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\begin{document}

\title{Risk factors for recurrent respiratory tract infections or acute
respiratory failure in children with spinal muscular atrophy}



\author[1]{Wenhui Guo}%
\author[1]{Linghui Meng}%
\author[1]{Ling Cao}%
\affil[1]{Capital Institute of Pediatrics}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Assessment of and intervention for
sleep-disordered breathing and malnutrition are related to respiratory
management for preventing recurrent respiratory tract infections (RRTIs)
and acute respiratory failure (ARF) in children with spinal muscular
atrophy (SMA). However, the specific standard has not been clarified.
\textbf{Purpose:} The study aimed to obtain the risk factors and the
predictive index for RRTIs and/or ARF in children with SMA.
\textbf{Methods:} In this retrospective study, the differences in
clinical characteristics in patients with or without RRTIs and ARF were
compared, and binary logistic regression analysis was carried out. The
best cutoff points of the positive predictive index were obtained.
\textbf{Results:} Type 1 (OR = 4.12, 95\% CI 1.30-13.07, P =.016) and
apnea hypopnea index (AHI) (OR = 1.14, 95\% CI 1.05-1.24, P =.001) were
risk factors, while body mass index z score (BMIz) (OR = 0.68, 95\% CI
0.49-0.94, P =.018) and mean pulse oxygen saturation (MSpO
\textsubscript{2}) (OR = 0.67, 95\% CI 0.50-0.91, P =.010) were
protective factors. The sensitivity and specificity of the standard of
MSpO \textsubscript{2} \textless{} 96\% and AHI \textgreater{} 10
events/h or BMIz \textless{} -1 with the occurrence of RRTIs and/or ARF
were 0.513 and 0.957, respectively. \textbf{Conclusion:} SMA Type 1,
BMIz, AHI and MSpO \textsubscript{2} should be used to estimate the risk
for RRTI or ARF in children with SMA. MSpO \textsubscript{2} \textless{}
96\%, and AHI \textgreater{} 10 events/h or BMIz \textless{} -1 should
be used as the intervention standard.%
\end{abstract}%



\sloppy


\textbf{Title}

Risk factors for recurrent respiratory tract infections or acute
respiratory failure in children with spinal muscular atrophy

\textbf{Author names and affiliations}

Wenhui Guo\textsuperscript{1}, Linghui Meng\textsuperscript{2}, and Ling
Cao\textsuperscript{1}.

\textsuperscript{1}Department of Pulmonology, Affiliated Children's
Hospital, Capital Institute of Pediatrics, Beijing, China.

\textsuperscript{2}Center for Evidence-Based Medicine, Capital Institute
of Pediatrics, Beijing, China.

\textbf{Correspondence}

Ling Cao, MD, Department of Pulmonology, Affiliated Children's Hospital,
Capital Institute of Pediatrics, 100020 Beijing, China.

Email: caoling9919@163.com

\textbf{Funding/Support}

This study was supported by the capital health development research
project (2020-1-2091)

\textbf{Keywords}

Spinal muscular atrophy in children; Respiratory tract infection; Acute
respiratory failure; Polysomnography; Risk factors.

\textbf{Abstract}

\textbf{Introduction:} Assessment of and intervention for
sleep-disordered breathing and malnutrition are related to respiratory
management for preventing recurrent respiratory tract infections (RRTIs)
and acute respiratory failure (ARF) in children with spinal muscular
atrophy (SMA). However, the specific standard has not been clarified.

\textbf{Purpose:} The study aimed to obtain the risk factors and the
predictive index for RRTIs and/or ARF in children with SMA.

\textbf{Methods:} In this retrospective study, the differences in
clinical characteristics in patients with or without RRTIs and ARF were
compared, and binary logistic regression analysis was carried out. The
best cutoff points of the positive predictive index were obtained.

\textbf{Results:} Type 1 (OR = 4.12, 95\% CI 1.30-13.07, P =.016) and
apnea hypopnea index (AHI) (OR = 1.14, 95\% CI 1.05-1.24, P =.001) were
risk factors, while body mass index z score (BMIz) (OR = 0.68, 95\% CI
0.49-0.94, P =.018) and mean pulse oxygen saturation
(MSpO\textsubscript{2}) (OR = 0.67, 95\% CI 0.50-0.91, P =.010) were
protective factors. The sensitivity and specificity of the standard of
MSpO\textsubscript{2}\textless{} 96\% and AHI \textgreater{} 10 events/h
or BMIz \textless{} -1 with the occurrence of RRTIs and/or ARF were
0.513 and 0.957, respectively.

\textbf{Conclusion:} SMA Type 1, BMIz, AHI and
MSpO\textsubscript{2}should be used to estimate the risk for RRTI or ARF
in children with SMA. MSpO\textsubscript{2}\textless{} 96\%, and AHI
\textgreater{} 10 events/h or BMIz \textless{} -1 should be used as the
intervention standard.



\textbf{1 INTRODUCTION}

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused
by deletion or mutation of the survival motor neuron 1 (SMN1) gene with
progressive muscle atrophy, weakness and paralysis. The incidence rate
of live births is approximately 1/11000. SMA in children is classified
into types 1-3 depending on the age of onset and maximal motor milestone
achieved.\textsuperscript{1} SMA is the primary genetic disease leading
to the death of children under two years old, and respiratory failure is
the most common cause of death.\textsuperscript{2} Nocturnal hypopnea is
the first respiratory problem in SMA, subsequently developing into
daytime hypopnea. Early pulmonary function can still be compensated.
However, patients are very prone to acute respiratory failure (ARF) once
pulmonary infection occurs. The more severe the case, the more likely
children are to have various respiratory complications, including
sleep-disordered breathing, recurrent pneumonia and
ARF.\textsuperscript{2,3} Appropriate and effective strategies of
respiratory management are crucial to stabilize lung function and reduce
the incidence of respiratory complications and mortality in children
with SMA. The literature and expert opinion support using a sleep study
to confirm when a patient has sleep-disordered breathing and needs to
use noninvasive ventilation to prevent recurrent respiratory tract
infections (RRTIs) and ARF. In addition, nutritional assessment and
intervention are also related to respiratory
management.\textsuperscript{2,4} However, there is still no specific
standard to evaluate and intervene in these respiratory problems.
Therefore, the aim of the present study was to obtain the risk factors
for RRTI and/or ARF and the specific values in children with SMA. This
is the largest study of polysomnography (PSG) in children with SMA
reported thus far.



\textbf{2 MATERIALS AND METHODS}

2.1 Setting and patients

The clinical data of SMA children in the division of respiratory and
sleep disorders of the Children's Hospital Affiliated with the Capital
Institute of Pediatrics in Beijing, China, from March 2016 to December
2021 were analyzed retrospectively. RRTIs and ARF were considered severe
conditions requiring intervention, and clinical characteristics were
analyzed to determine the risk factors for RRTIs and/or ARF in children
with SMA who had not started treatment with disease-modifying
medications or mechanical ventilation. This study was reviewed and
approved by the ethics committee of the Capital Institute of Pediatrics
(Identifier, SHERLL2019014). The study was exempt from informed consent.

2.2 Diagnostic criteria

SMA was diagnosed by a defect in the SMN1 gene localized to 5q11.2-q13.3
and classified into clinical groups on the basis of age of onset and
maximum motor function achieved: very weak infants unable to sit
unsupported (type 1), non-ambulatory patients able to sit independently
(type 2), and ambulant pediatric patients (type 3).\textsuperscript{1}

RRTIs were diagnosed by the following criteria: for children under two,
upper respiratory infection [?] 7 episodes/year, bronchitis [?] 3
episodes/year, or pneumonia [?] 2 episodes/year; two to five years old,
upper respiratory infection [?] 6 episodes/year, bronchitis [?] 2
episodes/year, or pneumonia [?] 2 episodes/year; over five years old,
upper respiratory infection [?] 5 episodes/year, bronchitis [?] 2
episodes/year, or pneumonia [?] 2 episodes/year. The number of lower
respiratory infections could replace the number of upper respiratory
infections, but not vice versa. The interval between onsets of
respiratory infection was at least seven days.\textsuperscript{5}

The diagnostic criterion of ARF caused by infectious pneumonia was
severe dysfunction of ventilation with arterial partial pressure of
oxygen \textless{} 8.0 kPa (60 mmHg) while breathing room air,
with/without arterial partial pressure of carbon dioxide
(PCO\textsubscript{2}) \textgreater{} 6.7 kPa (50
mmHg).\textsuperscript{6}

2.3 Inclusion and exclusion criteria

At enrollment, children were under eighteen years old and genetically
confirmed to have homozygous SMN1 gene alterations; all completed PSG
without signs of respiratory tract infection. Exclusion criteria
included the initiation of treatment with disease-modifying medications
or mechanical ventilation, alone or combined with the presence of other
congenital diseases or other neuromuscular disorders. All children were
divided into a disease group and a control group according to whether
RRTIs and/or ARF occurred within one year.

2.4 Data collection

The electronic and handwritten medical records created by doctors in the
division of respiratory and sleep disorders were reviewed to collect the
clinical data, including sex, age, height, weight, type of SMA, genetic
results, regular use of mechanical insufflation-exsufflation (MI-E),
number of occurrences of respiratory tract infection and ARF in one
year, past history and medication history. Spirometry was performed in
children over five years old who could complete the flow-volume loop
test using MasterScreen (Jaeger, Germany) equipment. The percent
predicted scores of spirometry were reported. PSG was attended by
trained pediatric sleep nurse using Alice 6 LDx (Philips, USA) equipment
and was scored using the American Academy of Sleep Medicine Version 2.3
pediatric criteria\textsuperscript{7} (see further details in
E-appendice 1). The age-specific body mass index z score (BMIz) was
obtained according to the WHO child growth standard and the 2000
American CDC growth curve standard.\textsuperscript{8,9}

2.5 Statistical analysis

Continuous data conforming to a normal distribution are represented by
(x \selectlanguage{ngerman}± s), and the differences between two groups were evaluated by the t
test. Data not conforming to a normal distribution are represented by M
(Q1, Q3), and the differences between two groups were evaluated by the
Mann--Whitney U test. Categorical variables are expressed as cases (\%),
and comparisons between groups were performed with the chi-square test
and Fisher's exact test. The differences in clinical indices between the
two groups were compared, and the variables with statistically
significant differences were included in the binary multivariate
logistic regression. The results showed the risk of each covariate in
the model and 95\% confidence interval to obtain the independent risk
factors for RRTIs and/or ARF in children with SMA. Receiver operating
characteristic (ROC) curves were constructed to determine the best
cutoff point for positive indicators that could best predict the
occurrence of RRTIs and/or ARF. The statistical significance of all
verifications was based on a bilateral P value \textless{} 0.05. SPSS
25.0 software was used for statistical processing, and GraphPad Prism
9.3.1 was used to draw ROC curves.

The clinical data were screened before logistic regression on the basis
of the clinical characteristics. The parameters of the spirometry were
not included because the test was not performed in children under five.
Because sleep stages vary greatly among children of different ages, for
instance, the sleep structure of infants is very different from that of
older children, such indicators with age differences were not
considered. In addition, in order to minimize the possible effects of
multicollinearity, the representative apnea hypopnea index (AHI) was
chosen because there is overlap among the parameters of respiratory
events in PSG; moreover, the AHI is the sum of apneas and hypopneas
occurring per hour. In addition, the mean pulse oxygen saturation
(MSpO\textsubscript{2}) with small individual differences was selected
because the standard deviation of MSpO\textsubscript{2} was less than
the lowest pulse oxygen saturation (LSpO\textsubscript{2}).



\textbf{3 RESULTS}

3.1 Clinical characteristics

During the study period, 115 patients were screened, and 109 patients
were enrolled, excluding 4 patients who had been using noninvasive
ventilators and 2 patients treated with nusinersen. The age of the 109
patients were 4.2 (2.1, 7.6) years, ranged (0.2-15.8) years. Fifty-two
patients were males. Twenty-three cases were type 1, 74 cases were type
2, and 12 cases were type 3. Thirty-four cases (31.2\%) had RRTIs, 20
cases (18.3\%) had ARF within one year, and 31 cases (28.4\%) used MI-E
regularly. The general characteristics, survival motor neuron 2 (SMN2)
copies, MI-E usage, main parameters of PSG and lung function of
different types of SMA are shown in Table 1.

3.2 Differences in sex, age, type, BMI and MI-E between the two groups

According to the group criteria, 109 patients were divided into the
disease group with 39 cases and the control group with 70 cases. The
proportion of type 1 was higher and the BMIz was lower in the disease
group than in the control group (P \textless{} 0.05). There was no
significant difference in sex, age or MI-E usage between the two groups.
(Table 2)

3.3 Differences in lung function between the two groups

Spirometry was performed in 21 of the 39 patients in the disease group
and 57 of the 70 patients in the control group. The percent predicted
scores representing restrictive ventilation dysfunction, including
forced vital capacity (FVC), inspiratory vital capacity (VC IN),
expiratory vital capacity (VC EX), forced expiratory volume in one
second (FEV1), peak expiratory flow (PEF), maximum expiratory flow at
75\% vital capacity (MEF\textsubscript{75}), maximum expiratory flow at
50\% vital capacity (MEF\textsubscript{50}) and maximum midexpiratory
flow at 25\% to 75\% vital capacity (MMEF\textsubscript{75/25}) in the
disease group were all lower than those in the control group (P
\textless{} 0.05). There was no significant difference in the FEV1 to
FVC ratio \% predicted to represent obstructive ventilation dysfunction
between the two groups (Table 2).

3.4 Differences in PSG between the two groups

End-tidal carbon dioxide (EtCO\textsubscript{2}) was measured in 9
patients in the disease group and 18 patients in the control group while
PSG was performed. Nonrapid eye movement stage 2 (N2) was higher and N3
was lower in the disease group. In addition, the respiratory arousal
index, AHI, \selectlanguage{english}[?] 3\% oxygen desaturation events and index were higher, and
the average oxygen desaturation, MSpO\textsubscript{2} and
LSpO\textsubscript{2} were lower (P \textless{} 0.05). Hypopnea was the
main respiratory event in children with SMA. The events, index, mean
time and longest time of hypopnea in the disease group were all higher
than those in the control group (P \textless{} 0.05). There was no
significant difference in apnea events between the two groups (Table 3).

3.5 Logistic regression analysis of risk factors for RRTIs and/or ARF in
children with SMA

Type 1, BMI, AHI and MSpO\textsubscript{2} with statistically
significant differences between the two groups were entered as
covariates into binary logistic regression, and all had statistical
significance (P \textless{} 0.05), as shown in Table 4. The risk for the
occurrence of RRTIs and/or ARF in SMA type 1 was approximately four
times higher than that in types 2 and 3. Meanwhile, the risks were
approximately 1.5, 1.1 and 1.5 times higher for every 1 decrease in
BMIz, 1 events/h increase in AHI and 1\% decrease in
MSpO\textsubscript{2,} respectively.

3.6 ROC curve analysis of BMIz, AHI and MSpO\textsubscript{2}

ROC curves were drawn to analyze the prediction efficiency of BMI, AHI
and MSpO\textsubscript{2} for RRTIs and/or ARF. The best cutoff points
of these three continuous variables were obtained by taking the maximum
Jordan index, and the sensitivity and specificity are shown in Figure 1
and Table 5. The diagnostic value of MSpO\textsubscript{2} was the best,
with the highest area under the receiver operating characteristic curve
(AUC). The sensitivity, specificity and accuracy of
MSpO\textsubscript{2} \textless{} 95.5\% with the occurrence of RRTIs
and/or ARF were 0.539, 0.886, and 0.761, respectively. To improve the
specificity and accuracy, the indicators were used in combination. With
the standard of MSpO\textsubscript{2} \textless{} 96\% and AHI
\textgreater{} 10 events/h or BMI \textless{} -1, the specificity and
accuracy were increased to 0.957 and 0.798, respectively, and the
sensitivity was 0.513.



\textbf{4 DISCUSSION}

SMA of type 1 is more severe, and both the age at death and the number
of people using ventilators are respectively earlier and more than those
in other SMA types.\textsuperscript{1,10} Most children with SMA type 1
over two years of age need tracheotomy or all-day noninvasive
ventilation for survival.\textsuperscript{11} Children with type 2 have
a progressive decline in overall function and need noninvasive
ventilation from five to thirteen years
old.\textsuperscript{12}Similarly, our study showed that the risk for
RRTIs and/or ARF in type 1 is approximately four times higher than that
in types 2 and 3. The average age of type 1 patients in our study was
over two years, but none of them had received disease-modifying
medications or long-term mechanical ventilation therapies. Among the 14
cases of type 1 with SMN2 copy number detected, five cases had 2 copies,
and nine cases had 3 copies, which indicated the milder SMA types 1b and
1c.\textsuperscript{1} This was because most of the patients who could
come to Beijing for treatment from other areas of China would have had
mild symptoms, and the type 1 population in China might carry more
copies of SMN2.\textsuperscript{13} Therefore, if all patients were
considered, the risk of type 1 RRTIs and/or ARF should be higher.

Malnutrition is common in children with SMA. Our study showed that
age-specific BMIz decreased in all three types and was lowest in type 1,
which was consistent with other studies.\textsuperscript{14}Malnutrition
in SMA is always related to the severity of pulmonary complications. For
example, children with dysphagia often have aspiration pneumonia and
respiratory distress and rely on mechanical ventilation
earlier.\textsuperscript{15} The age at gastrostomy is related to the
first appearance of ARF and initiation of continuous mechanical
ventilation.\textsuperscript{11} Similarly, our study showed that BMIz
is an independent risk factor for RRTIs and/or ARF in children with SMA,
and the risk increases by approximately one and a half times for every
one unit decrease in BMIz. In terms of mechanism, masticatory muscle
weakness, dysphagia and respiratory problems will reduce the intake of
calories, while the work of breathing will increase energy consumption.
As a result, the more severe the children are, the higher their risk of
malnutrition.\textsuperscript{1} Therefore, it is crucial to pay
attention to the BMIz level to prevent the occurrence of RRTIs and/or
ARF. The appropriate intervention includes adequate nutritional
supplementation, treatment with disease-modifying medications and
treatment with hypopnea.

PSG is the gold standard for the diagnosis of sleep-disordered
breathing, which can be used to monitor the problem of nocturnal
hypopnea in children with SMA. Although expert opinion supports using
PSG for diagnosing and noninvasive ventilation to prevent recurrent
RRTIs and ARF, there is still no specific
standard.\textsuperscript{2}The diagnostic criteria for obstructive
sleep apnea are only suitable for patients with obstructive problems in
the airway, not for patients with neuromuscular disorders mainly caused
by hypopnea.\textsuperscript{16} The Duchenne muscular dystrophy
guidelines\textsuperscript{17} have proposed the following indication
for nocturnal noninvasive ventilation:
PCO\textsubscript{2}\textgreater{} 6.7 kPa (50 mmHg) or \textgreater{}
1.3 kPa (10 mmHg) of the awake baseline at least 2\% of the total sleep
time, oxygen saturation \textless{} 88\% for at least five minutes, or
AHI \textgreater{} 5 events/h. This standard may be used as a reference
for SMA, but the data were not obtained from SMA patients themselves.
The questionnaires could be used to assess sleep disorders in
SMA.\textsuperscript{18} but have limitations of subjectivity because
nocturnal hypopnea can also be found in pediatric SMA patients without
clinical symptoms.\textsuperscript{19,20} Sleep-disordered breathing is
associated with RRTIs in children with SMA, and long-term noninvasive
ventilation can improve PSG scores and reduce the incidence of
respiratory tract infection.\textsuperscript{21} Our study used SMA
children as samples and analyzed the association between PSG scores and
the occurrence of RRTIs and ARF, which ensured the objectivity of the
results and applicability to SMA disease. Our study showed that AHI
\textgreater{} 10.2 events/h and MSpO\textsubscript{2} \textless{}
95.5\% suggested a high risk for RRTIs and/or ARF in children with SMA.

Lung function declines with age, and the severity is also related to the
type of SMA.\textsuperscript{22,23} Our study also showed that the FVC
and PEF \% predicted in type 2 were lower than those in type 3 and were
lower in the disease group than in the control group. The raw scores of
FVC and PEF in type 2 were approximately 60\% of the predicted scores,
which were approximately 90\% in type 3, approximately 40\% - 50\% in
the disease group, and approximately 60\% - 70\% in the control group.
Spirometry can only be performed with the cooperation of children over
five years old, so the lung function test could only be used for the
evaluation of older children with types 2 and 3. However, for SMA
patients, type 1 with younger age is more severe and requires closer
observation and proactive intervention. Therefore, for children under
five years old, especially those with type 1, it is more important to
pay attention to BMIz and PSG scores.

Our study showed that age, MI-E usage and EtCO\textsubscript{2} were not
associated with RRTIs and/or ARF. The reasons for these inconsistencies
with conventional thinking may be as follows. First, the patient's
condition should degenerate with age and progression of the disease. The
factor of age should be based on the type and severity of individual
cases. Therefore, there was no correlation in our study because the
subjects included all three types of SMA. The cutoff points of age to
assess the risk for RRTIs and/or ARF for each SMA type might be obtained
if the sample size was sufficient. Second, MI-E usage had a positive
effect on the intervention against respiratory problems in SMA patients
with types 1 and 2.\textsuperscript{2} However, our study did not show a
correlation, indicating that the effect of MI-E usage should be shown
only in patients who have a weak cough and need airway clearance
techniques. Finally, the diagnostic criterion for sleep-related
hypoventilation diseases is PCO\textsubscript{2} \textgreater{} 6.7 kPa
(50 mmHg), which accounts for more than 25\% of the total sleep time
according to the international classification of sleep
diseases.\textsuperscript{24} However, our study showed that in 27
cases, only one child of type 2 with severe adenoidal hypertrophy
complied with the criteria mentioned above. The OAI of this patient was
29.3 events/h, which was much higher than the HI representing hypopnea
of 5.0 events/h. Our study also did not show a correlation between
PCO\textsubscript{2} and hypoventilation in children with SMA. This
might be because the tested value of EtCO\textsubscript{2} in patients
with neuromuscular disorders was lower than the realistic
value.\textsuperscript{25} On the other hand, this might be consistent
with the finding from another study that higher values of
PCO\textsubscript{2} were not measured in type 1 than in types 2 and 3,
and PCO\textsubscript{2} levels during sleep might not be used to
accurately evaluate hypopnea in children with SMA.\textsuperscript{3,26}

Over the last decade, the approach to treating the respiratory
manifestations of SMA has shifted from a reactive approach only when
there is a clear indication to a proactive approach of applying
therapies earlier in the disease process.\textsuperscript{2} The use of
disease-modifying medications such as nusinersen may delay the decline
in lung function, but the effect on long-term improvement is
unknown.\textsuperscript{27-29} Proactive respiratory management and
nutrition support still play important roles in the improvement of
living conditions in SMA.\textsuperscript{30,31} Therefore, the
assessment of BMIz and PSG should be performed. Furthermore,
malnutrition and hypoventilation should be treated to prevent RRTIs and
ARF. Our study showed that the accuracy, sensitivity and specificity of
the standard of MSpO\textsubscript{2} \textless{} 96\% and AHI
\textgreater{} 10 events/h or BMIz \textless{} -1 with the occurrence of
RRTIs and/or ARF in SMA were 0.798, 0.513 and 0.957, respectively. The
high specificity meant that children with SMA who reached this standard
would almost certainly develop RRTIs or ARF and should receive
intervention.



\textbf{5 CONCLUSION}

Type of SMA, BMI, AHI and MSpO\textsubscript{2} are independent risk
factors and should be used to estimate the risk for RRTI or ARF in
children with SMA. MSpO\textsubscript{2} \textless{} 96\%, and AHI
\textgreater{} 10 events/h or BMIz \textless{} -1 should be used as the
intervention standard with high specificity.



\textbf{AUTHOR CONTRIBUTIONS}

Wenhui Guo, Ling Cao contributed to the study concept, data analysis and
interpretation, and writing of the manuscript. Wenhui Guo and Linghui
Meng contributed to statistical analysis.

\textbf{ACKNOWLEDGEMENTS}

This study was sponsored by the capital health development research
project (2020-1-2091). The authors thank Chao Chen and Shuo Li for
performing polysomnography and spirometry for children with SMA, and
Yujin Qu for providing the data of SMN2 copies of SMA children.

\textbf{CONFLICTS OF INTEREST}

The authors declare no conflicts of interest.

\textbf{DATA AVAILABILITY STATEMENT}

The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.

\textbf{ORCID}

Ling Cao: https://oricd.org/0000-0001-5633-1202

Wenhui Guo: https://oricd.org/0000-0002-9372-650X



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\end{enumerate}

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