Open access
Risk factors and biomarkers for post-­
To cite: Gai X, Cao W,
Rao Y, et al. Risk factors
and biomarkers for post-­
tuberculosis lung damage
in a Chinese cohort of male
smokers and non-­smokers:
protocol for a prospective
observational study. BMJ Open
2023;13:e065990. doi:10.1136/
bmjopen-2022-065990
► Prepublication history for
this paper is available online.
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the journal online (http://dx.doi.​
org/10.1136/bmjopen-2022-​
065990).
XG and WC are joint first
authors.
Received 22 June 2022
Accepted 10 September 2023
© Author(s) (or their
employer(s)) 2023. Re-­use
permitted under CC BY-­NC. No
commercial re-­use. See rights
and permissions. Published by
BMJ.
1
Department of Respiratory and
Critical Care Medicine, Peking
University Third Hospital, Beijing,
China
2
Tuberculosis Department,
Beijing Geriatric Hospital,
Beijing, China
3
Clinical Epidemiology Research
Center, Peking University Third
Hospital, Beijing, China
Correspondence to
Dr Yongchang Sun;
​suny@​bjmu.​edu.​cn
Protocol
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tuberculosis lung damage in a Chinese
cohort of male smokers and non-­
smokers: protocol for a prospective
observational study
Xiaoyan Gai,1 Wenli Cao,2 Yafei Rao,1 Lin Zeng ‍ ‍,3 Wei Xu,2 Haifeng Wu,2 Gen Li,2
Yongchang Sun ‍ ‍1
ABSTRACT
Introduction Post-­tuberculosis lung damage (PTLD) STRENGTHS AND LIMITATIONS OF THIS STUDY
refers to the residual pulmonary impairment following the ⇒ To our knowledge, this will be the first prospective
study to investigate post-­tuberculosis lung damage
completion of antituberculosis (TB) therapy, characterised
(PTLD) in a Chinese population with pulmonary tu-
by persistent respiratory symptoms and abnormal
pulmonary function. The risk factors and biomarkers for berculosis (TB).
PTLD have been scarcely investigated. More importantly, ⇒ This study will contribute to knowledge concerning
whether and to what extent cigarette smoking is involved the development and biomarkers of PTLD related to
in PTLD remain to be known. cigarette smoking.
Methods and analysis This prospective observational ⇒ Considering the low prevalence of smoking in fe-
males, only male adults are included in the study;
study will enrol 400 male smoking or non-­smoking
patients aged 25–65 years, with newly confirmed active therefore, the study is not representative of the
TB between 2022 and 2024, from the Department whole population.
of Respiratory and Critical Care Medicine at Peking ⇒ As the biosafety of technicians performing spirome-
University Third Hospital and the Tuberculosis Department try tests needs to be considered, the first time point
at Beijing Geriatric Hospital. Because females rarely for lung function evaluation is set at the completion
smoke in China, we will enrol only males in this study. of anti-­TB therapy.
Demographic data, smoking history and amount, clinical ⇒ Peripheral blood biomarkers will be analysed in this
symptoms, lung function, and chest CT findings will be study; however, they are not specifically representa-
prospectively collected. Respiratory questionnaires, lung tive of local effects within the lungs.
function measurements and chest CT examinations will
be performed immediately after, and 1 year, 2 years and
3 years after the completion of TB treatment. Peripheral
Globally, more than 10 million new TB cases
blood samples will be obtained at baseline and at the end
and 1.5 million deaths resulting from TB are
of anti-­TB therapy, and a Luminex xMAP-­based multiplex
reported annually.1 While the success rate
immunoassay will be used to measure inflammatory
of TB treatment has consistently increased
mediators and cytokines in serum. The collected data
over the past 20 years,2 a large proportion
will be analysed to determine the incidence and factors/
of patients who were cured of TB or who
biomarkers of PTLD according to smoking status.
completed their TB treatment still develop
Ethics and dissemination The study was approved by
sequela symptoms, including cough, fatigue,
the Ethics Committee of Peking University Third Hospital
weakness and shortness of breath after phys-
(approval number: (2022)271-­03; approval date: 8 June
ical activity, with reduced quality of life and
2022). The research results will be disseminated through
increased mortality in some cases.3 The
scientific and medical conferences and will be published in
an academic journal. long-­term sequelae following completion of
Trial registration number NCT04966052.
TB treatment can also be revealed by struc-
tural changes in chest imaging (eg, pulmo-
nary cavities, fibrosis, bronchiectasis, pleural
INTRODUCTION thickening, pulmonary arterial hyperten-
Tuberculosis (TB) is a major public health sion) and pulmonary function impairments
concern worldwide,1 particularly in low-­ (obstructive, restrictive or mixed patterns).4
income to middle-­ income countries such A large cross-­sectional survey conducted in
as China, which carry a high TB burden. China revealed that 610 (7%) out of 8680
Gai X, et al. BMJ Open 2023;13:e065990. doi:10.1136/bmjopen-2022-065990 1
Open access
participants had a history of pulmonary TB and that
post-­TB lung damage was associated with airway obstruc-
tion and small airway dysfunction.5
Post-­TB lung damage (PTLD)—defined as ‘evidence
of chronic respiratory abnormality, with or without symp-
toms, attributable at least in part to previous (pulmo-
nary) TB’—has recently received considerable attention.6
According to several studies, up to 50% of patients had
persistent health problems related to PTLD.4 6–10 TB
infection may lead to permanent changes in the lung
anatomy, consequently resulting in the loss of pulmo-
nary function. Several recent studies reported that adult
patients cured of TB were 2–4 times more likely to develop
persistent lung function abnormalities (airflow obstruc-
tion and limitation) than those who were not previously
infected.5 9 11 12 However, the risk factors for PTLD are not
well understood.
Cigarette smoke and TB can synergestically impair lung
function. Our previous study13 analysed the chest CT scans
of 231 patients with chronic obstructive pulmonary disease
(COPD) (82.1% with a history of smoking) and found that
45% of these patients had ‘healed’ TB lesions.13 Emphy-
sema was also reported to be more diffusely distributed
and severe in patients with TB lesions, which suggested
aggravated lung injury with coexposure to smoke and
TB.13 Nonetheless, many of the above-­mentioned studies
are limited by their small or moderate sample sizes,
and prospective cohort studies are warranted. Impor-
tantly, it remains unclear whether and to what extent
cigarette smoking is involved in PTLD. Considering the
significant harm and huge burden imposed by PTLD, it
is very important to explore the risk factors and serum
biomarkers related to PTLD. Efforts to reduce PTLD and
to improve long-­term pulmonary health should become
an integral part of TB management.
In this prospective cohort study, we aim to focus on
the effects of cigarette smoking on PTLD. In China, the
prevalence of cigarette smoking was reported to range
from 50% to 60% in TB cases.14–16 While it is uncommon
for women in China to smoke, the smoking prevalence
was reported to be 2%–12% in female patients with TB,
and from 53% to 75% in male patients with TB.14–16 In
consideration of this low proportion of female smokers,
females will not be included in this study. Only male
adult patients with newly confirmed pulmonary TB will
be eligible for enrolment, and the clinical manifesta-
tions and biomarkers of PTLD according to smoking
status will be analysed. Detailed data collection, chest
CT and pulmonary function tests will be performed.
Cytokine and mediator profiles in serum will be tested.
The patients will be followed and the examinations be
repeated immediately after the completion of anti-­TB
therapy, and 1 year, 2 years and 3 years thereafter. To the
best of our knowledge, this will be the first study to inves-
tigate risk factors and biomarkers for PTLD in a Chinese
cohort. This study will be valuable for clinical interven-
tions aimed at improving long-­term outcomes in patients
with TB.
2 Gai X, et al. BMJ Open 2023;13:e065990. doi:10.1136/bmjopen-2022-065990
Objectives
BMJ Open: first published as 10.1136/bmjopen-2022-065990 on 9 October 2023. Downloaded from http://bmjopen.bmj.com/ on April 5, 2024 by guest. Protected by copyright.
This prospective study aims to determine the incidence
of PTLD and long-­term changes in lung function after
completion of anti-­TB therapy in male adults, and to
understand the roles of potential risk factors including
cigarette smoking in the development of PTLD, thereby
providing data for implementation of prognostic and
therapeutic strategies for PTLD.
METHODS AND ANALYSIS
Study participants
This prospective observational study will enrol male adult
patients who are newly diagnosed with active TB from the
Department of Respiratory and Critical Care Medicine at
Peking University Third Hospital and the Tuberculosis
Department at Beijing Geriatric Hospital between 2022
and 2024. The study team will screen patients who are
newly diagnosed with active TB in an outpatient setting.
Inclusion criteria
Patients aged 25–65 years newly diagnosed with pulmo-
nary TB will be screened for study inclusion. One major
factor under investigation is cigarette smoking; therefore,
only male patients will be enrolled, given that women in
China rarely smoke.
Diagnosis of pulmonary TB
For patients with consistent symptoms and chest CT
findings, the diagnosis of pulmonary TB is definitively
established through isolation of Mycobacterium tuberculosis
(Mtb) from bodily secretion/fluid (sputum, bronchoal-
veolar lavage or pleural fluid) or tissue (pleural biopsy
or lung biopsy). Other pathogenic examinations include
acid-­
fast bacilli smear and nucleic acid amplification
testing.1 If the pathogenic results are negative, the diag-
nosis of pulmonary TB could be based on appropriate
clinical findings and supportive examinations (chest CT
in this study) conducted by a trained doctor according to
WHO criteria.1
Exclusion criteria
The following patients will be excluded from analysis: (1)
patients with persistent symptoms at treatment comple-
tion and tested positive for either sputum smear or
culture, indicative of treatment failure; (2) human immu-
nodeficiency virus-­ positive patients; (3) patients with
malignant neoplasms (eg, lung cancer) or severe cardio-
vascular and cerebrovascular diseases; (4) non-­compliant
patients who are unable to complete lung function tests
and (5) patients without lung parenchymal destruction
(such as tuberculous pleurisy).
All study participants will be required to provide written
informed consent. The study flow chart is presented in
figure 1.
Patient and public involvement
Neither the patients nor the public are involved in the
protocol design.
 Open access

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Figure 1 Study flow chart. CAT, Chronic Obstructive Pulmonary Disease Assessment Test; DLCO, diffusing capacity for
carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MRC, UK Medical Research Council; SGRQ,
St. George’s Respiratory Questionnaire; TB, tuberculosis.

Study protocol (employment and income), number of years of smoking,

This study will be conducted at Peking University Third
Hospital, and Beijing Geriatric Hospital and will involve
those diagnosed with active pulmonary TB. Data will be
collected at baseline prior to TB treatment, immediately
after, and 1 year, 2 years and 3 years after the completion
of treatment.
The following data of the study participants will
be recorded at baseline: age, socioeconomic status
smoking index (smoking index=number of cigarettes
smoked per day×years of smoking), symptoms, St. George’s
Respiratory Questionnaire (SGRQ) scores, COPD Assess-
ment Test (CAT) scores, with/without diabetes and blood
test results (complete blood count, CD4 lymphocyte
count, plasma glucose, glycated haemoglobin, haemo-
globin and albumin). Peripheral blood samples will be
obtained at baseline and at the end of anti-­TB therapy

Gai X, et al. BMJ Open 2023;13:e065990. doi:10.1136/bmjopen-2022-065990 3

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Table 1 Assessment and follow-­up schedule
Immediately after
Observation/ Screening/baseline completion of TB Follow-­up at Follow-­up at 2 Follow-­up at 3
investigation assessments treatment 1 year years years
Written informed  x    
consent
Demographics  x    
Medical history  x  x  x  x  x
Clinical examinations  x  x  x  x  x
Serum biomarkers  x  x
Chest CT  x  x  x  x  x
Spirometry    x  x  x  x
MRC Dyspnoea Scale  x    x  x  x
Borg breathlessness  x    x  x  x
scale
COPD Assessment  x  x  x  x  x
Test
Clinical COPD  x  x  x  x  x
Questionnaire
COPD, chronic obstructive pulmonary disease; MRC, UK Medical Research Council.

for the measurement of inflammatory mediators and
cytokines, which will be detected by multiplex immu-
noassays (interferon-­ gamma (IFN-γ), tumour necrosis
factor-α (TNF-α), interleukin (IL)-­1β, IL-­4, IL-­10, IL-­6,
IL-­8, α1-­proteinase inhibitor, matrix metalloproteinases
(MMPs), including MMP-­8, MMP-­9 and MMP-­12), tissue
inhibitor of metalloproteinase (TIMP). A symptom ques-
tionnaire survey, chest CT and lung function tests will be
performed according to standard procedures (table 1).
Prior to enrolment, patients will be informed of the
study as well as of the relevant examinations that will be
performed. Current smokers will be given smoking cessa-
tion advice as per clinical practice guidelines.
Primary outcome measures
Longitudinal changes in lung function measurements,
including forced expiratory volume in 1 s (FEV1), forced
vital capacity (FVC), FEV1/FVC and diffusing capacity
of the lungs for carbon monoxide (DLCO), will be
performed during follow-­up.
Quality control and data normalisation will be carried
out for the lung function tests. Lung function tests will be
performed using pulmonary function devices (JAEGER,
Germany) before and 20 min after administering the
aerosol bronchodilator salbutamol. The following lung
function measurements will be recorded for each patient:
FVC, FEV1, FEV1/FVC ratio (FEV1/FVC), maximal expi-
ratory flow at 75% of FVC (MEF25), maximal expiratory
flow at 50% of FVC (MEF50), maximal expiratory flow at
25% of FVC (MEF75), maximal mid-­expiratory flow, total
lung capacity (TLC), peak expiratory flow (PEF25, PEF50
and PEF75), DLCO, residual volume (RV) and RV/TLC
ratio (RV/TLC).
Lung function abnormalities will be classified as follows:
(1) airflow obstruction, postbronchodilator FEV1/
FVC<lower limit of normal (LNN); (2) low FVC, FEV1/
FVC≥LNN and FVC<80%; (3) normal lung function,
FEV1/FVC≥LNN and FVC≥80%; positive bronchial dila-
tion test, >200 mL; and>12% increase in the absolute FEV1
value or FVC following bronchodilator administration.
Secondary outcome measurements
TB lesions on lung CT scans after TB treatment will be
recorded. Parenchymal and airway lesions detected on CT
scans will be described as (a) fibrosis, (b) cavity, (c) bron-
chiectasis, (d) consolidation, (e) nodule and (f) aspergil-
loma.13 17 Semiquantitative analysis will be performed on
the lesions, and the degree of lesions will be estimated
visually and expressed as the percentage of each lung
field involved. For the purpose of evaluation, the lung is
divided into three regions—the upper region, defined as
the region above the carina; the middle region, located
between the carina and the lower pulmonary vein; and
the lower region, located below the level of the lower
pulmonary vein. The percentage of lesion range will be
scored.
Chest CT images will be interpreted by a respiratory
physician and a radiologist.
Quality of life and respiratory symptoms
TheCAT score (self-­administered), SGRQ and UK Medical
Research Council (MRC) Dyspnoea Scale will be used.
The CAT contains eight items assessing cough, phlegm,
chest tightness, sleep quality, energy, mood and mobility.
The MRC Dyspnoea Scale will be used to measure the
severity of dyspnoea on a scale of 0–4, with a grade of

4 Gai X, et al. BMJ Open 2023;13:e065990. doi:10.1136/bmjopen-2022-065990


0 indicating no significant activity limitations and higher
grades representing more severe dyspnoea. Data on TB
retreatment and all-­cause mortality will be recorded at all
follow-­up visits.
Serum cytokines/mediators and their correlation with lung lesions
and lung function
Serum cytokines/mediators will be detected at two time
points: at baseline prior to TB treatment, and after the
completion of TB treatment. The BioRad 40 plex Bio-­Plex
ProTMHuman Chemokine Panel (BioRad, Hercules,
CA) will be used on the Luminex xMAP (Luminex 200,
Austin Luminex, USA) to detect 40 chemokines in the
serum as per the manufacturer’s instructions. MMPs will
be measured using a separate multiplex kit (BioRad,
Hercules, California, USA). The correlations between
cytokines/mediators and lung lesions on CT and lung
function measurements will be analysed.
Sample size calculation
We will explore the association of different variables
with the development of PTLD, including age, gender,
body mass index, economic status, sputum positive/
negative culture, cigarette smoking, comorbidities such
as diabetes, serum albumin level, haemoglobin level
and chest imaging scores. There are 10 variables in the
logistic regression model. Considering the sample size
requirements of multiple logistic regression, 100–150
cases are required based on the 10–15 event per variable
rule. Assuming the incidence of PTLD is approximately
30%–50% as reported,10 18 a sample of 400 participants
is required. At the same time, we will compare the
difference of lung function measurements between the
smoking group and the non-­ smoking group after the
cure of pulmonary TB. According to our previous work
(unpublished data), it is estimated that the prevalence
rate of PTLD is 50% in the smoking group and 30% in
the non-­smoking group, respectively, and the proportion
of smokers and non-­smokers in patients with pulmonary
TB was 1:5. Given an α level of 0.05 and a power of 80%,
we calculated a required sample size of 365 using PASS
software.
Statistical analysis
Statistical analysis will be performed using SPSS software
V.19.0 (IBM). All data will be tested for normal distribu-
tion and homogeneity of variance. Normally distributed
measurement data satisfying the homogeneity of variance
will be expressed as mean±SD (x±s), and a t-­test will be
used to determine intergroup differences. Non-­normally
distributed data will be presented as median values (25%,
75%), and the rank-­sum test will be used to determine
intergroup differences. The χ2 test or exact probability
test will be performed for intergroup comparisons of
categorical data. A p<0.05 will be considered indicative of
statistical differences.
Manifestations of residual lung damage within 1 year
following the completion of TB treatment will be
Gai X, et al. BMJ Open 2023;13:e065990. doi:10.1136/bmjopen-2022-065990
Open access
analysed, including the accelerated decline in FEV1 and
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FVC (decrease of ≥100 mL), chronic respiratory symp-
toms (cough, dyspnoea, sputum production or wheezing
lasting for ≥n days/months), TB retreatment and all-­
cause mortality. A multivariate regression model will be
constructed to analyse factors for the decline in FEV1 and
FVC 1, 2 and 3 years after the completion of TB treatment.
ETHICS AND DISSEMINATION
This study was approved by the Research Ethics Commit-
tees of Peking University Third Hospital and Beijing
Geriatric Hospital in Beijing, China. All patients will
be required to provide written informed consent. All
patient data and study results will be treated as confi-
dential. Personal information of potential and enrolled
participants will be stored securely at the study site. All
laboratory specimens, reports, data collection, process
information and administrative forms will be identified
by a coded ID (identification) number only to maintain
participant confidentiality. All local databases will be
secured with password-­protected access systems. Partici-
pants’ study information will not be released outside of
the study without the written permission of the partici-
pants. The results of this study will be published in a peer-­
reviewed scientific/medical journal and presented at
scientific and medical conferences.
DISCUSSION
This prospective study aims to investigate risk factors
and biomarkers for PTLD in a Chinese cohort of male
smoking and non-­smoking patients with pulmonary TB.
Baseline data for patients with newly confirmed pulmo-
nary TB will be procured. Respiratory questionnaires,
lung function measurements and chest CT examinations
will be completed during a 3-­year follow-­up. This study
will provide insights for developing clinical interventions
aimed at improving outcomes for patients with PTLD.
There is a high incidence rate of PTLD in low-­income
and middle-­ income countries, which warrants more
attention. A recent study in Malawi showed that approx-
imately 34% of the patients had pulmonary dysfunction
at the time of TB treatment completion.18 After 3 years’
follow-­up, approximately 27.9% of the patients still exhib-
ited reduced pulmonary function.19 Moreover, chronic
respiratory diseases such as COPD and bronchiectasis
have been found to be highly prevalent in the post-­TB
period.20
In this study, we will focus on the effect of cigarette
smoking on PTLD. Tobacco smoke contains various
harmful chemicals that can induce multiple chronic
diseases (including bronchitis and emphysema) and
impair lung function. Furthermore, TB is an important
risk factor for COPD.13 21–23 A multinational study showed
that adults with a history of TB had a much higher risk of
airflow obstruction than adults without a history of TB.8
Patients with COPD showing evidence of ‘healed’ TB on
5
Open access
chest imaging also had more severe emphysema, poorer
lung function, and higher hospitalisation and mortality
rates.24 25 A retrospective cohort study involving patients
with COPD revealed that patients with a history of TB had
more severe symptoms, significantly reduced lung func-
tion, and a higher frequency of acute exacerbations.26
According to a recent study, tobacco smoke and TB
have a synergistic effect.27 A retrospective analysis of risk
factors for airflow limitation (FEV1/FVC<70%) showed
that smoking could exacerbate the progression of airflow
limitation in Korean patients with non-­active TB.28 The
predicted FEV1/FVC curve indicated that patients with
non-­active TB lesions on chest radiographs developed
airflow limitation after 35 pack-­years of smoking, whereas
those without non-­active TB lesions on chest radiographs
developed airflow limitation after 88 pack-­ years. With
respect to the development of airflow limitation, these
results suggest a potential interaction between non-­
active TB and smoking.28 The mechanisms of interac-
tions between cigarette smoke and Mtb infection remain
unclear. Our previous study showed that Mtb infection
promoted cigarette smoke-­ exposed macrophages to
polarise toward both M1 and M2 phenotypes, along with
enhanced production of MMP9 and MMP12.27 In an
earlier study, we reported increased cytokine production
and impaired cell metabolism in natural killer cells after
coexposure to cigarette smoke and purified protein deriv-
ative.29 30
Lung function assessment plays a critical role in
the evaluation of chronic lung injury and serves as the
primary outcome measure within this cohort of PTLD.
The study aims to describe the pattern of spirometry
abnormalities, including airway obstruction, low FVC
and normal spirometry. To identify airflow obstruction,
two internationally recognised standards are commonly
used: FEV1/FVC<0.7 and FEV1/FVC<LLN.18 31 32 Initially,
our study protocol defined airway obstruction as post-
bronchodilator FEV1/FVC<0.7. However, considering
that the FEV1/FVC ratio decreases with age and may lead
to overdiagnosis of airway obstruction among healthy
elderly individuals,31 32 we have adopted FEV1/FVC<LLN
as the criterion since March 2023. This revised crite-
rion, FEV1/FVC<LLN, will be consistently applied to all
patients, regardless of their enrolment date. Both those
enrolled prior to the revised criteria and those recruited
thereafter will be analysed using the FEV1/FVC<LLN
parameter. This standardised approach ensures unifor-
mity and enables reliable comparisons across the entire
study population.
In our study, cytokine/mediator profiles in serum will
be measured in patients with pulmonary TB, and their
association with PTLD will be explored. MMPs and TIMP
are biomarkers of pulmonary and extrapulmonary TB.
A study in India showed that baseline plasma levels of
MMPs and TIMPs may be associated with adverse treat-
ment outcomes (treatment failure, all-­cause mortality or
recurrent TB).33 Pretreatment IL-­6 was recently reported
to be associated with treatment failure.34 This study will
6 Gai X, et al. BMJ Open 2023;13:e065990. doi:10.1136/bmjopen-2022-065990
explore biomarkers related to PTLD, and identify those
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at risk of developing anatomical and/or physiological
lung abnormalities with or without respiratory symptoms
after the completion of anti-­TB therapy. These results are
expected to provide evidence for better targeted preven-
tive measures and more effective management of PTLD.
Our study has several limitations. First, because ciga-
rette smoking is uncommon in Chinese women, we will
enrol only male adults, aged 25–65 years, who will not
be representative of the whole population. Therefore,
the results need to be interpreted in the context of this
specific population. Second, it is important to measure
spirometry at baseline. However, in consideration of
biosafety for technicians performing spirometry tests, the
first time point to test lung function is set at the comple-
tion of anti-­TB therapy. Third, the biomarkers measured
in peripheral blood may indicate a systemic response to
pulmonary TB and may not be markers closely related
to local lung lesions. Sputum or bronchoalveolar lavage
samples may be warranted in future studies.
Acknowledgements The authors are indebted to the patients who will participate
in this study.
Contributors YS conceived the study. XG and WC were responsible for editing
the protocol and recruiting the study participants. LZ contributed to sample size
estimation and statistical analysis. XG, WC, YR, LZ, WX, HW, GL and YS participated
in the project and were involved in the acquisition, analysis and interpretation of the
data. The final version of the manuscript was reviewed and approved by all authors.
Funding This study will be supported by the National Natural Science Foundation
(No. 81970041), the National Natural Science Foundation of China Youth Fund
Project (No. 81400038) and the Capital’s Funds for Health Improvement and
Research (2022-­2G-­40910).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iDs
Lin Zeng http://orcid.org/0000-0001-8707-5854
Yongchang Sun http://orcid.org/0000-0003-3281-8854
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