of CKD and
acute-on-chronic kidney injury. In addition, significantly higher blood urea nitrite, lower
eGFR, lower serum albumin, lower lymphocyte counts, and higher NLR were identified in
patients with S. aureus infection. Patients with S. aureus infection were also associated with
increased ventilator use and ICU admissions, a longer period of hospitalization, higher
mortality, and higher CURB65 score. Notably, the SMART-COP score, a pneumonia severity score
without consideration of renal function, was similar between patients with or without S. aureus
infection, implying the association between renal impairment and susceptibility to S. aureus
infection. (Table 4). Of the isolated S. aureus, 60% were methicillin resistant S. aureus (MRSA),
most of which (96.8%) were not sensitive to empirical treatment. However, patients with
MRSA did not have more mortality or other adverse outcomes (Table 5). These findings
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?by Fisher?s Exact test.
eGFR, estimated glomerular filtration rate; GNB, gram-negative bacillus; Ps. aeruginosa, Pseudomonas aeruginosa; Kl. pneumoniae, Klebsiella pneumoniae; GPC,
grampositive coccus; S. aureus, Staphylococcus aureus; Strep., Streptococcus; WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte
indicated that in patients with pneumonia, S. aureus is associated with decreased renal
function and its characteristic immune cell profile, specifically elevated NLR, which might be the
cause of worse pneumonia-related outcomes in patients with decreased renal function.
The main findings of the present study included a higher risk of S. aureus infection, and higher
NLR in pneumonia patients with eGFR < 55 mL/min/1.73 m2. Furthermore, in pneumonia
patients with S. aureus infection, lower eGFR, lymphocyte counts, and higher NLR were
observed. It is plausible that decreased eGFR is associated with higher pneumonia-related
mortality through disturbed immunity and vulnerability to S. aureus infection. Notably, in
clinical practice, fungi in sputum microbiological samples are more often interpreted as
colonization. Therefore, our analysis focused on S. aureus.
We preliminarily revealed higher risk of S. aureus infection in pneumonia patients with
decreased renal function. Previously, a prospective observational study in Spain showed that
Streptococcus pneumoniae was the most frequent cause of pneumonia in patients with CKD.
Additionally, the overall etiology of pneumonia and the occurrence of S. aureus in patients
with CKD were similar to those in individuals without CKD [
]. A possible explanation for
the discrepancy between this previous study and the present study might be that vaccination
for pneumococci has been universally provided to elderly ( 75 years of age) since 2007 and
newborns since the beginning of 2015 in Taiwan. In 2005, two small-scale studies showed that
S. pneumoniae was the most frequent causative pathogen of pneumonia in Taiwan,
contributing to 24?26% of cases [
]. It is thus reasonable that pneumococci vaccination has caused
a decline in the incidence of S. pneumoniae infection in Taiwan.
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Fig 2. Risk of isolation of specific pathogens in patients with eGFR of < 55.3 mL/min/1.73 m2. Odds ratios for specific pathogens were calculated using a
multivariate logistic regression model adjusted by age and gender. CI, confidence interval; eGFR, estimated glomerular filtration rate; Ps. aeruginosa, Pseudomonas
aeruginosa; Kl. pneumoniae, Klebsiella pneumoniae; S. aureus, Staphylococcus aureus; Strep., Streptococcus.
The present single-center study in Taiwan revealed microbiologic features of pneumonia
that deviate from most published reports [
], showing increased significance of
gram-negative bacilli and S. aureus and a decreased role for S. pneumoniae. To date, a nationwide analysis
?by Exact Wilcoxon two-sample test.
eGFR, estimated glomerular filtration rate; WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio. Continuous variables
with normal distribution were expressed as mean ? standard deviation, while those deviated from normal distribution were expressed as medium (1st, 3rd quartile).
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Fig 3. The association between immune cell profiles and mortality in patients hospitalized with pneumonia. A. The odds ratios for mortality in patients with
eGFR 55 mL/min/1.73 m2. B. The odds ratios for mortality in patients with eGFR < 55 mL/min/1.73 m2. WBC, white blood cell; NLR, neutrophil-to-lymphocyte
ratio; MLR, monocyte-to-lymphocyte ratio.
of the pathogenic etiologies of pneumonia in Taiwan has not been performed; thus, we were
unable to compare with national microbiological data between these studies. One possible
explanation for the microbiology results might be that the study site was located in a
community comprising an aged population and numerous healthcare facilities, which leads to a higher
frequency of healthcare-associated pneumonia and deviated microbiological results. Indeed,
the resistance to methicillin is highly prevalent in S. aureus in the present study.
In this study, we preliminarily revealed NLR as a marker of mortality in pneumonia
patients with decreased renal function. Recently, NLR has been evaluated as a predictor of
outcome for various infectious diseases, which, however, provided inconsistent results [
a study enrolling 395 patients with community-acquired pneumonia, NLR was acceptable for
predicting mortality with an area under the ROC curve of 0.701 . In our study, overall, the
association between NLR and mortality was insignificant. Nonetheless, based on subgroup
analysis of patients with eGFR < 55 mL/min/1.73 m2, NLR was significantly associated with
mortality of pneumonia, which remained insignificant in the group with eGFR 55 mL/min/
1.73 m2. This indicated a potential connection between elevated NLR, decreased renal
function, and mortality of pneumonia. However, the underlying disturbance of immunity in
patients with decreased renal function remains to be investigated.
The other preliminary finding of this study was that pneumonia patients with S. aureus
infection exhibited significantly higher NLR than those without, implying an association
between higher NLR and S. aureus infection. In support to our finding, a study enrolling 121
patients with infective endocarditis, of which Staphylococcus was the most frequent pathogen
(33%), NLR > 7.1 predicted adverse outcomes [
]. Nonetheless, solid evidence suggesting a
causative relationship between NLR and susceptibility to S. aureus infection has not been
The limitations of the present study, as previously stated, included the single center design,
such that the microbiology results might have been affected by regional epidemics. Another
limitation is the retrospective design and inability to control potential some confounding
factors, including prior antibiotic use. In addition, in this study, community-acquired pneumonia
and healthcare-associated pneumonia were not considered separately, which might also affect
the results. In this study, we used the results of sputum cultures for microbiology analysis,
which are usually considered as likely cause of pneumonia. However, since bronchoscopy is
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?by Exact Wilcoxon two-sample test.
S. aureus, Staphylococcus aureus; CKD, chronic kidney disease; AKI, acute kidney injury; ACKI, acute-on-chronic kidney injury; DM, diabetes mellitus; CHF, congestive
heart failure; COPD, chronic obstructive pulmonary disease; BUN, blood urea nitrite; eGFR, estimated glomerular filtration rate; WBC, white blood count; NLR,
neutrophil-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ICU, intensive care unit.
Continuous variables with normal distribution were expressed as mean ? standard deviation, while those deviated from normal distribution were expressed as medium
(1st, 3rd quartile).
not routinely performed in patients with pneumonia, the more reliable bronchial aspirate
culture could not be discussed extensively in the present study. Finally, there was only a small
number of ESRD patients in the present study that a separated analysis for pathogen in this
group of patients is not feasible. The strength of the present study included the relatively large
number of cases and the complete microbiology data. Notably, despite the significant role of S.
aureus in pneumonia patients with decreased eGFR, gram-negative bacilli (P. aeruginosa and
K. pneumoniae) also contributed significantly to pneumonia in this population.
This study showed a significantly higher risk of S. aureus in pneumonia patients with
decreased renal function, which might cause higher pneumonia-related mortality in this
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S. aureus, Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant
Staphylococcus aureus; CKD, chronic kidney disease; AKI, acute kidney injury; eGFR, estimated glomerular filtration
rate; ICU, intensive care unit. Continuous variables with normal distribution were expressed as mean ? standard
deviation, while those deviated from normal distribution were expressed as medium (1st, 3rd quartile).
population. Moreover, both in patients with decreased renal function and in patients with S.
aureus, higher NLR was detected, implying an association between higher NLR and
susceptibility to S. aureus infection. However, the causative relationship remains to be defined.
The present work was inspired by Dr. Shau-Ku Huang, the Distinguished Investigator with the
Division of Environmental Health and Occupational Medicine.
Conceptualization: Chun-you Chen, Shih-chang Hsu, Chi-won Suk, Chung-te Liu.
Data curation: Chun-you Chen, Shih-chang Hsu, Hui-ling Hsieh, Chi-won Suk, Chung-te
Formal analysis: Shih-chang Hsu, Chung-te Liu.
Methodology: Chung-te Liu.
Project administration: Chung-te Liu.
Supervision: Yuan-pin Hsu, Yuh-mou Sue, Tso-Hsiao Chen, Feng-yen Lin, Chun-ming Shih,
Jaw-wen Chen, Shing-jong Lin, Po-hsun Huang, Chung-te Liu.
Writing ? original draft: Chung-te Liu.
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Writing ? review & editing: Chung-te Liu.
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