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\begin{document}

\title{Free triiodothyronine is associated with poor outcome after acute
ischemic stroke}



\author[1]{Yue Song}%
\author[2]{Changqiang Yang}%
\author[1]{Hua Wang}%
\affil[1]{Sichuan University West China Second University Hospital}%
\affil[2]{Sichuan University West China Hospital}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Aims It is unclear whether thyroid hormones are associated with
functional outcome after ischemic stroke. We aimed to investigate the
impact of thyroid hormones at admission on functional outcome at 3
months after acute ischemic stroke. Methods A total of 480 consecutive
patients for ischemic stroke within 48 hours of onset were enrolled in
this study. Thyroid hormones including thyroid-stimulating hormone
(TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were
measured at admission and functional outcomes were assessed at 3 months
with the modified Rankin Scale (mRS) ranging from 0 to 6. Poor outcome
was defined as mRS[?]3. Results FT3 levels at admission were considerably
lower in poor outcome patients than those with good outcome at 3 months
(3.53\selectlanguage{ngerman}±0.70pmol/L vs 4.04±0.68pmol/L, respectively; P\selectlanguage{english}<0.001). Lower
levels of FT3 were observed with higher mRS scores. Multivariable
logistic regression analysis revealed that FT3 levels were significantly
associated with risk of poor outcome at 3 months independent of
conventional risk factors such as age, NIHSS score and recanalized
therapy. In addition, patients in the bottom quartile of FT3 levels had
a 2.56-fold higher risk of developing poor outcome compared with
patients in the top quartile (OR=2.56; 95\%CI 1.15-5.69, p =0.021). The
sensitivity and specificity of FT3 (\selectlanguage{english}[?]3.69pmol/L) predicting poor outcome
were 62.70\% and 72.03\% respectively. Conclusion Our study suggests
that FT3 levels at admission are significantly and independently
associated with risk of poor outcome after ischemic stroke and lower FT3
levels can be regarded as a prognostic biomarker for poor outcome at 3
months.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Free triiodothyronine is associated with poor outcome after
acute ischemic stroke}

\textbf{Abstract}

\textbf{Aims}

It is unclear whether thyroid hormones are associated with functional
outcome after ischemic stroke. We aimed to investigate the impact of
thyroid hormones at admission on functional outcome at 3 months after
acute ischemic stroke.

\textbf{Methods}

A total of 480 consecutive patients for ischemic stroke within 48 hours
of onset were retrospectively enrolled in this study. Thyroid hormones
including thyroid-stimulating hormone (TSH), free triiodothyronine
(FT3), and free thyroxine (FT4) were measured at admission and
functional outcomes were assessed at 3 months with the modified Rankin
Scale (mRS) ranging from 0 to 6. Poor outcome was defined as mRS[?]3.

\textbf{Results}

FT3 levels at admission were considerably lower in poor outcome patients
than those with good outcome at 3 months (3.53\selectlanguage{ngerman}±0.70pmol/L vs
4.04±0.68pmol/L, respectively; P\selectlanguage{english}<0.001). Lower levels of FT3 were
observed with higher mRS scores. Multivariable logistic regression
analysis revealed that FT3 levels were significantly associated with
risk of poor outcome at 3 months independent of conventional risk
factors such as age, NIHSS score and recanalized therapy. In addition,
patients in the bottom quartile of FT3 levels had a 2.56-fold higher
risk of developing poor outcome compared with patients in the top
quartile (OR=2.56; 95\%CI 1.15-5.69, p~=0.021). The sensitivity and
specificity of FT3 (\selectlanguage{english}[?]3.69pmol/L) predicting poor outcome were 62.70\%
and 72.03\% respectively.

\textbf{Conclusion}

Our study suggests that FT3 levels at admission are significantly and
independently associated with risk of poor outcome after ischemic stroke
and lower FT3 levels can be regarded as a prognostic biomarker for poor
outcome at 3 months.

\textbf{Keywords:} Acute ischemic stroke, Thyroid hormones, Free
triiodothyronine, Functional outcome

\textbf{What is known?}

Ischemic stroke severity and prediction of functional outcome are
assessed with standardized clinical criteria. However, the prognostic
value of these clinical parameters in ischemic stroke is quite
subjective and insufficient. Thyroid hormones play a neuroprotective
role in the recovery of post-ischemic stroke.

\selectlanguage{english}\textbf{What is new?}

FT3 levels at admission are significantly and independently associated
with risk of poor outcome after ischemic stroke and lower FT3 levels can
be regarded as a prognostic biomarker for poor outcome at 3 months.

\textbf{Introduction}

The burden of stroke in china is very serious and the annual stroke
mortality rate is approximately 1.6 million, which has exceeded heart
disease to become the leading cause of death and adult disability (1).
Of all stroke types, ischemic stroke is the most prevalent accounting
for 69.6\% (2). Currently, ischemic stroke severity and prediction of
functional outcome are assessed with standardized clinical criteria (3,
4). However, the prognostic value of these clinical parameters in
ischemic stroke is quite subjective and insufficient, such that
identification of new biomarkers may potentially improve the accuracy of
the current prognostic scales for functional outcome.

Recent studies suggest that serum concentrations of thyroid hormones are
altered in the acute phase of ischemic stroke and may have a potential
influence on functional outcome (5, 6). There are some evidences that
thyroid hormones play a neuroprotective role in the recovery of
post-ischemic stroke (7) and display a protective association between
subclinical hypothyroidism and better outcomes(8, 9) However, other
studies suggest that lower serum concentrations of T3 are associated
with poor outcome after ischemic stroke (6, 10).In addition, it is not
well recognized whether there are any associations between FT3, the
bioactive form of T3, and functional outcome of ischemic stroke. Studies
on the relationship between FT3 levels and functional outcomes after
ischemic stroke are controversial(10-16) .Thus, our study aimed to
investigate whether the serum concentrations of thyroid hormones on
admission, including thyroid stimulating hormone (TSH), free
triiodothyronine (FT3), and free thyroxine (FT4) were associated with
3-month functional outcome in acute ischemic stroke.

\textbf{Material and Methods}

\textbf{Study population}

We performed a single-center, retrospective, observational study.
Patients with acute ischemic stroke who were hospitalized in West China
Hospital, Sichuan University from May 1, 2018 to October 1, 2019 were
enrolled. The inclusion criteria were as follows: (1) age\selectlanguage{english}[?]18 years, (2)
ischemic stroke confirmed by clinical symptoms and computed tomography
(CT) or magnetic resonance imaging (MRI) on admission, (3)ischemic
stroke onset within 48 hours before admission. The exclusion criteria
were as follows: (1) history of thyroid diseases such as hyperthyroidism
or hypothyroidism, (2) acute hemorrhagic stroke and transient ischemic
stroke. The diagnosis and treatment of all patients with acute ischemic
stroke were based on Chinese guidelines (17).

\textbf{Data collection}

Data of demographic features (age, gender, weight, and height), risk
factors (diabetes mellitus, hypertension, atrial fibrillation, excessive
alcohol consumption, smoking), history of concomitant cardiovascular
diseases (coronary heart disease and heart failure), blood pressure and
stroke severity were collected at admission. Stroke severity on
admission was assessed with the National Institutes of Health Stroke
Scale (NIHSS) (3). Immediately after admission, white blood cell,
hemoglobin, platelet, glucose, albumin, estimated Glomerular Filtration
Rate, uric acid, triglyceride, total cholesterol, high density
lipoprotein cholesterol were measured and serum levels of TSH, FT3, and
FT4 in the following morning were collected. In addition, head computed
tomography or magnetic resonance imaging was performed at admission. All
the measurements were performed by the laboratory and radiological
staffs in our hospital. The stroke subtype was determined by the Trial
of Org 10172 in Acute Stroke Treatment subtype classi\selectlanguage{english}fication system
(18). We classified ischemic stroke as large-artery atherosclerosis,
cardio-embolism, small-artery occlusion and unclassified (other
determined or undetermined etiology) subtypes.

\textbf{End points}

Functional outcome of all patients was assessed with the modified Rankin
Scale (mRS) at 3 months after ischemic stroke, with scores ranging from
0 (no symptoms) to 6 (death) (19). Information of functional outcome was
collected via direct or telephone interviews with patients or family
members by trained neurologists. The mRS score was dichotomized into
good outcome (mRS score 0--2) and poor outcome (mRS score 3--6) (20).

\textbf{Statistical analysis}

All the data were analysed using IBM SPSS Statistics Version 21 (IBM
Corp., Armonk, NY, USA). Normally distributed continuous data were
presented as the mean +- standard deviation. Data with a skewed
distribution were expressed as the median (quartile). Categorical
variables were expressed as percentage. The baseline characteristics
between the two groups were compared using Student's t-tests,
Mann--Whitney U tests or Chi-Square tests, depending on the appropriate
value properties. Logistic regression analysis was used for correlation
analysis. The results of poor outcome at 3~months were present as odds
ratios (ORs) and 95\% confidence intervals (CIs). The AUC of the
receiver operator characteristic (ROC) curve was computed using the
predicted probability of poor outcome. The results were considered
significant when P \textless{} 0.05.

\textbf{Results}

Of the 539, we excluded 25 patients without data of thyroid indices, 10
patients diagnosed with hyperthyroidism or hypothyroidism and 24
patients lost follow-up. Eventually, we included 480 ischemic stroke
patients. During 90 days follow-up, 244(50.8\%) patients have poor
outcome. The baseline characteristics (demographic, clinical, and
laboratory data) according to the functional outcome assessed by the mRS
score were presented in Table 1. Compared to the patients with good
outcome, those with poor outcome were older, lower hemoglobin, albumin,
eGFR and higher White Blood Cell, NIHSS score. The proportions of female
(p=0.001) , atrial fibrillation(p\selectlanguage{english}<0.001), coronary heart disease/heart
failure\selectlanguage{english}(P=0.001\selectlanguage{english}) and recanalized therapy\selectlanguage{english}(P=0.005\selectlanguage{english})were also
significantly higher in the poor outcome group compared to the good
outcome group. In addition, patients with poor outcome had lower level
of TSH, FT3\selectlanguage{english},but higher FT4 levels.

To explore the independent risk factors for 3-month poor outcome, we
selected variables P \textless{} 0.1 in univariate analysis to perform
multivariable logistic regression analysis. It revealed that lower FT3
level was an independent risk factor of poor outcome at 3 months (OR=
0.561; 95\%CI 0.375-0.841, P=0.005). In addition, older age (OR = 1.023,
95\% CI 1.001-1.047, P=0.044), higher NIHSS score (OR=1.286, 95\%CI
1.213-1.363, P\selectlanguage{english}<0.001) and no recanalized therapy (OR = 3.527, 95\% CI
1.808-6.880, P\selectlanguage{english}<0.001) were also independent risk factors of poor
outcome. However, TSH and FT4 levels were not statistical after
adjusting for other variables (See Table 2).

Patients were divided into quartile groups according to FT3 levels. The
distribution of mRS scores at 3 months differed according to FT3
quartile (Q1, Q2, Q3, Q4) (Fig1) since higher mRS scores were observed
with lowering FT3 levels. Further analyses were performed by
constructing two models to explore the relationship between FT3 and poor
outcome. In model 1 adjusted for gender, AF, CHD/HF, Hemoglobin, WBC,
ALB, eGFR, TSH, TG, TC, FT4 and TOAST Classification, lower FT3 levels
were associated with a worse functional outcome at 3 months (OR=4.63;
95\% CI 2.33-9.02, p~\textless{} 0.001 for tertile1 vs. tertile4;
OR=2.42; 95\% CI 1.35-4.35, p~=0.003 for tertile2 vs. tertile4). In
model 2, after further adjusting variables of age, NIHSS score and
recanalized therapy on the basis of model 1, compared with those in the
1st quartile, FT3 levels in the 4th quartile were still signi\selectlanguage{english}ficantly
associated with poor outcome (OR=2.56; 95\% CI 1.15-5.69, p~=0.021) (See
Table 3). Additionally, the ROC curve analysis (Fig2) revealed that
serum level of FT3\textless{}3.69pmol/L in AIS patients was a powerful
predictor of poor outcome (sensitivity 62.70\%; specificity 72.03\%; AUC
0.713).

\textbf{Discussion}

Our study showed that lower FT3 levels were associated with poor outcome
at 3 months after acute ischemic stroke, and this association remained
significant after adjusting for the effect of risk factors and
comorbidities. There were two previous studies consistent with our
\selectlanguage{english}findings. Ambrosius et al (16) found that in acute ischemic stroke
patients lower free T3 levels were an important factor related to
unfavorable outcome. Zhang et al (14)found that FT3 was significantly
decreased in AIS patients with poor outcome and served as an independent
predictor for neurological outcomes for which the cut-off value of FT3
was 4.38pmol/L. However, O'Keefe et al (11) enrolled 129 ischemic stroke
patients and found that low FT3 value was not associated with poor
outcome at 3 months in the multivariate analysis when other known
predictors of outcome such as stroke severity (NIHSS) were controlled.
The contradictory findings could be due to the relatively small sample
size of the study. In addition, our study also showed that the
detrimental effect of FT3 level on functional outcome increased as FT3
level decreased and neither TSH nor FT4 were associated with poor
outcome at 3 months after ischemic stroke. There was one previous study
to con\selectlanguage{english}firm and strengthen our \selectlanguage{english}findings. Satoshi et al (21)retrospectively
enrolled 398 consecutive ischemic stroke patients to investigate the
association of admission serum thyroid hormone concentration with
functional outcomes and a dose-effect relationship between FT3 levels
upon admission and poor outcome was noticed. In addition, critical
illness could result in decreased peripheral conversion of FT4 to FT3 in
the absence of a primary thyroid disorder indicating that FT3 might be
more sensitive to the influence of critical illness than FT4, TSH(22),
which indirectly supported our findings as well.

The potential pathophysiological mechanism linking low levels of FT3 to
poor outcome is not well established. Previous study indicates that low
T3 syndrome is independently associated with the risk of hemorrhagic
transformation in acute ischemic stroke (23). Low FT3 levels at
admission are independently associated with Post-stroke infection
occurrence and may contribute to poor outcome(24).Although it is unknown
whether administration of exogenous thyroid hormone in ischemic stroke
patients improves outcomes, in animal experiment demonstrate that
administration of T3 could modulate neuronal plasticity mechanisms to
enhance functional outcome after stroke(25). Therefore, further
well-designed studies and randomized controlled trials are needed to
demonstrate the underlying mechanism between FT3 and functional outcome
and whether supplementation of T3 could reduce disability after acute
ischemic stroke.

Several limitations should be considered in the interpretation of our
study. First, it was based on single center data, thus inevitably
leading to selection bias. Second, we only measured the thyroid hormone
levels once and not dynamically as a function of time. Another
limitation was that we did not have the opportunity to measure total T3
and T4 levels, which might have given slightly different results.

\textbf{Conclusion}

Our data suggests that low FT3 levels at admission are independently
associated with poor outcome in acute ischemic stroke after 3 months.
Further investigations are needed to explore the mechanisms underlying
the association and their potential exploitation in terms of therapeutic
strategies to reduce disability after acute ischemic stroke.

\textbf{Figure legend}

Fig1. Distribution of modified Rankin Scale scores at 3 months according
to FT3 quartile

Fig2. Receiver operating characteristic analysis of FT3 for the
prediction of 3-month poor outcome after ischemic stroke.

\textbf{Table1. Baseline characteristics (demographic, clinical and
laboratory data) according to functional status at 3 months}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{variable} & \textbf{Good outcome n=236} & \textbf{Poor outcome
n=244} & \textbf{P value}\tabularnewline
\midrule
\endhead
Age (years) & 64.53\selectlanguage{ngerman}±14.22 & 70.11\selectlanguage{ngerman}±12.02 &
<0.001\textsuperscript{**}\tabularnewline
female(n,\%) & 69(29.2) & 107(43.8) &
0.001\textsuperscript{*}\tabularnewline
BMI (kg/m2) & 23.5\selectlanguage{ngerman}±3.2 & 23.1\selectlanguage{ngerman}±3.2 & 0.213\tabularnewline
smoking(n,\%) & 78(33.0) & 76(31.1) & 0.655\tabularnewline
Alcohol consumption(n,\%) & 64(27.1) & 57(23.3) & 0.343\tabularnewline
History of stroke(n,\%) & 23(9.7) & 26(10.6) & 0.742\tabularnewline
Hypertension(n,\%) & 131(55.5) & 144(59.0) & 0.437\tabularnewline
AF(n,\%) & 50(21.1) & 101(41.4) &
<0.001\textsuperscript{**}\tabularnewline
DM(n,\%) & 60(25.4) & 64(26.2) & 0.840\tabularnewline
CHD/HF(n,\%) & 47(19.9) & 81(33.2) &
0.001\textsuperscript{*}\tabularnewline
SBP at admission & 140.58\selectlanguage{ngerman}±25.82 & 142.27\selectlanguage{ngerman}±22.76 & 0.449\tabularnewline
DBP at admission & 81.86\selectlanguage{ngerman}±15.78 & 80.40\selectlanguage{ngerman}±14.53 & 0.293\tabularnewline
Hemoglobin (g/L) & 139.09\selectlanguage{ngerman}±17.87 & 134.14\selectlanguage{ngerman}±20.15 &
0.005\textsuperscript{*}\tabularnewline
Platelet (10\^{}9/L) & 181.20\selectlanguage{ngerman}±60.95 & 173.41\selectlanguage{ngerman}±66.84 &
0.183\tabularnewline
White Blood Cell (10\^{}9/L) & 7.63\selectlanguage{ngerman}±2.75 & 8.48\selectlanguage{ngerman}±3.16 &
0.002\textsuperscript{*}\tabularnewline
Glu (mmol/L) & 7.97\selectlanguage{ngerman}±3.31 & 8.27\selectlanguage{ngerman}±3.30 & 0.316\tabularnewline
Albumin (g/L) & 42.41\selectlanguage{ngerman}±4.15 & 40.70\selectlanguage{ngerman}±4.09 &
<0.001\textsuperscript{**}\tabularnewline
eGFR (ml/min/1.73m2) & 85.12\selectlanguage{ngerman}±19.29 & 79.69\selectlanguage{ngerman}±21.62 &
0.004\textsuperscript{*}\tabularnewline
Uric Acid(\selectlanguage{greek}μ\selectlanguage{english}mol/L) & 363.86\selectlanguage{ngerman}±106.12 & 349.23\selectlanguage{ngerman}±106.93 & 0.162\tabularnewline
TG (mmol/L) & 1.35(0.93, 2.05) & 1.23(0.88, 1.73) & 0.05\tabularnewline
TC (mmol/L) & 4.40\selectlanguage{ngerman}±1.04 & 4.26\selectlanguage{ngerman}±0.91 & 0.055\tabularnewline
HDL (mmol/L) & 1.24\selectlanguage{ngerman}±0.35 & 1.27\selectlanguage{ngerman}±0.37 & 0.334\tabularnewline
NIHSS score & 3(2, 7) & 13(8, 17) &
<0.001\textsuperscript{**}\tabularnewline
TOAST classification & & & <0.001\textsuperscript{**}\tabularnewline
LAA(n,\%) & 65(27.5) & 94(38.5) &\tabularnewline
CE(n,\%) & 51(21.6) & 94(38.5) &\tabularnewline
SAO(n,\%) & 93(39.4) & 36(14.8) &\tabularnewline
Unclassified(n,\%) & 27(11.4) & 20(8.2) &\tabularnewline
Recanalized therapy(n,\%) & 60(25.4) & 91(37.2) &
0.005\textsuperscript{*}\tabularnewline
TSH(mU/ L) & 1.97(1.29, 3.22) & 1.29(0.73, 2.51) &
<0.001\textsuperscript{**}\tabularnewline
FT3(pmol/L) & 4.04\selectlanguage{ngerman}±0.68 & 3.53\selectlanguage{ngerman}±0.70 &
<0.001\textsuperscript{**}\tabularnewline
FT4(pmol/L) & 16.05\selectlanguage{ngerman}±2.55 & 16.64\selectlanguage{ngerman}±2.69 &
0.014\textsuperscript{*}\tabularnewline
\bottomrule
\end{longtable}

Values are mean\selectlanguage{ngerman}±standard deviation, n (\%), or M (P25, P75). M (P25,
P75): median (25th percentile, 75th percentile).BMI, body mass index;
AF, atrial \selectlanguage{english}fibrillation; DM, diabetes mellitus; CHD, coronary heart
disease; HF, heart failure; eGFR, estimated Glomerular Filtration Rate;
TG, triglyceride; TC, total cholesterol; HDL-C\selectlanguage{english},, high density lipoprotein
cholesterol; Glu; glucose, NIHSS, National Institutes of Health Stroke
Scale; TOAST, Trial of Org 10 172 in acute stroke treatment; LAA, Large
artery atherosclerosis; CE, cardio-embolism; SAO, Small artery
occlusion; TSH; thyroid-stimulating hormone, FT3;free triiodothyronine,
FT4;free thyroxine. \textsuperscript{*} : P\selectlanguage{english}<0.05; \textsuperscript{**}:
P\selectlanguage{english}<0.001.

\textbf{Table2. Multiple logistic regression analysis of predictors for
poor outcome.}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Variables} & \textbf{OR} & \textbf{95\%CI} & \textbf{P
value}\tabularnewline
\midrule
\endhead
Age Female CHD/HF AF Hemoglobin WBC ALB Egfr TG TC NIHSS No recanalized
therapy TSH FT3 FT4 TOAST classification LAA CE SAO Unclassified & 1.023
1.162 1.116 & 1.001-1.047 0.657-2.055 0.618-2.015 0.418-2.169
0.989-1.019 0.968-1.143 0.910-1.031 0.987-1.015 0.897-1.288 0.881-1.543
1.213-1.363 1.808-6.880 0.871-1.203 0.375-0.841 0.990-1.208 Reference
0.306-1.643 0.368-1.332 0.236-1.371 & 0.044\textsuperscript{*} 0.605
0.716 0.906 0.615 0.232 0.322 0.873 0.436 0.283
<0.001\textsuperscript{**} <0.001\textsuperscript{**} 0.779
0.005\textsuperscript{*} 0.078 Reference 0.422 0.278
0.209\tabularnewline
& 0.952 1.004 1.052 0.969 1.001 1.075 1.166 1.286 3.527 1.023 0.561
1.094 1 0.709 0.700 0.568 & &\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*} : P<0.05. \textsuperscript{**}: P<0.001.

\textbf{Table3. Odds ratios for poor outcome according to the quartiles
of FT3}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{FT3 quartiles} & \textbf{Model 1} & \textbf{Model 1} &
\textbf{Model 1} & \textbf{Mode 2} & \textbf{Mode 2}\tabularnewline
\midrule
\endhead
& \textbf{OR (95\%CI)} & \textbf{OR (95\%CI)} & \textbf{P value} &
\textbf{OR (95\%CI)} & \textbf{P value}\tabularnewline
Q1(<3.26pmol/L) & Q1(<3.26pmol/L) & 4.63 (2.33-9.02) &
<0.001\textsuperscript{*} & 2.56 (1.15-5.69) &
0.021\textsuperscript{*}\tabularnewline
Q2(3.26-3.79pmol/L) & Q2(3.26-3.79pmol/L) & 2.42 (1.35-4.35) &
0.003\textsuperscript{*} & 1.88 (0.96-3.71) & 0.066\tabularnewline
Q3(3.79-4.26 pmol/L) & Q3(3.79-4.26 pmol/L) & 1.24 (0.69-2.23) &
0.465 & 0.95 (0.48-1.87) & 0.885\tabularnewline
Q4(>4.26 pmol/L) & Q4(>4.26 pmol/L) & 1 (reference) & - & 1
(reference) & -\tabularnewline
\bottomrule
\end{longtable}

Model 1 was adjusted for gender, AF, CHD/HF, Hemoglobin, WBC, ALB, eGFR,
TSH, TG, TC, FT4 and TOAST Classification; Model 2 was further adjusted
variables of age, NIHSS score and recanalized therapy on the basis of
Model 1.

\textsuperscript{*} : P<0.05.

\textbf{Funding}

The work was supported by National Natural Science Foundation of China
(number: 81401239).

\textbf{Disclosures}

We disclose any conflict of interest, including specific financial
interests and relationships and affiliations relevant to the subject.

\textbf{Ethical standard}

Our study was conducted in accordance with the Declaration of Helsinki
and was approved by the Ethics Committee of West China Hospital, Sichuan
University.

\textbf{Informed consent}

The study is based on a retrospective analysis of examinations already
performed, justified by good clinical practice. All patients have signed
an informed consent for the management of their data.

\textbf{Disclosures}

We disclose any conflict of interest, including specific financial
interests and relationships and affiliations relevant to the subject.

\textbf{Authorship}

SY, YCQ and WH conceptualized and designed the study, SY, YCQ and WH
drafted the initial manuscript, and reviewed and revised the manuscript.
SY collected data. YCQ performed data analysis. All authors approved the
final manuscript as submitted and agree to be accountable for all
aspects of the work.

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